Journal of Pharmaceutical Analysis

Unraveling pyrrolizidine alkaloid-induced liver damage with an integrative spatial lipidomics framework

Yilin Chen, Jie Xu, Thomas Ka-Yam Lam, Yanqiao Xie, Jianing Wang, Aizhen Xiong, Zhengtao Wang, Zongwei Cai, Linnan Li, Li Yang

2026, 16(1) doi: 10.1016/j.jpha.2025.101340

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Pyrrolizidine alkaloids (PAs), a class of secondary metabolites widely distributed in plants and the accidental ingestion or improper use of foods and herbs containing PAs, can lead to irreversible liver damage. Considering that the toxic mechanism of PAs is closely associated with metabolism, the hepatotoxicity was analyzed from the perspective of lipid metabolism. An integrated analytical approach was employed, combining mass spectrometry imaging (MSI) with liquid chromatography-mass spectrometry (LC-MS), to comprehensively investigate the spatial and temporal dynamics of lipid metabolites during PA exposure. The final lipidomics results combined with RNA sequencing showed that time-dependent changes in metabolite levels after the administration of PAs, involving the pathways of fatty acids, glycerophospholipids, glycerolipids and sphingolipids. Among them, phosphatidylcholines (PC), phosphatidylethanolamines (PE), phosphatidylinositols (PI) and sphingomyelins (SM) were downregulated to varying degrees within 0–24 h, while phosphatidylglycerol (PG), ceramides (Cer), diacylglycerols (DG) and triacylglycerols (TG) were upregulated. Notably, certain lipids exhibited distinct spatial distributions; for example, elevated levels of TG (56:13) were localized near the hepatic portal vein. Subsequently, the changes of lipid subclasses recovered within 24–48 h. Transcriptome RNA sequencing was used to enrich for key pathway-related differential genes Pemt, Gpat, etc. to explain the regulation of the hepatotoxic lipid pathway. The integration of MSI with LC-MS spectroscopy of endogenous metabolites provided intuitive insights into the alterations and spatial distribution of lipid metabolism in mice. Consequently, this study may enhance specific assessments and facilitate early diagnosis of acute toxicity associated with PAs.

A novel method for screening antihyperuricemic drugs by combining aptamer sensor array, exonuclease III-DNA walker and linear discriminant analysis

Shiquan Zheng, Jiale Ke, Hanren Chen, Huaze Shao, Fengxin Zheng, Runhui Zhang, Zean Zhao, Jianxin Pang, Lihong Liu

2026, 16(1) doi: 10.1016/j.jpha.2025.101345

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The lack of a cell-based screening method limits urate-lowering drug development. A novel method combining aptamer sensor array (ASA), exonuclease III (Exo III)- powered 3D DNA walker (DW), and linear discriminant analysis (LDA) was developed for detecting uric acid (UA) in cell lysates, referred to as ASA–Exo III-DW–LDA. Three aptamers (Apts) with different affinities for UA and its structurally similar compound, xanthine (Xan), were used to design the ASA. The combination of ASA and Exo III-DW enabled the detection of UA at the picomolar level, whereas LDA was employed to differentiate UA signals from the mixed signals of UA and Xan. Significantly, Pearson correlation analysis revealed a strong correlation between our method and the ¹⁴C radioactive labeling method for urate anion exchanger 1 (URAT1) inhibitors, with r = 0.9880 for lesinurad and r = 0.9777 for benzbromarone. Using our method, kaempferol was identified as a promising hit compound for inhibiting the URAT1, because of its low half-maximal inhibitory concentration (IC₅₀) (18.96 μM) low toxicity in mouse renal tubular epithelial cells (mTECs), and significant urate-lowering effect in hyperuricemic mice at 5 mg/kg. Overall, this method is sensitive, cost-effective and safe, offering a novel strategy for routine urate-lowering drug screening in standard laboratories.

Development of a dual-chamber derivatization method for the determination of cyanide in sodium nitroprusside and its preparation via HS-GC-ECD

Jinqi Zheng, Xinyu Zhao, Caixia Li, Chenxiao Yan, Pingping Chen, Xiao Gu, Liya Hong, Su Zeng

2026, 16(1) doi: 10.1016/j.jpha.2025.101353

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The acute toxicity of cyanide and its pharmaceutical residues has fueled interest in the development of analytical methods for its determination, particularly for sodium nitroprusside (SNP), a widely used vasodilator with potential cyanide residues. In this study, a dual-chamber derivatization bottle was designed to establish an interconnected gas environment, thereby facilitating chloramine T-mediated cyanide conversion to cyanogen chloride (CNCl) without direct contact with SNP. Subsequent determination of the analytes was undertaken using a headspace-gas chromatography-electron capture detector (HS-GC-ECD). The challenges of analyzing cyanide and the rapid degradation of SNP were addressed simultaneously. The method was subjected to rigorous validation, encompassing specificity, linearity, limit of detection (LOD), limit of quantitation (LOQ), accuracy, precision, and robustness. The validation process revealed a notable degree of linearity within the range of 0.012–1.56 μg/mL, with a LOQ of 12.0 ng/mL. The method was found to be both accurate and precise, thus satisfying the requisite criteria. This method facilitates reliable cyanide monitoring in degradation-prone pharmaceuticals.

CXCL8/SDC1 axis mediates tumor stem cell interactions to drive remote transfer in thyroid cancer

Wenjuan Wang, Jian Zhou, Baorui Tao, Ning Kong, Jie Shao

2026, 16(1) doi: 10.1016/j.jpha.2025.101354

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This study explores the molecular mechanisms behind the remote transfer of thyroid cancer (THCA) by investigating the interaction network of C-X-C motif chemokine ligand 8⁺ (CXCL8⁺ monocytes and syndecan-1⁺ (SDC1⁺) tumor stem cells using single-cell and spatial transcriptome sequencing. Tumor samples from THCA patients were analyzed using single-cell RNA sequencing (scRNA-seq), spatial transcriptome sequencing, and tumor tissue transcriptome analysis. Data were processed with Seurat and CellChat R packages, integrated via the SPOTlight package, and correlated with clinical data from the UCSC Xena database. Functional pathway enrichment analyses were performed using Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genome (KEGG). In vitro, a co-culture system of monocytes and THCA stem cells was developed, and protein levels were measured via enzyme-linked immunosorbent assay (ELISA) and Western blotting. The self-renewal and migration of follicular thyroid carcinoma (FTC) 238-S cells were assessed through sphere formation, colony formation, Cell Counting Kit-8 (CCK-8), and Transwell assays. In vivo, a subcutaneous tumor xenograft model and a lung metastasis model were established in nude mice. Transcriptomic analyses identified the CXCL8/SDC1 axis as a key mediator of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling activation, promoting THCA stem cell self-renewal, invasion, and metastasis. CXCL8/SDC1 expression was significantly higher in the high-risk C1 subtype of THCA patients and correlated with a worse prognosis. In vitro and animal studies confirmed that the CXCL8/SDC1 axis drives tumor progression and metastasis. The interaction between CXCL8⁺ monocytes and SDC1⁺ tumor stem cells activates the JAK-STAT pathway, facilitating the remote transfer of THCA. Targeting the CXCL8/SDC1 axis may provide novel therapeutic strategies for improving THCA patient outcomes.

Luteolin attenuates RA-associated chronic pain by targeting the LDHA/H3K9la/NFATC2 axis to suppress Th17 cell differentiation and central infiltration

Yuepeng Jiang, Yang Zhao, Xiao Ma, Xiaoxuan Zhao, Mengjia Zheng, Junjun Wen, Cunrui Yuan, Xinyi Ding, Chengping Wen

2026, 16(1) doi: 10.1016/j.jpha.2025.101373

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Chronic joint pain in rheumatoid arthritis (RA) represents a persistent therapeutic challenge, and although luteolin (LUT) exhibits established anti-inflammatory properties, its precise mechanism for alleviating RA-associated chronic pain remains undefined. Through systematic investigation in collagen-induced arthritis (CIA) mice, we demonstrated that LUT administration effectively attenuated chronic pain by modulating spinal cluster of differentiation 4 positive T (CD4⁺ T) cell dynamics and suppressing microglial activation. Integrated multi-omics profiling (cleavage under targets and tagmentation (CUT&Tag), RNA sequencing (RNA-seq), and metabolomics) coupled with functional validation revealed nuclear factor of activated T cells 2 (NFATC2) as the central transcriptional regulator governing T helper 17 (Th17) cell differentiation and spinal infiltration through protein kinase C epsilon (PRKCE)-signal transducer and activator of transcription 3 (STAT3) signaling transduction. Significantly, our mechanistic studies uncovered a previously unrecognized epigenetic cascade: LUT-mediated suppression of lactate dehydrogenase A (LDHA) activity disrupts glycolysis-fueled histone 3 lysine 9 lactylation (H3K9la), thereby epigenetically silencing NFATC2 transcription. Translational studies using RA patient-derived CD4⁺ T cells confirmed LUT's capacity to normalize pathological hyperactivity of the LDHA/H3K9la/NFATC2 axis, concomitantly regulating CD4⁺ T dynamics. Biophysical validation through molecular docking, surface plasmon resonance (SPR), and molecular dynamics (MD) simulations established LUT's direct binding to LDHA with high affinity. Collectively, these findings delineate a novel therapeutic paradigm wherein LUT alleviates RA-associated chronic pain by orchestrating Th17 differentiation and migratory capacity through coordinated blockade of the LDHA-H3K9la-NFATC2 signaling network, highlighting its potential as a disease-modifying agent for chronic pain management in RA.

Synergistic antibacterial and anti-inflammatory potentials of dual-loaded self-healing hydrogel for methicillin-resistant Staphylococcus aureus-infected wound healing

Sangyu Hu, Weigang Zhong, Yuzhu Pei, Yutong Zhou, Jianfeng Wang, Xuming Deng, Zihao Teng, Lei Xu

2026, 16(1) doi: 10.1016/j.jpha.2025.101376

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The emergence of drug-resistant bacterial infection and persistent biofilm colonization pose a rigorous challenge to effective wound healing and regeneration, necessitating the innovative therapeutic strategies to combat these pressing clinical crises. Herein, nortriptyline, a novel United States Food and Drug Administration (FDA)-approved tricyclic antidepressant was uncovered to effectively potentiate bactericidal activities of β-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA). Mechanistically, nortriptyline functions by disrupting the microbial iron homeostasis and potentiation of Fenton chemistry-mediated oxidative stress, concomitant with metabolic reprogramming via tricarboxylic acid (TCA) cycle dysregulation and membrane destabilization. To enhance combination therapy-mediated therapeutic potential in wound management, the dual-loaded self-healing hydrogel OHA-PLL@AN was engineered to exhibit excellent biocompatibility and antibacterial potentials through molecular cross-linking of oxidized hyaluronic acid (OHA) and ε-polylysine (PPL). The therapeutic efficacy of OHA-PLL@AN was further validated in a murine model with MRSA-infected cutaneous wounds. OHA-PLL@AN therapy significantly attenuated the inflammatory response, concurrently promoting angiogenesis and accelerating the cutaneous wounds healing. Collectively, these findings underscore the dual drug-loaded self-healing hydrogel OHA-PLL@AN with anti-infection and anti-inflammatory properties as a novel therapeutic strategy for drug-resistant bacterial infected wounds therapy.

Targeting SH3GL1 for prognosis and immune response in breast cancer

Si Si, Hong Yu, Hao Zhang, Jianqiao Yin, Ziwei Li, Ning Wang, Xiaopeng Yu

2026, 16(1) doi: 10.1016/j.jpha.2025.101377

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The cuproptosis-related gene (CRG) SH3GL1 is identified as a pivotal regulator in breast cancer (BRCA) progression and immune regulation in this study. Through gene expression profiling and meta-analysis of public datasets, SH3GL1 was found to be overexpressed in BRCA tumor tissues and correlated with poor prognosis. Single-cell RNA sequencing pinpointed SH3GL1's expression in epithelial cells and its critical interactions with immune cells, particularly T cells and monocytes. Functional experiments confirmed SH3GL1's role in promoting immune cell migration and modulating drug sensitivity. Moreover, high SH3GL1 expression was linked to reduced immunotherapy response, as revealed by TIDE scoring, suggesting its contribution to the immune microenvironment complexity in high-risk BRCA groups. These results emphasize SH3GL1's dual role as a prognostic biomarker and a target for therapeutic intervention in BRCA, providing new insights into personalized cancer treatment approaches.

FPS_P/N: A two-dimensional mass spectrometry utilization program with precursor ion determination for accurately distinguishing anthocyanin from other flavonoids

Ya-Hui Ge, Lili Zhang, Shilin Gong, Wen Miao, Li Zhang, Weibin Bai, Jian-Lin Wu, Na Li

2026, 16(1) doi: 10.1016/j.jpha.2025.101385

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Anthocyanins, a unique class of flavonoids with flavylium skeletons, are valued for antioxidant properties. However, distinguishing anthocyanins from co-existing flavonoids using conventional automated tandem mass spectrometry (MS) analysis methods remains challenging. This difficulty arises from low specificity of MS features and confusion of precursor ions, leading to substantial false confidence annotations. To address it, we have developed the strategy of positive (POS)-to-negative (NEG) primary MS (MS¹) intensity ratios detecting with fast polarity switching (FPS), termed FPS-POS/NEG, to determine their specific precursor ions. Moreover, we developed an automated program leveraging FPS-POS/NEG strategy (FPS_P/N) streamlining screening candidate pool with molecular networking analysis from MS¹ and secondary MS (MS²), determining precursor ions with FPS-POS/NEG, and annotation with MS². This program enables simultaneous capture of positive and negative signals in a single run and accurate determination of precursor ions for anthocyanins (5.98–9.28) and other flavonoids (−2.52 to 2.08). The underlying mechanisms were elucidated by difference in protonated and deprotonated Gibbs free energy (ΔG) and in-source fragmentation (ISF). FPS-POS/NEG strategy was validated across a broad pH range (0.1%–2% formic acid (FA)) and demonstrated high alignment accuracy (retention time difference, 0.011 min) and consistency (relative standard deviation (RSD), 0.38%–4.62%). Using blueberry, 20 anthocyanins (nonacylated and acylated) and 14 additional flavonoids were annotated. With two-dimensional integration of positive and negative MS¹ intensities with intensity ratios, FPS_P/N program provides a novel way to identify anthocyanins from other flavonoids. We anticipate this innovative method will enhance the high-throughput qualification of anthocyanins and other flavonoids in complex samples.

Integrating high-resolution bioassay profiling with affinity-based ligand fishing for unveiling galloylated derivatives as novel catechol-O-methyltransferase inhibitors in Paeonia lactiflora Pall.

Jiaming Yuan, Zhuoping Zheng, Zhongkang Wang, Hao Tian, Lingling Xi, Jacques Crommen, Tingting Zhang, Jincai Wang, Zhengjin Jiang

2026, 16(1) doi: 10.1016/j.jpha.2025.101449

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Catechol-O-methyltransferase (COMT) inhibition is a critical therapeutic strategy for Parkinson's disease (PD), yet clinical inhibitors face limitations in bioavailability and hepatotoxicity, driving demand for novel natural scaffolds. In this study, we developed an integrated analytical platform by coupling high-resolution bioassay profiling (HRBP) and affinity-based ligand fishing system to effectively characterize bioactive compounds targeting COMT in Paeonia lactiflora Pall. (the most frequently used core herb in tradition Chinese medicine prescriptions for PD treatment). Parallel high-performance liquid chromatography with diode-array detection and tandem mass spectrometry (HPLC-DAD-MS/MS) coupled with nanofractionation enabled real-time bioactivity mapping via 384-well COMT inhibition assays, while semi-preparative liquid chromatography (LC) was employed to further identify co-eluted components. HRBP and immobilized COMT ligand fishing identified 16 and 21 candidates, respectively, with 5 overlapping bioactive markers. Notably, the potent inhibitors galloylpaeoniflorin (half maximal inhibitory concentration (IC₅₀) = 16.2 ± 3.4 μM) and 1,2,3,4,6-O-pentagalloylglucose (IC₅₀ = 3.1 ± 0.5 μM) exhibited comparable potency to the positive control morin (IC₅₀ = 10.1 ± 0.7 μM). Molecular docking results further revealed the critical interactions and binding sites between the active compounds and COMT. The validated platform demonstrates significant potential for rapid discovery of plant-derived enzyme inhibitors, bridging advanced separation, bioactivity screening, and mechanistic validation in neurodegenerative therapeutic development.

Large-scale evaluation of HIV-1 DNA drug resistance testing as a robust tool for clinical decision-making: A nationwide study in China

Caihong Wu, Limin Zhang, Zhong Chen, Wencui Ma, Yanhua Fu, Ke Yang, Mei Liu, Yanjun Li, Xiaohong Chen, Mingjie Hou, Min Liu, Aihua Deng, Qingxia Zhao, Lukun Zhang, Quan Wang, Jun Peng, Yongli Li, Keji Deng, Jingsong Bai, Hai Long, Yaokai Chen, Hui Wang, Yun He, Jin Li, Jiahui Guo, Bianchuan Cao, Yizhi Cui, Min Wang, Tuofu Zhu, Jun Yao, Tong Wang

2026, 16(1) doi: 10.1016/j.jpha.2025.101513

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Human immunodeficiency virus type 1 (HIV-1) drug resistance remains a major challenge in HIV/AIDS management, particularly in individuals with low-level viremia (LLV) where RNA-based drug resistance testing (DRT) often fails. Although HIV-1 DNA DRT represents a promising alternative, its clinical utility has been constrained by insufficient evidence. This nationwide study in China enrolled 9,428 people living with HIV (PLWH), analyzing 10,903 samples spanning a wide viral load (VL) spectrum. To improve RNA detection, an optimized primer design combined with an extracellular particle (EP)-HIV co-isolation technique was developed. We then evaluated the reproducibility of drug resistance mutation (DRM) profiles between paired RNA and DNA DRTs using Sanger sequencing (SS), with single-molecule sequencing employed to establish a dominant sequence threshold. Our findings demonstrated that primer optimization and EP-co-isolation significantly enhanced RNA amplification success. DRMs were prevalent across all VL strata. The combined concordance and degeneracy rates (C/D rates) (where multiple DNA DRMs included all RNA-derived DRMs) between RNA and DNA DRTs ranged from 90.4% to 100% in different gene regions, with higher discordance rates observed in the nucleoside reverse transcriptase inhibitor (NRTI) and non-NRTI (NNRTI) regions. Based on Stanford penalty scores across 25 antiretroviral drugs, the degeneracy group showed a 98.3% ± 1.7% interpretation agreement. Even within the discordance group, mean agreement remained high (89.5% ± 5.0%), with only four NNRTIs exhibiting agreement below 85%. The dominant sequence proportion threshold for HIV-1 DNA was determined to be 24.6%. This study provides strong evidence supporting the integration of HIV-1 DNA DRT into clinical practice for reliable drug resistance surveillance and treatment monitoring.

ERBB2 mutations promote recurrence and metastasis in non-muscle-invasive bladder cancer via HIF-1 phosphorylation: Insights from whole exome sequencing

Xu Wang, Long Jin, Xinlin Zou, Ankang Zhu, Mingyu Li, Haitao Fan

2026, 16(1) doi: 10.1016/j.jpha.2025.101519

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This study investigates the role of ERBB2 mutations in promoting recurrence and metastasis of non-muscle-invasive bladder cancer (NMIBC). Analysis of whole exome sequencing (WES) data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases revealed a significant association between ERBB2 mutations and immune cell infiltration. To validate these findings, formalin-fixed, paraffin-embedded tumor tissues from patients with recurrent NMIBC were analyzed, with a focus on ERBB2 mutations. In addition, bladder cancer cell lines carrying wild type or mutant ERBB2 were established using clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) technology. Functional experiments, including Western blotting, protein stability assays, and ubiquitination analyses, demonstrated that ERBB2 mutations promote hypoxia-inducible factor-1 (HIF-1) phosphorylation, leading to its stabilization and enhancing the proliferative, migratory, and invasive capacities of tumor cells. Furthermore, flow cytometry, 5-ethynyl-2′-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and Transwell assays confirmed the impact of these mutations on cellular behavior, while drug sensitivity assays indicated increased susceptibility of ERBB2-mutant cells to therapeutic agents. In vivo studies using mouse models further supported these findings, showing that ERBB2 mutations promote tumor growth, metastasis, and macrophage infiltration. Collectively, these results suggest that ERBB2 mutations drive NMIBC progression by stabilizing HIF-1 through phosphorylation, thereby facilitating tumor development and immune modulation, and underscore the potential of ERBB2 as a therapeutic target for preventing NMIBC recurrence and metastasis.

Applications of quantitative ¹³C NMR in pharmaceutical analysis: From small molecule drugs to biopolymers

Qi Tang, Sinan Wang, Xiongqi Zhai, Seon Beom Kim, Prabhakar Achanta, Gonzalo R. Malca-Garcia, Yuzo Nishizaki, Yi Wang, Yu Tang

2026, 16(1) doi: 10.1016/j.jpha.2025.101346

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Chemical integrity is indispensable for advancing healthcare by ensuring the availability of high quality, safe, and effective pharmaceutical products. Ingredient quantification is particularly pivotal in this process. Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for both qualitative and quantitative analysis for complex systems. Compared with 1D quantitative ¹H NMR (¹H qNMR), quantitative ¹³C NMR (¹³C qNMR) holds some unique advantages. This technique offers a broader chemical shift range and the resulting much lesser signal overlap compare to ¹H NMR spectroscopy. This review summarizes relevant studies on the use of ¹³C qNMR as a quantification technique, along with a focus on quantitative principles, influencing factors, and technical improvements of ¹³C NMR. The review also highlights its applicability in quantifying diverse molecular structures in pharmaceutical analysis. In addition, potential of low-field NMR, artificial intelligence (AI)-driven method development, and hyphenation of NMR with other techniques for ¹³C qNMR analysis is discussed and summarized as well. As a versatile method, ¹³C qNMR holds great potential, and ongoing research is expected to unlock its full capabilities and expand its range of applications.

Recent advances in nanomaterial-based optical biosensors and their biomedical and biopharmaceutical applications

Mengjia Xu, Lutfun Nahar, Kenneth J. Ritchie, Chenxu Wang, Li Cheng, Zimiao Wu, Satyajit D. Sarker, Mingquan Guo

2026, 16(1) doi: 10.1016/j.jpha.2025.101349

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Optical biosensors are gaining popularity owing to their portability, miniaturization, no requirement for additional attachments, and rapid responsiveness. These features render them suitable for various applications including at-home diagnostics, pharmacology, and continuous molecular monitoring. The integration of functionalized low-dimensional nanomaterials (zero-dimensional (0D), 1D, 2D, and 3D) has redirected focus towards the design, fabrication, and optimization of optical biosensors. This review summarizes the fundamental mechanisms underlying optical biosensing. The key mechanisms include localized surface plasmon resonance (LSPR), photoluminescence (PL), surface enhancement Raman scattering (SERS), nanozyme-based colorimetric strategies, chemiluminescence, bioluminescence, and electrochemiluminescence. The advantages of various low-dimensional nanomaterials for different types of optical biosensors are presented. This comparison emphasizes their potential superiority in targeted biosensing applications. Therefore, promoting optical biosensing techniques and recent developments in advanced biosensing strategies for biomedical research and biopharmaceutical applications are necessary to establish their future directions.

Ferroptosis and retinal ganglion cell death in glaucoma: Mechanisms and therapeutic approaches

Minggao Qin, Xueqin He, Weiwen Qiu, Yanjing Peng, Yequan Liao, Jusen Zhao, Lianxiang Luo, Qiuli Zhang

2026, 16(1) doi: 10.1016/j.jpha.2025.101355

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Glaucoma represents a predominant worldwide etiology of permanent vision impairment; it is clinically manifested through progressive neuronal atrophy in retinal ganglion cells (RGCs) and is accompanied by axonal degeneration in the optic pathway. Given the limited efficacy of conventional intraocular pressure-lowering therapies in halting RGC degeneration, the exploration of novel neuroprotective strategies has become imperative. An increasing amount of research emphasizes the pathogenic role of ferroptosis, a metal ion-associated programmed cellular demise mechanism recently implicated in neurodegenerative cascades, as a pivotal executor of RGC demise and putative central mechanism in glaucomatous pathology. This comprehensive review systematically examines the mechanistic interplay between ferroptosis and established contributors to glaucomatous optic neuropathy, including oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, and neuroinflammation. We provide evidence demonstrating that retinal ferroptosis is associated with the death of RGCs and discuss current therapeutic strategies to mitigate retinal ferroptosis, including treatments with natural products and gene therapy. Furthermore, by understanding ferroptosis, we provide insights into potential therapeutic targets and offer valuable directions for future research and clinical applications.

Pharmacological mechanisms of natural products with antidepressant effects: A focus on the programmed cell death regulation

Guangheng Zhang, Shimeng Lv, Shengchuan Bao, Weijie Zhao, Yunhao Yi, Haonan Gao, Xia Zhong, Xiangyu Li, Fengzhao Liu, Yitong Lu, Siyuan Sun, Jing Teng

2026, 16(1) doi: 10.1016/j.jpha.2025.101356

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Depression is a prevalent mental disorder characterized by persistent disinterest and a depressed mood, with severe cases potentially leading to suicide. In recent years, the incidence of depression has steadily increased, making it the second-largest global health burden. The pathogenesis of depression involves a series of complex pathological mechanisms, although the key underlying causes remain unclear. Programmed cell death (PCD), including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, involves highly organized gene expression processes that may influence the occurrence and development of depression by regulating cellular fate. Furthermore, numerous studies have shown that natural products can modulate PCDs through various signaling pathways, presenting significant potential for managing depression. Natural products offer benefits such as cost-effectiveness, fewer side effects, and other advantages, making them viable supplements or alternatives to traditional antidepressant drugs. To explore this potential, we reviewed studies demonstrating the antidepressant effects of natural products through multi-target modulation of PCDs. In addition, we discussed the toxicity and clinical applications of these natural products. This study highlights that diverse core biological pathways and targets are involved in determining the fate of depression-associated brain cells, including the PI3K/Akt signaling pathway, caspase-8, GSDMD, and others. In conclusion, the multi-target mechanisms of PCD regulation by natural products may provide a promising foundation for the future development of novel antidepressant medications.

Tumor-associated macrophages in hepatocellular carcinoma: Cellular plasticity and therapy resistance in crosstalk

Tianhao Zhang, Xi Zhao, Tingting Gao, Fang Ma

2026, 16(1) doi: 10.1016/j.jpha.2025.101384

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Hepatocellular carcinoma (HCC) is the predominant type of liver cancer. There are different risk factors for HCC including viral infection, liver fibrosis, non-alcoholic fatty liver disease, environmental factors and genomic alterations. The tumor microenvironment (TME) has been proposed as a potent regulator of tumor malignancy comprised of normal and cancerous cells. Macrophages are among the most abundant cells in the TME, known as tumor-associated macrophages (TAMs) that can control proliferation, metastasis, immune reactions and therapy response of tumor cells. In the present review, the function of TAMs in the regulation of HCC progression was evaluated. TAMs are prognostic factors in HCC that increase in TAM infiltration into TME can cause undesirable outcome in patients. Moreover, M2 polarization of macrophages can impair function of other immune cells such as T cells and natural killer (NK) cells to mediate immune evasion. TAMs demonstrate association with other biological events including autophagy and glycolysis. There is mutual interaction between TAMs and exosomes that TAM-mediated exosome secretion regulates HCC progression, while exosomes derived from other cells can also affect TAMs. Inhibition of macrophage recruitment, their depletion and increasing M1 polarization are promising approaches in HCC therapy. The natural products and nanostructures have been also recently introduced for the regulation of macrophages in HCC therapy.

Targeted nano-drug delivery systems for tumor immunotherapy

Shan Lian, Wenyong Yang, Yan Zeng, Ranran Tang, Kui Wang

2026, 16(1) doi: 10.1016/j.jpha.2025.101408

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While being a safe and effective precision therapy strategy, tumor immunotherapy still fails in many patients due to the immunosuppressive tumor microenvironment. Emerging evidence has indicated that the targeted nano-drug delivery systems can accurately deliver therapeutic agents to potentiate the efficacy of immunotherapy. This review will outline recent advances in applying targeted nano-drug delivery systems in immunotherapy, with an emphasis on their crucial roles in regulating innate immune responses, adaptive immune responses, and immunogenic cell death. We will also discuss the current challenges and future opportunities for the clinical translation of targeted nano-drug delivery systems for tumor immunotherapy.

A comprehensive review on herbal approaches for treatment of urinary tract infections: Scope and challenges

Md Saddam, Sujeet K. Mishra, Neelam Singh, Shyam Baboo Prasad, Smriti Tandon, Hemant Rawat, Ganesh Dane, Vijay Kumar, Ajay Kumar Meena, Ravindra Singh, Arjun Singh, Ch V. Narasimhaji, Narayanam Srikanth, Rabinarayan Acharya

2026, 16(1) doi: 10.1016/j.jpha.2025.101414

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Urinary tract infections (UTIs) have become a major health concern globally, necessitating effective treatments for mitigating discomfort and avert complications. The uropathogens commonly associated with UTIs in humans such as Bacillus species, Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Escherichia coli (E. coli) are progressively developing resistance to current treatments and medications. The ancient wisdom of Ayurvedic medicines and its holistic approach can contribute to UTI treatment due to its lower toxicity, effectiveness against pathogens, and cost efficiency making it a viable option to complement or replace conventional treatments. This review delineates the key probable interactions between the bioactive components of antibacterial herbal drugs and UTI pathogens. Herbal drugs are rich in antioxidants such as flavonoids and polyphenols which can effectively neutralize free radicals and inhibit the formation of bacterial biofilms. These actions help alleviate oxidative stress and contribute to their anti-inflammatory effects. Certain specific herbs traditionally identified for their anti-inflammatory and antibacterial activity have been evaluated for their efficacy towards treatment of UTIs. Finally, the review addresses the challenges associated with herbal treatments of UTIs including issues related to standardization, dosage, and potential interactions with conventional medications that need to be overcome for broader acceptance and application.

Beyond conventional therapies: Gut microbiota modulation and macromolecular drugs in the battle against cardiometabolic diseases

Jingyue Wang, Jing Qu, Mengliang Ye, Ru Feng, Xiang Hui, Xinyu Yang, Jingyu Jin, Qian Tong, Xianfeng Zhang, Yan Wang

2026, 16(1) doi: 10.1016/j.jpha.2025.101416

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Cardiometabolic diseases (CMDs) represent an ongoing major global health challenge, driven by complex interactions among genetic, environmental, microbiome-related, and other factors. While small-molecule drugs and lifestyle interventions can provide clinical benefits, they are possible to be constrained by the limited druggability of key target proteins, the potential risks of off-target effects, and difficulties in maintaining long-term adherence. In recent years, gut microbiota modulation and macromolecular drugs have emerged as promising therapeutic strategies. Gut microbiota modulation (e.g., probiotics, synbiotics, or natural products) exerts systemic metabolic and immune effects, supporting a therapeutic approach targeting multiple diseases. Meanwhile, macromolecular drugs (e.g., peptides, antibodies, and small nucleic acids) offer precise, pathway-targeted interventions. Despite advancements, limitations remain in addressing ethical considerations in microbiota modulation and optimizing targeted delivery systems, all of which may hinder clinical translation. Here, we provide a comprehensive overview of therapeutic approaches for CMDs, with a focus on obesity, type 2 diabetes mellitus (T2DM), and atherosclerosis (AS). The review is structured around three key aspects: i) conventional therapies, including small-molecule drugs and lifestyle interventions; ii) emerging therapies encompassing gut microbiota modulation, macromolecular drugs, and their interactions; and iii) challenges and opportunities for comorbidity management, microbiota ethics, and artificial intelligence (AI)-driven therapeutic optimization. We hope this review enhances the understanding of small-molecule drugs, lifestyle interventions, gut microbiota modulation, and macromolecular drugs in the management of CMDs, thereby fostering medical innovation and contributing to the development of system-based comprehensive therapeutic paradigms.

Pharmacokinetics, efficacy, and safety of a novel aripiprazole microsphere-based long-acting injectable formulation for schizophrenia: A multicenter, randomized controlled trial

An-Ning Li, Sheng-Chun Jin, De-Wei Shang, Jian-Xiong Guo, Hua-Li Lin, Ming Zhang, Bo Wei, Feng Wan, Yun-Long Tan, Li-Li Wang, Jian-Chu Zhou, Ping Liu, Lian-Lian Fan, Ju-Shui Sun, Bin Chen, Yimin Cui, Gang Wang

2026, 16(1) doi: 10.1016/j.jpha.2025.101350

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Abstract: