Background and purpose. Efficient endothelial regeneration is fundamental to microcirculatory restoration and hard tissue repair. CPNE7 family peptides have previously been shown to regulate osteogenesis and chondrogenesis, however, their involvement in vascular reconstruction has not been explored. Experimental approach. In this study, we investigated the effect of two peptides derived from CPNE7, CDP4 and UG28, on human endothelial cells in vitro, evaluating their influence on proliferation, migration, chemotaxis, capillary-like structure formation, and secretion of growth factors and cytokines. Key results. UG28 demonstrated the strongest pro-angiogenic activity, enhancing EC proliferation, directional migration, and pseudocapillary network formation, while CDP4 also promoted migration and early vascular organization; neither peptide showed cytotoxicity nor induced immune activation, and both were compatible with chitosan matrices. Conclusion and implications. CPNE7-derived peptides—especially UG28—are potent and safe pro-angiogenic agents with high translational potential, and their compatibility with chitosan supports their applicability in next-generation regenerative therapies targeting endothelial and microvascular repair.
Biliary tract cancers (BTCs) are aggressive, molecularly heterogeneous malignancies, and most patients present with unresectable or metastatic disease at diagnosis. For more than a decade, gemcitabine–platinum chemotherapy served as the first-line standard of care, with only modest survival benefit. The phase 3 TOPAZ-1 and KEYNOTE-966 trials have now established chemoimmunotherapy with immune checkpoint inhibitors as the new standard front-line regimen, and the phase 2 IMbrave151 trial is evaluating whether adding antiangiogenic therapy provides further benefit. Nonetheless, only a minority of patients derive durable clinical benefit from immunotherapy. Conventional predictive biomarkers—deficient mismatch repair or high microsatellite instability, tumor mutational burden, and PD-L1 expression—have limited discriminatory value in BTC, largely because of profound intratumoral heterogeneity. Emerging biomarkers and composite multi-feature models show greater promise for refining patient stratification. Investigational modalities, including therapeutic cancer vaccines, chimeric antigen receptor T cells, and tumor-infiltrating lymphocyte therapy, have shown preliminary antitumor activity but require validation in larger cohorts. Multiple combination regimens aimed at reversing the immunosuppressive tumor microenvironment are under active investigation, and disease-specific protocols for managing hepatobiliary immune-related adverse events remain an unmet clinical need. In this review, we synthesize the latest evidence on biomarkers, clinical trials, combination strategies, cellular therapies, and safety management for immunotherapy in advanced BTC, and we highlight persistent challenges and future research directions.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally, with chronic hepatitis B virus (HBV) infection as the predominant risk factor. Systemic therapies including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and ICI-antiangiogenic combinations have revolutionized advanced HCC treatment. However, treatment-induced liver injury is a major concern, especially in HBV-related HCC patients with pre-existing inflammation, fibrosis, and cirrhosis, which raises risks of treatment interruption, impaired efficacy, and acute liver failure. Liver injury arises from direct cytotoxicity, immune-mediated hepatitis, vascular damage, and HBV reactivation. This review summarizes the pathophysiological mechanisms of treatment-related liver injury in HBV-related HCC, analyzes the hepatotoxic profiles of tyrosine kinase inhibitors, immune checkpoint inhibitors, combination regimens and emerging agents, and proposes a structured clinical management framework including pretreatment risk assessment, prophylaxis, monitoring, differential diagnosis and severity-based interventions supported by multidisciplinary care. It aims to offer evidence-based guidance for clinicians to preserve liver function while safely administering effective antitumor therapy. The review also highlights key knowledge gaps and future research directions, including predictive biomarkers, personalized risk stratification and proactive safety evaluation of new drugs.
Lutetium-177 (177Lu)–based Radioligand Therapy (RLT) has emerged as an important modality in precision oncology, with demonstrated clinical benefit in selected malignancies. Its clinical relevance is underscored by regulatory approvals of Lutathera® for neuroendocrine tumours and Pluvicto® for metastatic castration-resistant prostate cancer. However, despite these advances, the field faces significant challenges that limit broader clinical translation and optimisation. In this review, we provide a critical and balanced evaluation of the current 177Lu RLT landscape, integrating evidence from clinical trials, emerging targets, and translational studies. We highlight that much of the existing evidence is derived from small, non-randomised studies with inherent risk of bias, limiting the strength of clinical conclusions. Key challenges include the lack of standardised and clinically actionable dosimetry, insufficient predictive biomarkers beyond target expression, vulnerability of isotope supply chains, and the development of drug-evasive traits in malignant cells. In addition, heterogeneity in trial design and limited long-term safety data further constrain clinical implementation. We propose a strategic roadmap to advance 177Lu RLT toward a more rigorous, reproducible, and equitable precision oncology framework, emphasising the transition from empiric application to evidence-based personalisation.
BackgroundPatients with anaplastic lymphoma kinase (ALK)-positive malignancies increasingly rely on ALK inhibitors (ALKis) as first-line therapy, yet thromboembolism (TE) across the ALKi family and its impact on patients’ safety remain incompletely characterized, particularly in the real-world populations.ObjectiveThe aim of this study was to evaluate the real-world TE risks associated with ALKis using pharmacovigilance data mining and to identify and characterize the high-risk contributors to TE.MethodsWe extracted 52,808 adverse event (AE) reports from the FDA Adverse Event Reporting System (2013–2024), including 17,124 ALKi-treated patients. TE signal strength was calculated via disproportionality analysis and presented by the lower limit of reporting odds ratio (ROR025) and information component (IC025). Multivariate logistic regression and time-to-onset (TTO) analyses were conducted to characterize the risk factors.ResultsAmong ALKi users, 251 TE cases were identified. Crizotinib exhibited significant TE safety signals for embolism (ROR025 = 2.66; IC025 = 1.19), pulmonary artery thrombosis (ROR025 = 4.94; IC025 = 1.01), pulmonary thrombosis (ROR025 = 1.29; IC025 = 0.13), and venous thrombosis limb (ROR025 = 1.66; IC025 = 0.08). Older age (OR = 1.006, P = 2.40e-06), male sex (OR = 1.47, P = 2.00e-16), and crizotinib use (OR = 2.79, P = 1.59e-05) independently predicted fatal TE outcomes. Female patients <65 years experienced earlier TE onset (median 14 vs. 44–53 days; P = 0.006).ConclusionThis study validates the elevated TE safety signal strength of crizotinib in the real-world settings, while no disproportionate TE signals were detected for other ALKi in the FAERS database. Clinicians could prioritize agent-specific risks, especially in older male patients and during early treatment phases.
BackgroundSlow transit constipation (STC) is characterized by delayed intestinal transit and impaired defecation, with enteric nervous system (ENS) injury and inflammatory dysregulation contributing to its pathogenesis. Acteoside (ACT), a natural phenylethanoid glycoside, has anti-inflammatory and neuroprotective properties. However, its therapeutic effect and mechanism in STC remain unclear.MethodsThe effects of ACT were investigated in a loperamide (LOP)-induced STC-like mouse model. Intestinal motility, colonic morphology, and ENS integrity were evaluated by functional assays, hematoxylin and eosin (H&E) staining, and immunofluorescence. Transcriptomic analysis was performed to screen ACT-responsive inflammatory pathways. NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and cytokine production were assessed by Western blotting, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Nlrp3-knockout (Nlrp3-KO) mice were used for genetic validation.ResultsACT shortened defecation latency, increased fecal water content and pellet number, and improved intestinal propulsion. ACT also alleviated colonic histopathological injury, restored muscular layer thickness, preserved HuC/D-positive myenteric neurons, and increased PGP9.5-positive nerve fiber density. Transcriptomic analysis identified NLRP3-related inflammatory signaling within broader high-dose ACT-responsive transcriptional changes. At the molecular level, high-dose ACT reduced the protein levels of NLRP3, cleaved-caspase-1, and cleaved-interleukin-1β (IL-1β) expression and reduced IL-1β, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) production. Nlrp3 deficiency partially reproduced ACT-mediated protection against STC-like phenotypes, inflammasome activation, and ENS injury, whereas ACT retained additional protective effects in Nlrp3-KO mice, suggesting that NLRP3-independent mechanisms may also contribute.ConclusionACT alleviates LOP-induced STC-like injury, and this protection is associated with attenuation of NLRP3 inflammasome activation and preservation of ENS integrity, while additional NLRP3-independent mechanisms may also contribute.
ObjectiveTo analyze the efficacy of amiodarone-inclusive protocol and the safety of amiodarone in fetal tachyarrhythmia treatment.MethodsPubMed, Web of Science, Medline and Embase were searched. Randomized controlled trials, cohort studies, case series and case reports on the efficacy of amiodarone-based therapy and the amiodarone-related safety in fetal tachycardia were included. Case reports were presented separately and descriptively synthesized, while case series and cohort studies were included in the meta-analysis. Outcomes included conversion of the fetal rhythm and the occurrence of adverse effects induced by amiodarone in the fetus. This research was registered in PROSPERO (No.CRD42024560291).ResultsWe analyzed 107 pregnancies treated with amiodarone from 27 studies. A descriptive synthesis of 18 case reports yielded a cardioversion rate of 81.0% for amiodarone-inclusive protocol, which was further supported by a quantitative analysis of nine studies showing a pooled cardioversion rate of 69.9% (95% CI: 57.6%–81.2%). In the hydropic subgroup fetus, cardioversion rates ranged from 53.8% to 87.5% (median, 63.4%). Overall, adverse events were reported in 29 fetuses, with thyroid dysfunction being the most prevalent. The pooled incidence of thyroid dysfunction was 21.2% (95% CI:11.4%–32.6%).ConclusionAmiodarone-inclusive protocol may be effective in fetal tachycardia management, particularly in refractory cases. These findings support amiodarone as an adjunctive therapy rather than monotherapy. Although its use was related to a risk of transient neonatal thyroid dysfunction, there was insufficient data to support an increase in the severe adverse reactions.Systematic Review ResgistrationPROSPERO (No. CRD42024560291).
IntroductionPediatric adverse drug reactions are difficult to evaluate after approval because pediatric trial evidence is limited and spontaneous-report systems differ in product naming, event coding, seriousness fields, and duplicate submissions.MethodsWe developed a manufacturer-aware benchmark for pediatric pharmacovigilance signal concordance using the FDA Adverse Event Reporting System (FAERS)/AERS as the source system, Canada Vigilance as a cross-system reporting-signal comparator, and JADER for descriptive third-country context. Active ingredients and five clinically adjudicated serious endpoint families were harmonized before detectable manufacturer cross-filing was screened.ResultsThe supervised benchmark contained 628 drug–endpoint–period rows: 147 manufacturer-screened Canada Vigilance reporting-signal positives and 481 Canada Vigilance co-report-absent comparators. An endpoint-conditioned FAERS co-reporting comparator achieved an area under the precision–recall curve (AUPRC) of 0.753. Elastic-net logistic regression reached 0.767, and a LightGBM comparator reached 0.774, but clustered paired-difference intervals versus the conditioned co-report comparator included zero. In 30 repeated drug-held-out partitions, chemical structure increased the mean AUPRC from 0.764 to 0.796, but the corresponding increment was –0.003 under unseen-scaffold partitions; target and pathway indicators produced no further material increase. Future-period support was concentrated in anaphylaxis: 40 drug pairs remained after manufacturer screening, including 37 with FAERS source exposure, and four of five FAERS scores ranked supported pairs above permutation expectations.DiscussionClinical label specificity, detectable duplicate screening, and fair source-signal comparators materially influenced model evaluation. The resulting resource provides a reproducible reference for pediatric signal triage and for testing whether new pharmacological features or models add information beyond established reporting statistics.
BackgroundALK/ROS1 tyrosine kinase inhibitors (TKIs) have improved outcomes in molecularly selected malignancies, but trial populations do not fully represent the age and clinical heterogeneity encountered in routine care. Comparative post-marketing evidence on age-related and drug-specific reporting patterns remains limited.MethodsWe analyzed US Food and Drug Administration Adverse Event Reporting System data from 2004 Q1 through 2026 Q1. The study included 38,479 primary-suspect reports with known age for crizotinib, entrectinib, brigatinib, lorlatinib, repotrectinib, cabozantinib, or ceritinib. Reports were stratified as 0–17, 18–44, 45–64, or ≥65 years. A preferred term (PT) was considered positive only when prespecified criteria for ROR, PRR, BCPNN, and MGPS were all met. We evaluated formal drug-exposure-by-age interactions, drug-level PT-spectrum similarity, clinical priority, and reported time to onset (TTO) with Weibull modeling.ResultsPositive PT counts were 64, 159, 230, and 178 across the four age groups, respectively, and 299 in the all-age analysis. Of 255 PTs eligible for formal interaction testing, 127 had an interaction false-discovery rate <0.05; 95 remained after exclusion of concepts not interpretable as adverse events. Descriptive displays highlighted pediatric skeletal concerns and neurologic or functional vulnerability in older reports, while formal contrasts distinguished these patterns from within-stratum signal detection. Drug-level positive-PT spectra showed generally low pairwise similarity, and target-set overlap correlated weakly with signal-spectrum similarity (Spearman ρ = 0.212, P = 0.356). TTO was evaluable for 15,810 reports (41.1%). Weibull estimates were below one across fitted pooled age groups, consistent with an early-failure reporting pattern.ConclusionThese findings support surveillance based on both age and the prescribed agent rather than a uniform class profile. The early reporting pattern favors close assessment soon after treatment initiation. FAERS signals remain hypothesis-generating and require confirmation in longitudinal patient-level data.
IntroductionThe reduction of α7 nicotinic acetylcholine receptor (nAChR) in the hippocampus con-stitutes one of the neuropathological features observed in the brains of individuals with Alzheimer’s disease (AD), and α7 nAChR is crucial to cognitive process. However, studies involving α7 nAChR knockout mice have not demonstrated any abnormal brain structure or damage to hippocampal neurons, a discrepancy likely driven by widespread developmental compensatory signaling reprogramming triggered by permanent whole-body α7 nAChR deletion from embryonic stages. This limitation renders traditional knockout lines unable to recapitulate the adult-onset, hippocampus-restricted α7 nAChR insufficiency characteristic of human AD, creating an unaddressed knowledge gap regarding whether isolated α7 nAChR loss in mature hippocampal neurons independently drives AD-related neurodegeneration and cognitive dysfunction.MethodsTo resolve this limitation, we established a spatially and temporally restricted knockdown mouse model via stereotaxic intrahippocampal injection of adeno-associated virus encoding Chrna7-targeted short hairpin RNA (shRNA) in 4-month-old mice. We assessed behavioral performance via open field test, novel object recognition test, Y-maze and Barnes maze 1 month post-viral delivery to quantify cognitive function; 2 months after injection, we harvested brain tissues to measure Aβ deposition, tau hyperphosphorylation, neuronal loss, astrocytic and microglial activation using immunofluorescence staining, and performed transcriptome RNA sequencing to profile genome-wide transcriptional alterations.ResultsThe knockdown of α7 nAChR in the hippocampus of adult mice rapidly induced cognitive deficits, impairments in learning and memory, and led to the increase of amyloid-β levels, Tau protein aggregation, neuronal damage, and the activation of astrocytes and microglia. Transcriptomic analysis revealed that the differentially expressed genes were significantly enriched in pathways related to inflammatory signaling.DiscussionOur study demonstrates that selective depletion of hippocampal α7 nAChR in adult mice is sufficient to trigger a spectrum of AD-like pathological alterations. Importantly, our AAV-mediated region-specific knockdown paradigm fully eliminates the developmental compensatory bias inherent to constitutive global α7 nAChR knockout animals by restricting receptor suppression exclusively to mature hippocampal neurons in post-developmental mice, closely recapitulating the spatial-temporal pattern of α7 nAChR loss in human AD brains. Our work provides novel pharmacological insights into α7 nAChR as a promising therapeutic target for AD pathological intervention.
Pharmacogenomics (PGx) is a key component of precision medicine, linking genetic variation to drug response, effectiveness, and toxicity. However, Middle Eastern and North African (MENA) populations remain underrepresented in global genomic databases, limiting PGx’s clinical utility in these regions. This review examines the current state of pharmacogenomics in the United Arab Emirates (UAE), focusing on genomic initiatives, population-specific variation, and challenges in clinical implementation. National genomic programs, including the Emirati Genome Program, have begun to address this gap by generating ancestry-specific data. Studies of UAE populations reveal clinically relevant variation in pharmacogenes that affect commonly used drugs such as warfarin, clopidogrel, and statins, as well as rare and understudied variants with potential functional impact. Additional evidence highlights the role of HLA diversity and genetic factors in metabolic and inflammatory conditions. Despite these advances, implementation remains constrained by gaps in healthcare professional education, infrastructure, regulatory frameworks, and public awareness. The UAE is well-positioned to advance PGx through targeted clinical integration, the development of local reference systems, and strengthened policy support. These efforts are essential to enable effective, population-specific precision medicine in the region.
Background: Chronic myeloid leukemia is commonly treated with tyrosine kinase inhibitors, and numerous clinical trials have been conducted globally. However, the overall registration distribution, trial development patterns, and public availability of trial results remain unclear. This study aimed to map the global landscape of such trials and assess the public availability of their results.Methods: This registry-based cross-sectional landscape analysis searched five major public clinical trial registries up to 19 March 2026. Results availability among eligible completed trials was assessed using registry records and a supplementary bibliographic search. Two reviewers independently screened trials, extracted data, and resolved discrepancies by adjudication. Descriptive statistical analysis was conducted using R software. We focused on completed trials finished for at least 2 years to evaluate publication.Results: A total of 125 trials were included, of which 96 (76.8%) were interventional studies and 23 (18.4%) were randomized. Trials were concentrated in the United States, Europe, China, and Australia. Most trials targeted BCR-ABL1 and were Phase II studies, whereas Phase I and Phase IV studies were less common. Among 52 eligible completed pharmacological trials, publicly identifiable results were available for 25 trials (48.1%). Among the 44 trials with reported clinical phase, results availability was 77.8% (7/9) for Phase III trials and 0% (0/4) for Phase I trials. Results availability varied descriptively across drug groups, although no drug-specific comparison remained statistically significant after adjustment for multiple testing.Conclusion: Global trials are geographically and developmentally unbalanced, with incomplete public availability of trial results. Future research should strengthen international collaboration, optimize trial phase distribution, support novel agent development, and promote timely and complete public disclosure of trial results.
Hyperprolactinemia (HPRL) is a common adverse reaction induced by antipsychotic therapy in patients with schizophrenia, which greatly undermines medication adherence and impairs physiological functions of multiple body systems. In this real-world study, we analyzed retrospective prolactin testing data to compare the incidence of HPRL between schizophrenia patients and patients with other psychiatric disorders, so as to identify clinical high-risk factors. Meanwhile, hormones including thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), free triiodothyronine (FT3), tetraiodothyronine (T4), Triiodothyronine (T3), and estradiol that closely correlated with prolactin metabolism were also included in the analysis. The results indicated that female patients with schizophrenia had the highest risk of HPRL (19.31%, n = 2009), and women during the prime reproductive (25–40 years) showed the highest average prolactin concentration (1,389.22 ± 50.138 mIU/L, n = 966). Distinct antipsychotics usage rates were observed among different clinical subgroups. Risperidone, paliperidone and sulpiride showed an increasing trend with elevated PRL levels, whereas quetiapine and aripiprazole were more frequently prescribed in the low-risk HPRL group. Antipsychotics showed divergent dopamine D2/D3 and 5-HT2A receptor-binding affinities (Ki values), and we constructed a weighted multi-receptor affinity index that demonstrated a strong linear correlation with the PRL risk score (R2 = 0.878). Additionally, the average incidence of extrapyramidal symptoms (EPS) increased with rising PRL levels (P = 2.24E-10). Further analysis of EPS risk revealed distinct safety profiles across antipsychotics, with aripiprazole—characterized by low HPRL liability—demonstrating a higher EPS risk. The severe HPRL group presented a tendency of decreased thyroid function (TSH, P = 0.0027; FT4, P = 0.000031; FT3, P = 0.0076; T4, P = 0.0025) and a significant reduction in estradiol levels (P = 0.000049). Based on homogeneous clinical real-world data, this study comprehensively evaluated multiple antipsychotic medications simultaneously. It provides empirical clinical evidence for individualized medication strategies in patients with comorbid HPRL and EPS, and offers real-world evidence for the clinical early risk recognition, and long-term medication decision-making among patients with multiple adverse reactions concurrently.
IntroductionGlutamate‐induced neurotoxicity is a shared pathological mechanism across neurodegenerative and neuropsychiatric disorders, but the mechanistic contributions of the sigma‐1 receptor remain unsolved and underappreciated.MethodsThis scoping review focuses on the pharmacological gaps in σ1R agonists by synthesizing mechanistic and bibliometric trends across the most influential literature in the field currently. To map how σ1R agonism has historically been thought of and where mechanistic blind spots still persist, we analyzed the top 100 most cited articles from Web of Science, Scopus, and Google Scholar. This approach was grounded in established scientometric methodology for capturing dominant scientific findings and research trajectories, using a PICO‐structured framework and evaluating how σ1R agonists influence and modulate glutamate‐induced excitotoxicity compared with non‐σ1R interventions, focusing on neuroprotection, calcium regulation, mitochondrial stability, and translational readiness.ResultsAlthough several agonists like PRE‐084, pridopidine, SA4503 and other neurosteroids show mechanistic convergence on ER-mitochondria signaling and calcium homeostasis, citation patterns reveal substantial gaps. These gaps include limited post‐2015 mechanistic studies and preclinical bottlenecks that have impeded clinical translation.DiscussionDespite convergent mechanisms among several agonists, progress toward clinical translation remains limited by challenges in ligand specificity and model fidelity, and the predominance of preclinical evidence. Addressing these limitations may facilitate the development of σ1R-targeted therapies for neurodegenerative and other neurological disorders characterized by disrupted calcium signaling and glutamatergic dysfunction.
IntroductionTubulointerstitial fibrosis (TIF) is a major pathological feature of progressive chronic kidney disease (CKD), yet effective pharmacological therapies remain limited. Bruceine A (BA), a quassinoid isolated from Brucea javanica, has been reported to exert renoprotective effects in glomerular diseases. However, its pharmacological role in renal TIF and the underlying mechanisms remain poorly defined.MethodsIn this study, we investigated the effects of BA in two classic animal models of TIF, unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI), as well as in TGF-β1-stimulated HK-2 cells.ResultsBA significantly attenuated renal histopathological injury, inflammatory responses, and fibrotic changes in both in vivo models, and improved renal function in UIRI mice. BA dose-dependently suppressed TGF-β1-induced epithelial-mesenchymal transition (EMT) and fibrotic responses in HK-2 cells. Mechanistically, RNA sequencing identified Wnt7a as a BA-responsive gene in fibrotic kidneys. BA consistently reduced Wnt7a expression in vivo and in vitro, while integrated RNA-seq and network pharmacology analyses implicated PI3K/AKT signaling as a key downstream pathway, which was further supported by reduced PI3K and AKT phosphorylation after BA treatment. Moreover, recombinant Wnt7a protein and the AKT agonist SC79 partially reversed BA-mediated suppression of fibrotic marker expression in HK-2 cells. Recombinant Wnt7a also partially restored PI3K/AKT activation.DiscussionCollectively, these findings suggest that BA attenuates renal tubulointerstitial injury and fibrosis, potentially through modulation of the Wnt7a/PI3K/AKT signaling pathway, supporting its potential as a therapeutic candidate for TIF.
IntroductionOsteoarthritis (OA) exhibits substantial heterogeneity in synovial immune profiles, which may underlie variable analgesic responses to standard biological and neuromodulatory treatments. Remodeling the immune microenvironment while targeting nociceptive pathways may improve therapeutic consistency.MethodsAnalgesic efficacy of platelet-rich plasma (PRP) combined with transient receptor potential vanilloid 1 (TRPV1) antagonism was evaluated in a monosodium iodoacetate (MIA)-induced rat OA model. Synovial immune polarization, inflammatory signaling, peripheral and central sensitization were assessed mechanistically. Clinical outcomes were analyzed in a cohort of 140 OA patients receiving combination or single-agent therapy.ResultsCombined PRP and TRPV1 blockade produced stronger analgesia than either treatment alone in rats. The combination shifted synovial macrophages toward an anti-inflammatory M2 phenotype, suppressed NF-κB signaling, and reduced pro-inflammatory cytokines. It also decreased dorsal root ganglion excitability and spinal glial activation, indicating reduced peripheral and central sensitization. In OA patients, combination therapy yielded superior pain relief, functional improvement, and reduced sensitization-related phenotypes.DiscussionThese findings support a neuroimmune model in which synovial immune heterogeneity influences treatment responsiveness. Concurrent immune remodeling via PRP and nociceptor inhibition via TRPV1 antagonism represents a promising strategy to achieve more reliable analgesia in OA.
[This corrects the article DOI: 10.3389/fphar.2020.602364.].
Radiotheranostic agents enable paired diagnostic imaging and targeted radiopharmaceutical therapy through the selection of appropriate radioisotopes. Radiotheranostics are typically composed of a targeting vector, a chelator or prosthetic group for radiolabeling and an optional linker for optimizing their pharmacokinetic properties. The chemokine receptor 4 (CXCR4) is a promising target for molecular imaging and therapy across a broad range of pathological conditions, including cancer, cardiovascular disorders, infectious and autoimmune diseases. The elucidation of CXCR4 crystal structures, together with extensive structure-activity relationship studies, has accelerated the design of novel small molecule and peptide-based CXCR4-targeted radiopharmaceuticals. These molecules have served as scaffolds that can be chemically modified to optimize their pharmacokinetic properties and maximize accumulation at the target organ. In oncology, the peptide-based theranostic pair Pentixafor/Pentixather has advanced into early-stage clinical evaluations for imaging and therapy. This review summarizes the current landscape of CXCR4 radiopharmaceuticals, and highlights key structural features and chemical modifications that lead to enhanced receptor affinity as well as improved pharmacokinetic and in vivo targeting properties for theranostic applications.
Nephrolithiasis associated with metabolic syndrome represents a growing global public health burden with a 5-year recurrence rate of up to 50%. Current first-line preventive strategies, primarily potassium citrate and thiazide diuretics, only correct urinary chemical abnormalities symptomatically, and patient adherence remains below 50% at 1 year. Importantly, these approaches fail to address the core pathological basis of tubular injury driven by metabolic dysregulation. Mitochondrial dysfunction is the central mechanistic hub linking systemic metabolic stress to intrarenal lithogenic susceptibility. In the setting of metabolic syndrome, impaired mitochondrial biogenesis and excessive mitochondrial reactive oxygen species (mtROS) production in renal tubular epithelial cells activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, establishing a self-perpetuating vicious cycle of “metabolic disturbance, mitochondrial damage, inflammatory amplification, calcium oxalate crystal deposition'. This core pathogenic loop has not been targeted by existing therapeutic strategies. Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), exerts pleiotropic renoprotective effects independent of its canonical glucose-lowering actions. It coordinately activates peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) through two complementary pathways: transcriptional upregulation through the PKA/CREB axis, and post-translational deacetylation via the AMPK/SIRT1 pathway. This dual activation restores mitochondrial homeostasis, reprograms tubular lipid metabolism, attenuates oxidative stress, and suppresses inflammatory cascades. This review is the first to systematically integrate the mitochondrial pharmacology of liraglutide with the pathophysiology of nephrolithiasis. It critically appraises the strengths and limitations of preclinical and clinical evidence, identifies key knowledge gaps in the field, and proposes a phased translational research roadmap encompassing mechanistic validation, biomarker development, and clinical trial design. This work provides a solid theoretical foundation for repurposing GLP-1RAs for the prevention of this condition.
