TISSUE & CELL
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2023
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IF 2.6
Jing Cong,Mubai Li,Yu Wang,Hongli Ma,Xinming Yang,Jingshu Gao,Long Wang,Xiaoke Wu
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder affecting women at reproductive age. The therapeutic effect of electroacupuncture (EA) on PCOS has been revealed, while the anti-PCOS mechanisms of EA have not been fully explored. In this study, PCOS were induced in rats by daily injection with dehydroepiandrosterone (DHEA) for 20 days and EA treatment was performed for 5 weeks. The mRNA expression profiles in ovarian tissues from control, PCOS, and EA-treated rats were examined by high-throughput mRNA sequencing. 5'-aminolevulinate synthase 2 (Alas2), a vital rate-limiting enzyme of the heme synthesis pathway, was selected to be further studied. PCOS led to the upregulation of Alas2 mRNA, whereas EA treatment restored this change. In vitro, primary ovarian granulosa cells (GCs) were challenged with H 2 O 2 to mimic the oxidative stress (OS) state in PCOS. H 2 O 2 induced apoptosis, OS, mitochondrial dysfunction, as well as Alas2 overexpression in GCs, while lentivirus-mediated Alas2 knockdown evidently restrained the above impairments. In summary, this study highlights the crucial role of Alas2 in cell apoptosis, OS, and mitochondrial dysfunction of PCOS GCs and provides potential therapeutic candidates for further investigation on PCOS treatment.
研究领域:
生殖医学
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内分泌学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2026
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IF 7.5
Wen-yuan Zhang,Qian-qian Wei,Tao Zhang,Chunmei Geng,Hai-yan Wu,Chang-shui Wang,Jing Chen,Lei Feng,Pei Jiang
Background and Purpose Despite breakthroughs in immunotherapy and targeted therapies, chemotherapy remains indispensable in oncology. Experimental Approach This study seeks to pinpoint key pathways in doxorubicin (DOX)-treated mouse hippocampus, utilising comprehensive transcriptomic and metabolomic analyses, and validating the mechanisms in vitro and in vivo. Key Results Our multi-omics investigation revealed that sustained DOX exposure induced significant down-regulation of 5-aminolevulinate synthase 2 (ALAS2) and its catalytic product 5-aminolevulinic acid (5-ALA) in the hippocampal region. ALAS2 deficiency was specific to hippocampal neurons, which were more sensitive to oxidative damage than astrocytes or microglia. In vivo and in vitro studies demonstrated that 5-ALA administration or ALAS2 overexpression protected the brain from DOX-induced neurotoxicity. ALAS2 catalyses the condensation of glycine and succinyl-CoA to form 5-ALA, the key precursor of haem. Beyond its role in erythropoiesis, haem is a metabolite that modulates cellular redox homeostasis through interactions with the BACH1 (BTB and CNC homology 1)/NRF2 (nuclear factor erythroid 2 like 2) pathway. We found that DOX suppressed the ALAS2/5-ALA axis, thereby enhancing BACH1 stability. This stabilised BACH1 competes with NRF2 for binding to antioxidant response elements (AREs) in target gene promoters. Conversely, reinforcing the ALAS2/5-ALA axis elevated intracellular haem levels, promoting BACH1 degradation and enhancing NRF2 activity. Using a zebrafish model, we further highlighted the antioxidant and neuroprotective role of 5-ALA against DOX-induced neurotoxicity. Conclusions and Implications In conclusion, this study elucidates a novel endogenous neuroprotective mechanism wherein the ALAS2/5-ALA axis modulates the BACH1/NRF2 pathway. 5-ALA shows promise for repurposing to mitigate chemotherapy-associated neurotoxicity. Graphical
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高影响因子
MEDIATORS OF INFLAMMATION
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2026
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IF 4.2
Zenghui Hao,Jinbao Han,Ting Yao,Zheng Zhao,Wei Fan,Zaiqun Jiang,Yunting Wang,Xiaoqian Yang,Zhilin Xu
Neonatal necrotizing enterocolitis (NEC) is an intestinal disease that occurs in the neonatal period. The purpose of this study was to investigate the role of 5′‐aminolevulinate synthase 2 (ALAS2) in NEC‐induced intestinal injury. In a neonatal mouse, NEC model was induced by high‐osmolarity formula and hypoxia‐cold stress, and ALAS2 expression was significantly downregulated in ileal tissues ( p < 0.01), coinciding with elevated oxidative stress (increased Fe 2+ /malondialdehyde [MDA] and decreased superoxide dismutase [SOD]), inflammation (increased TNF‐α/interferon‐gamma [IFN‐γ]), and ferroptosis activation (increased acyl‐CoA synthetase long‐chain family member 4 [ACSL4] and decreased ferritin heavy chain 1 [FTH1] with mitochondrial shrinkage). In vitro, tumor necrosis factor‐alpha (TNF‐α)/IFN‐γ‐treated intestinal epithelial cell (IEC) exhibited progressive ALAS2 suppression and increased necrosis. Crucially, lentivirus‐mediated ALAS2 overexpression reversed these effects, reducing cell necrosis by 22% while suppressing ferroptosis markers (Fe 2+ accumulation, lipid reactive oxygen species [ROS], and mitochondrial depolarization) and oxidative damage (decreased MDA and restored glutathione [GSH]/catalase [CAT]/SOD). Untargeted metabolomics further revealed ALAS2‐mediated modulation of nutrient metabolism and redox pathways. Collectively, ALAS2 ameliorates NEC by blocking oxidative stress‐driven ferroptosis in IECs, proposing a novel therapeutic target.
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高影响因子
DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY
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2025
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IF 2.4
Wei-Wei Fang,Yi-Xin Wu,Yi-Bin Cao,Xin-Jiang Lu,Jian-Rao Hu
Hypoxia compromises host defense in fish by impairing macrophage function, but the underlying mechanisms remain unclear. This study elucidates the molecular mechanisms by which hypoxia disrupts monocytes/macrophages (MO/MФ) function in Japanese sea bass ( Lateolabrax japonicus ), with a particular focus on the regulatory role of heme biosynthesis and its key gene, 5'-aminolevulinate synthase 2 ( ALAS2 ). Phylogenetic analysis confirmed high evolutionary conservation of ALAS2 across vertebrates, supporting its fundamental role in heme metabolism. Transcriptomic analysis revealed that hypoxia induced the upregulation of genes involved in heme biosynthesis of MO/MФ, particularly ALAS2 . Functional assays demonstrated that heme accumulation under hypoxic conditions impaired MO/MФ phagocytic and bactericidal activities, while also promoted the production of pro-inflammatory cytokines. These dysfunctions were mediated by the ALAS2 -heme signaling axis, which orchestrated inflammatory responses and metabolic reprogramming throughout the study. Knockdown of ALAS2 enhanced phagocytic activity and suppressed pro-inflammatory cytokine expression, suggesting its critical role in modulating MO/MФ function under hypoxia. Furthermore, inhibition of heme synthesis improved fish survival rates and reduced bacterial burdens during Vibrio harveyi infection. These findings elucidate the pivotal role of heme in regulating MO/MФ function and host defense under hypoxic conditions, providing mechanistic insights into hypoxia-induced immune suppression in aquaculture.
研究领域:
水产养殖
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鱼类免疫学
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分子免疫学
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血液学
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微生物感染
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PubMed
高影响因子
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