Ren Lai

BACKGROUND: ApoB (apolipoprotein B)-containing lipoproteins are causal risk factors for atherosclerotic coronary artery disease (CAD). Since LL-37 (human cathelicidin peptide) binds to ApoB-100 in this pathological context, we investigated whether the circulating LL-37–ApoB-100 complex could serve as a biomarker for CAD. METHODS: We performed surface plasmon resonance and protein-protein docking to demonstrate the direct LL-37–ApoB-100 interaction. We developed a specific polyclonal antibody against the complex and measured its levels in human atherosclerotic plaques and plasma, as well as in Apoe ^−/− mice. An observational case-control study of 1103 patients undergoing coronary angiography from 2 independent centers assessed the association between LL-37–ApoB-100 and obstructive CAD. RESULTS: We identified that LL-37 directly interacted with multiple distinct binding sites on ApoB-100. Plasma levels of LL-37–ApoB-100 complex were significantly elevated in human patients with atherosclerosis. Consistently, levels of this complex were positively correlated with atherosclerotic plaque area in Apoe ^−/− mice. In the observational cohort from center 1, plasma LL-37–ApoB-100 levels were also significantly elevated in patients with obstructive CAD and strongly correlated with disease severity (Gensini score; r =0.60, P P P <0.001) for the upper quartiles. Observational analyses in center 2 showed consistent results. CONCLUSIONS: Circulating LL-37–ApoB-100 levels are strongly associated with angiographically documented CAD, highlighting LL-37–ApoB-100 as an independent predictor for CAD.

Major depressive disorder (MDD) ranks among the leading causes of disability worldwide. Current treatments often yield suboptimal outcomes, largely due to an incomplete understanding of its underlying pathology. There is, therefore, a pressing need to identify novel core pathological targets. Iron serves as an essential cofactor for several key enzymes in tryptophan (Trp) metabolism, playing a central role in its regulatory pathways. Iron deficiency (ID) can profoundly disrupt Trp metabolic homeostasis in both the peripheral and central nervous systems. This review synthesizes preclinical and clinical evidence to elucidate how ID drives the pathogenesis of MDD through the following interconnected mechanisms: (1) Impairing the activity of tryptophan hydroxylase (TPH), thereby reducing the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin; (2) Skewing the kynurenine pathway (KP) flux toward neurotoxic metabolites via the “dysfunctional activation” of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO); (3) Disrupting gut microbiota-mediated indole metabolism, compromising intestinal barrier integrity, and amplifying neuroinflammatory responses. These metabolic disturbances collectively contribute to a vicious pathological cycle involving neurochemical imbalance, a neurotoxic microenvironment, peripheral-central inflammatory crosstalk, and ferroptosis-mediated neuronal damage, ultimately entrenching the depressive phenotype. Furthermore, this review outlines multidimensional therapeutic strategies targeting the iron-Trp metabolic axis for depression. In conclusion, we propose that the iron-Trp metabolic axis represents a promising cross-diagnostic target for MDD, offering new theoretical insights and practical avenues for its precision treatment.

Venous thromboembolism (VTE) remains a leading contributor to maternal morbidity and mortality during pregnancy and the immediate postpartum period. Although pregnancy is recognized as a hypercoagulable state, the molecular mechanisms underlying this prothrombotic shift remain incompletely characterized. In this study, lactoferrin was identified as an enhancer of coagulation factor XIa (FXIa) activity. Elevated plasma concentrations of lactoferrin were observed in pregnant women and found to be estrogen dependent, mediated through estrogen response elements (EREs) within the lactoferrin gene promoter. In murine models, pregnancy-induced thrombotic pathology was ameliorated by either genetic knockout of lactoferrin or pharmacological blockade using HS9, a peptide that selectively inhibits lactoferrin-mediated potentiation of FXIa. Notably, HS9 (1 mg/kg) exhibited a substantially reduced hemorrhagic profile compared with low-molecular-weight heparin. These findings identify lactoferrin as a physiological modulator of gestational hypercoagulability and implicate it as a potential therapeutic target for pregnancy-associated VTE, with the capacity to reduce thrombotic risk while preserving hemostatic integrity.

Plants have evolved diverse strategies to defend against herbivores, including structural barriers such as trichomes and tough leaves, the production of toxic secondary metabolites, the emission of volatile organic compounds (VOCs), and the recruitment of natural predators to deter herbivory. However, the molecular mechanisms underlying their ability to deter large herbivorous mammals remain poorly understood. In this study, we demonstrate that the order Piperales, which is particularly rich in VOCs, employs a conserved chemical defense strategy targeting herbivorous mammals. Behavioral assays, transgenic models, and electrophysiological analyses revealed that VOCs from Piperales species, particularly Houttuynia cordata , activate TRPA1—a sensory ion channel critical for detecting irritants—in mice and herbivores such as cattle and goats. A stable derivative of the key VOC houttuynin, sodium houttuyfonate (SH), selectively activated TRPA1 by binding conserved cysteine residues, triggering aversion in herbivorous mammals. Crucially, TRPA1 activation sites upon VOC application were conserved across herbivorous species, suggesting that Piperales plants employ a conserved evolutionary strategy to defend against herbivorous mammals. Our findings reveal a compelling case of lineage-specific defensive adaptation within Piperales, providing novel insights into plant-herbivore interactions. This research deepens our understanding of the critical role of chemical defenses in plant survival, adaptation, and ecological niche specialization.