Malignant tumors represent a major threat to global health. Conventional anti-tumor pharmacotherapy often encounters challenges such as drug resistance, highlighting an urgent need for the development of novel therapeutic strategies. Fatty acid synthase (FASN), the key enzyme catalyzing de novo fatty acid synthesis, is subject to precise regulation at multiple levels, including transcriptional control, various post-translational modifications such as ubiquitination and phosphorylation, as well as modulation by diverse signaling pathways. Recent studies have revealed that FASN is aberrantly overexpressed in various malignant tumors and is closely associated with tumor progression and poor patient prognosis. FASN is a homodimer composed of seven functional domains that catalyzes the NADPH-dependent condensation of acetyl-CoA and malonyl-CoA to generate saturated fatty acids, primarily palmitic acid. Its stability is regulated by multiple ubiquitin ligases and deubiquitinating enzymes. Additionally, FASN is subject to upstream regulation via neural precursor cell-expressed developmentally downregulated 8 (Nedd8) modification and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, thereby establishing a metabolic-signaling positive feedback loop. As a core executor of metabolic reprogramming, FASN promotes tumorigenesis through dual mechanisms. First, its fatty acid synthesis product, palmitate, participates in membrane phospholipid synthesis, lipid raft formation, and protein palmitoylation, thereby activating several key oncogenic signaling pathways, including PI3K/AKT/mTOR, wingless-type MMTV integration site family member (Wnt)/β‑catenin, and signal transducer and activator of transcription 3 (STAT3)/matrix metalloproteinase (MMP), leading to tumor development and progression. Second, FASN plays a pivotal role in modulating the anti-tumor functions of immune cells and remodeling the tumor immune microenvironment. Specifically, FASN enhances immune checkpoint inhibition by inducing programmed death-ligand 1 (PD-L1) palmitoylation, suppresses the activation of cytotoxic T lymphocytes and natural killer cells, and promotes the polarization of M2-type macrophages, consequently facilitating tumor immune evasion and malignant progression. Precisely due to its significant overexpression in tumor cells, its critical functional role, and its differential expression compared to normal cells, FASN has emerged as a highly promising target for anti-tumor drug development. Highly selective small-molecule inhibitors, notably represented by TVB-2640, have advanced to clinical trial stages and demonstrated favorable anti-tumor activity. Furthermore, the combination of FASN inhibitors with other chemotherapeutic agents or targeted drugs can overcome the limitations of monotherapy through synergistic effects or by resensitizing tumor cells to conventional drugs, achieving a “1+1>2” therapeutic outcome. With the advancement of modern traditional Chinese medicine (TCM), numerous active ingredients derived from TCM have been confirmed to exert anti-tumor effects by modulating FASN-related pathways. This integrated approach leverages the precision of Western medicine while simultaneously harnessing the holistic regulatory benefits of TCM to alleviate the side effects of radiotherapy and chemotherapy. Despite the promising prospects of FASN-targeted therapies, challenges remain, including tumor cell metabolic plasticity, tumor context-dependent responses, and heterogeneity. This review systematically summarizes the molecular structure, physiological functions, and mechanisms of FASN in tumorigenesis, as well as recent advances in targeted therapies. Future directions—including the precise identification of responsive patient populations using spatial transcriptomics, the development of novel combination regimens, and the active exploration of integrative strategies combining traditional Chinese and Western medicine—will facilitate the clinical translation of FASN-targeted therapies and open new avenues for improving the quality of life and prognosis of cancer patients.

Objective Magnetoreception, the remarkable ability of diverse animals to sense and utilize the geomagnetic field for orientation and navigation, remains a molecularly unresolved mystery in sensory biology. The putative magnetoreceptor (MagR, previously known as IscA1) is a highly conserved iron-sulfur protein implicated in both magnetoreception and iron metabolism; however, the functional diversity among its cross-species homologs remains poorly understood. Cellular morphology is a key genetically determined trait that can be altered through genetic or environmental modifications—a process known as cell morphology engineering. Constructing engineered cells with specific morphological features and magnetic sensitivity to achieve remote, non-invasive magnetic modulation represents a crucial goal in this field with significant application potential. Therefore, this study aims to systematically investigate the effects of MagR heterologous expression on bacterial morphology and magnetic sensing capabilities, screen for MagR-based magnetically sensitive morphology engineering pathways, and reveal the underlying molecular mechanisms. Methods We systematically screened 28 MagR homologous genes from diverse prokaryotic and animal taxa to evaluate their expression and corresponding phenotypic effects in Escherichia coli (E. coli). To compare the differential magnetic responses among bacteria expressing various recombinant MagR proteins, we utilized high-throughput automated bright-field microscopic imaging and scanning electron microscopy (SEM). Furthermore, comprehensive biochemical and biophysical characterizations of iron and iron-sulfur cluster binding were performed using Ferrozine colorimetric assays, electron paramagnetic resonance (EPR) spectroscopy, ultraviolet-visible (UV-Vis) absorption, and circular dichroism (CD) spectroscopy. Additionally, 100 mT static magnetic field (SMF) exposure experiments were conducted to assess magnetically tunable phenotypes, while the intrinsic magnetic properties of purified MagR proteins were directly measured using a superconducting quantum interference device (SQUID) magnetometer. Results Our results demonstrated that the heterologous expression of MagR homologs induced varying degrees of bacterial filamentation. From this comprehensive screen, two distinct morphological patterns were identified: hydra (Hydra vulgaris) MagR (hyMagR) promoted uniform cell elongation and filamentation, exhibiting robust magnetic sensitivity manifested as significantly enhanced filamentation under the 100 mT SMF. In contrast, pigeon (Columba livia) MagR (clMagR) induced only low-frequency, extreme filamentation (sporadically exceeding 80 μm) with a relatively weaker magnetic morphological response. Mechanistically, our data unambiguously proved that these phenotypic differences are primarily driven by distinct iron redox preferences rather than total cellular iron accumulation. Specifically, hyMagR preferentially binds ferrous iron (Fe²⁺), whereas clMagR favors ferric iron (Fe³⁺) and forms more stable iron-sulfur clusters. Intriguingly, although SQUID magnetometry showed that purified clMagR exhibited approximately five-fold higher mass magnetic susceptibility than hyMagR, its cellular magnetic response was weaker. We hypothesize that the Fe²⁺-preferred intracellular environment associated with hyMagR overexpression primes the cell for enhanced generation of reactive oxygen species (ROS) via the Fenton reaction. Exposure to an SMF synergizes with this primed redox state, triggering the bacterial SOS response and upregulating cell division inhibitors to efficiently induce uniform filamentation. Conclusion Our findings identify the Fe²⁺/Fe³⁺ redox state as a critical determinant of MagR-mediated morphological remodeling and magnetic responsiveness. This discovery suggests a potential strategy for engineering magnetically responsive cellular systems for synthetic biology applications, and provides a plausible framework, which potentially combines intrinsic protein magnetism with redox-state modulation, for further investigating the evolutionary mechanisms of MagR-mediated magnetoreception.

Objective Magnetoreception, the remarkable ability of diverse animals to sense and utilize the geomagnetic field for orientation and navigation, remains a molecularly unresolved mystery in sensory biology. The putative magnetoreceptor (MagR, previously known as IscA1) is a highly conserved iron-sulfur protein implicated in both magnetoreception and iron metabolism; however, the functional diversity among its cross-species homologs remains poorly understood. Cellular morphology is a key genetically determined trait that can be altered through genetic or environmental modifications—a process known as cell morphology engineering. Constructing engineered cells with specific morphological features and magnetic sensitivity to achieve remote, non-invasive magnetic modulation represents a crucial goal in this field with significant application potential. Therefore, this study aims to systematically investigate the effects of MagR heterologous expression on bacterial morphology and magnetic sensing capabilities, screen for MagR-based magnetically sensitive morphology engineering pathways, and reveal the underlying molecular mechanisms. Methods We systematically screened 28 MagR homologous genes from diverse prokaryotic and animal taxa to evaluate their expression and corresponding phenotypic effects in Escherichia coli (E. coli). To compare the differential magnetic responses among bacteria expressing various recombinant MagR proteins, we utilized high-throughput automated bright-field microscopic imaging and scanning electron microscopy (SEM). Furthermore, comprehensive biochemical and biophysical characterizations of iron and iron-sulfur cluster binding were performed using Ferrozine colorimetric assays, electron paramagnetic resonance (EPR) spectroscopy, ultraviolet-visible (UV-Vis) absorption, and circular dichroism (CD) spectroscopy. Additionally, 100 mT static magnetic field (SMF) exposure experiments were conducted to assess magnetically tunable phenotypes, while the intrinsic magnetic properties of purified MagR proteins were directly measured using a superconducting quantum interference device (SQUID) magnetometer. Results Our results demonstrated that the heterologous expression of MagR homologs induced varying degrees of bacterial filamentation. From this comprehensive screen, two distinct morphological patterns were identified: hydra (Hydra vulgaris) MagR (hyMagR) promoted uniform cell elongation and filamentation, exhibiting robust magnetic sensitivity manifested as significantly enhanced filamentation under the 100 mT SMF. In contrast, pigeon (Columba livia) MagR (clMagR) induced only low-frequency, extreme filamentation (sporadically exceeding 80 μm) with a relatively weaker magnetic morphological response. Mechanistically, our data unambiguously proved that these phenotypic differences are primarily driven by distinct iron redox preferences rather than total cellular iron accumulation. Specifically, hyMagR preferentially binds ferrous iron (Fe²⁺), whereas clMagR favors ferric iron (Fe³⁺) and forms more stable iron-sulfur clusters. Intriguingly, although SQUID magnetometry showed that purified clMagR exhibited approximately five-fold higher mass magnetic susceptibility than hyMagR, its cellular magnetic response was weaker. We hypothesize that the Fe²⁺-preferred intracellular environment associated with hyMagR overexpression primes the cell for enhanced generation of reactive oxygen species (ROS) via the Fenton reaction. Exposure to an SMF synergizes with this primed redox state, triggering the bacterial SOS response and upregulating cell division inhibitors to efficiently induce uniform filamentation. Conclusion Our findings identify the Fe²⁺/Fe³⁺ redox state as a critical determinant of MagR-mediated morphological remodeling and magnetic responsiveness. This discovery suggests a potential strategy for engineering magnetically responsive cellular systems for synthetic biology applications, and provides a plausible framework, which potentially combines intrinsic protein magnetism with redox-state modulation, for further investigating the evolutionary mechanisms of MagR-mediated magnetoreception.

Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC₅₀ = 0.049 μmol/L, huBuChE IC₅₀ = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.

The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K⁺ channels, or Ca²⁺-activated K⁺ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
Animals ; Histamine/metabolism* ; Male ; Oxidopamine/toxicity* ; Rats ; Ventral Thalamic Nuclei/physiopathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Parkinson Disease/metabolism* ; Neurons/physiology* ; Humans ; Optogenetics

OBJECTIVE: To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A (SV2A) influences the distribution of amyloid precursor protein (APP) in the trans-Golgi network (TGN), endolysosomal system, and cell membranes and to reveal the effects of SV2A on APP amyloid degradation. METHODS: Colocalization analysis of APP with specific tagged proteins in the TGN, ensolysosomal system, and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP. APP, β-site amyloid precursor protein cleaving enzyme 1 (BACE1) expressions, and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing. RESULTS: APP localization was reduced in the TGN, early endosomes, late endosomes, and lysosomes, whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons. Moreover, Arl5b (ADP-ribosylation factor 5b), a protein responsible for transporting APP from the TGN to early endosomes, was upregulated by SV2A. SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis. In addition, products of APP amyloid degradation, including sAPPβ, Aβ _1-42, and Aβ _1-40, were decreased in SV2A-overexpressed cells. CONCLUSION These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway, which slows APP amyloid degradation.
Amyloid beta-Protein Precursor/genetics* ; Membrane Glycoproteins/genetics* ; Animals ; Protein Transport ; Nerve Tissue Proteins/genetics* ; Humans ; Mice ; Endosomes/metabolism* ; trans-Golgi Network/metabolism*

OBJECTIVE: We aimed to investigate the patterns of fasting blood glucose (FBG) trajectories and analyze the relationship between various occupational hazard factors and FBG trajectories in male steelworkers. METHODS: The study cohort included 3,728 workers who met the selection criteria for the Tanggang Occupational Cohort (TGOC) between 2017 and 2022. A group-based trajectory model was used to identify the FBG trajectories. Environmental risk scores (ERS) were constructed using regression coefficients from the occupational hazard model as weights. Univariate and multivariate logistic regression analyses were performed to explore the effects of occupational hazard factors using the ERS on FBG trajectories. RESULTS: FBG trajectories were categorized into three groups. An association was observed between high temperature, noise exposure, and FBG trajectory ( P < 0.05). Using the first quartile group of ERS1 as a reference, the fourth quartile group of ERS1 had an increased risk of medium and high FBG by 1.90 and 2.21 times, respectively (odds ratio [ OR] = 1.90, 95% confidence interval [ CI]: 1.17-3.10; OR = 2.21, 95% CI: 1.09-4.45). CONCLUSION An association was observed between occupational hazards based on ERS and FBG trajectories. The risk of FBG trajectory levels increase with an increase in ERS.
Humans ; Male ; Adult ; Blood Glucose/analysis* ; China ; Prospective Studies ; Occupational Exposure/adverse effects* ; Risk Factors ; Middle Aged ; Steel ; Fasting/blood* ; Metal Workers ; East Asian People

Objective To analyze the risk factors for prolonged length of hospital stay in patients with peritoneal dialysis associated peritonitis(PDAP)and construct a nomogram based on Logistic regression model.Methods A retrospective study was conducted on patients with PDAP who were hospitalized at the Affiliated Hospital of Jiangsu University from January 2013 to December 2023.Using the 75th percentile of hospitalization time as the cutoff(>21 days),the patients were divided into prolonged length of hospital stay group and normal length of hospital stay group.Clinical data were compared between the two groups.Logistic regression analysis was used to analyze the risk factors for prolonged hospital stay in PDAP patients and to construct a nomogram.Results A total of 131 PDAP patients were included in this study,including 40 cases in prolonged length of hospital stay group and 91 cases in normal length of hospital stay group.Multivariate Logistic regression analysis showed that Gram-negative bacteria detected in ascites(OR=6.012,95% CI=1.878-19.248,P=0.003)and elevated platelet count(OR=1.010,95% CI=1.005-1.015,P<0.001)were independent risk factors for prolonged length of hospital stay,while elevated serum chloride(OR=0.885,95% CI=0.802-0.978,P=0.016)was a protective factor.Based on the above three indicators,a nomogram was constructed.The multivariate Logistic regression model showed an area under the receiver operating characteristic curve(AUC)of 0.755,with an internal validation AUC of 0.727 using the Bootstrap method.The calibration curve indicated that the predicted probability was consistent with the actual probability.The decision curve showed that the model was clinically applicable when the threshold probabilities were 9%-10%,13% and 18%-92%.Conclusion A nomogram,based on the detection of gram-negative bacteria in ascites,platelet count and serum chloride,was helpful for clinical screening PADP patients at risk for prolonged length of hospital stay,and can provide a basis for optimizing clinical decision-making.
Humans ; Nomograms ; Risk Factors ; Peritoneal Dialysis/adverse effects* ; Retrospective Studies ; Length of Stay ; Peritonitis/etiology* ; Logistic Models ; Male ; Female ; Middle Aged ; Aged

Objective To evaluate the value of gastric contrast-enhanced ultrasound in diagnosing extraluminal duodenal diverticulum. Methods A retrospective analysis was conducted on 40 cases of extraluminal duodenal diverticula confirmed by upper gastrointestinal barium meal and gastroduodenoscopy,all of whom underwent gastric contrast-enhanced ultrasound examination.The detection rate and imaging features of duodenal diverticula were retrospectively analyzed. Results Gastric contrast-enhanced ultrasound detected 34 out of 40 cases of extraluminal duodenal diverticula,with the detection rate (85.0%) higher than that (10.0%,4/40) of conventional fasting ultrasound (P<0.001).Gastric contrast-enhanced ultrasound demonstrated higher detection rate for single diverticula than for multiple diverticula (97.1% vs.44.4%,P<0.001) and was particularly effective for duodenal diverticula in the descending segment (91.7%).According to imaging features,duodenal diverticula were classified into sac-like,gas-containing mass,and air-line types. Conclusion Gastric contrast-enhanced ultrasound facilitates the detection of extraluminal duodenal diverticula in the descending segment,allows concurrent visualization of biliary-pancreatic system pathologies,and enables comprehensive assessment of the association between duodenal diverticula and biliary-pancreatic diseases,demonstrating significant clinical value.
Humans ; Diverticulum/diagnostic imaging* ; Male ; Retrospective Studies ; Duodenal Diseases/diagnostic imaging* ; Ultrasonography ; Female ; Middle Aged ; Contrast Media ; Aged ; Adult ; Young Adult