Life sciences最新文献

Aims: Depression is a prevalent mood disorder characterized by persistent low mood and cognitive deficits that severely impaired quality of life. Despite intensive research, its precise pathogenesis remained elusive, and a considerable proportion of patients were refractory to existing therapies. Recent work has highlighted ventral tegmental area (VTA) dopaminergic (DAergic) neurons in the pathophysiology of depression because of their central role in reward processing and motivation. In this study, we provided direct evidence that VTA^DA neurons were implicated in the alterations evoked by 21-day chronic restraint stress (CRS) in mice.

Materials and methods: Employing in vivo fiber photometry, chemogenetics, behavioral tests, and immunofluorescence, we investigated the effect of VTA^DA neurons of regulation on depressive behavior of the CRS mice.

Key findings: The activity of VTA^DA neurons was markedly decreased in CRS exposed animals. Chemogenetic activation of these neurons alleviated depression like symptoms, whereas their inhibition induced depression like phenotypes in the absence of stress. Electroacupuncture (EA) has garnered substantial clinical attention for mood disorders because of its established safety, minimal adverse effects, and robust therapeutic efficacy. Here, EA at specific acupoints reversed CRS induced behavioral deficits and restored VTA^DA neuron activity. However, chemogenetic inhibition of VTA^DA neurons during EA abolished its antidepressant effects.

Significance: Collectively, our findings provided mechanistic insight into the contribution of VTA^DA neurons to CRS induced depression.

Aims: Ferroptosis, the cell death induced by iron accumulation, contributes to the pathogenesis of Parkinson's disease (PD). While transient receptor potential vanilloid 2 (TRPV2) is known to mediate pathological processes in neurodegenerative diseases, its specific role in ferroptosis in PD remains largely unknown. This study aims to investigate the underlying mechanisms of TRPV2 in PD.

Materials and methods: An MPTP-induced mouse model of PD and MPP⁺-induced SH-SY5Y cellular model were established. To investigate the role and mechanism of TRPV2 in PD, AAV2/9 TRPV2 was injected into the substantia nigra (SN) of mice. In parallel, SH-SY5Y cells were transfected with si-TRPV2, pc-TRPV2, TRPV2-S339A, or pc-PTEN-induced putative kinase 1 (PINK1) plasmids, or treated with ferroptosis inhibitor ferrostatin-1.

Key findings: Our results demonstrated that TRPV2 expression was dramatically decreased in PD, particularly in dopaminergic neurons. Notably, overexpression of TRPV2 obviously improved neurological impairment and ferroptosis, whereas TRPV2 knockdown strongly exacerbated these effects. Interestingly, ferrostatin-1 reversed the detrimental effect of TRPV2 knockdown in PD in vitro. Furthermore, bioinformatics analysis and our experimental results indicate that TRPV2 is phosphorylated by PINK1 at serine 339. Additionally, the protective roles of PINK1 overexpression in inhibiting ferroptosis were abolished by TRPV2 interference or TRPV2-S339A.

Significance: These findings implicate a neuroprotective role for TRPV2 in PD, potentially through a mechanism involving its regulation of ferroptosis via phosphorylation by PINK1.

Aims: Recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder in which immune dysregulation has been increasingly implicated. This study aimed to elucidate how interferon-γ (IFN-γ) signaling affects trophoblast function and metabolism and to explore the underlying immunometabolic mechanisms contributing to RPL pathogenesis.

Materials and methods: Human trophoblast cells were treated with IFN-γ to assess proliferation, apoptosis, migration, and invasion. Metabolic alterations were analyzed using Seahorse extracellular flux assays, glucose uptake measurements, and metabolomic profiling. Molecular mechanisms were investigated by examining IDO1 expression, kynurenine production, aryl hydrocarbon receptor (AHR) activation, and hypoxia-inducible factor-1α (HIF-1α) signaling. IDO1 expression was further evaluated in chorionic villi from RPL patients and healthy controls.

Key findings: IFN-γ selectively suppressed trophoblast migration and invasion without affecting proliferation or apoptosis. IFN-γ markedly upregulated IDO1, leading to increased kynurenine accumulation and activation of AHR signaling through nuclear translocation and ARNT dimerization, thereby shifting trophoblasts toward an epithelial-like phenotype. Concurrently, IFN-γ stabilized HIF-1α and enhanced glycolytic flux, glucose uptake, and lactate secretion, accompanied by reduced tricarboxylic acid cycle intermediates. Pharmacological inhibition of glycolysis with 2-DG attenuated IFN-γ-induced IDO1 expression in a dose-dependent manner. Aberrant IDO1 expression was also observed in chorionic villi from RPL patients.

Significance: These findings demonstrate that IFN-γ signaling impairs trophoblast invasion through coordinated activation of the IDO1/kynurenine/AHR axis and metabolic reprogramming, revealing an immunometabolic mechanism that may contribute to the pathogenesis of recurrent pregnancy loss.

Cold-induced injuries, such as hypothermia and frostbite, pose significant health risks and have limited therapeutic options. Drug repurposing using integrated bioinformatics approaches offers an effective strategy for identifying potential agents. In this study, we aimed to identify thermogenic compounds through drug repurposing and validate their efficacy in a cold-exposure animal model. Gene expression signatures from brown and inguinal white adipose tissues from cold-exposed mice (5 °C, 7 days) were obtained from transcriptomic profiles and compared with drug-induced gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database. The top-ranked compounds predicted from cold exposure-associated transcriptomic signatures were administered to cold-exposed C57BL/6J mice. Core body temperature, lipid metabolism, and thermogenic markers were measured, and the role of PPARγ was evaluated using siRNA transfection and the antagonist T0070907 in adipocytes. LINCS screening identified five candidates with significant signature alteration, including Fmoc-l-leucine, which significantly improved cold tolerance in the cold-exposure model. Fmoc-l-leucine maintained core body temperature, reduced lipid accumulation in adipose tissue, and upregulated the expression of thermogenic genes. In addition, it promoted white adipose tissue browning (increased Ucp1, Cidea, and Dio2 expression) and mitochondrial biogenesis. PPARγ inhibition suppressed these effects, confirming its role in the efficacy of Fmoc-l-leucine. No hepato- or nephrotoxicity was observed at pharmacological doses. These findings demonstrate that drug repurposing is an effective approach for identifying agents that confer cold protection and highlight the clinical potential of Fmoc-l-leucine.

In clinics, glucocorticoids (GC) are frequently recommended as immunosuppressive and anti-inflammatory medications. The side effects of GC are the main concerns, which mostly include insulin resistance (IR), vascular changes, and fatty liver. Knowing the mechanism underlying GC-induced hepatic steatosis and vascular alterations helps identify a target to prevent these side effects.

Aim: The target of this investigation was to assess the beneficial influences of pirfenidone (PFD) versus dexamethasone (DEX)-induced steatohepatitis and vascular resistance.

Main methods: Rats were classified haphazardly into five categories: control group, PFD control group, DEX group and two groups received PFD for 14 days (50 and 100 mg/kg) by oral route and injected with DEX (1 mg/kg) over the second week of the study.

Key findings: PFD reverted morphological alterations, mitigate oxidative dysfunctions, elevated lipid profile and normalize liver transaminases. PFD also attenuated inflammatory markers, PFD also downregulated aortic NF-κB, JNK, ET-1, VCAM and VEGF that were dysregulated by DEX. Moreover, hepatic and aortic IRS1, AKT, P-AKT (ser⁴⁷³) level, aortic eNOS and CD34 levels were elevated upon PFD treatment. Furthermore, PFD pretreatment decreased hepatic and aortic levels of autophagy biomarkers.

Conclusion: PFD may provide hepato- and vasculo-protective effects via its insulin-sensitization, hypoglycemic, hypolipidemic, antioxidant and anti-inflammatory activities.

Ferroptosis is a novel form of regulated cell death characterized by iron-dependent lipid peroxidation，which is mediated by multi-pathway cascades involving dysregulated iron metabolism, polyunsaturated fatty acids (PUFAs) oxidation, and impaired antioxidant defense systems. This form of cell death is closely implicated in the pathophysiology of various human diseases, including cancer, neurological disorders, ischemia-reperfusion injury, renal damage, and hematological diseases. Recent studies have expanded the understanding of ferroptosis to plants, where it plays pivotal roles in responding to biotic/abiotic stresses, activating defense signaling networks, and maintaining metabolic homeostasis. These findings provide new insights into how plants adapt to adverse environments and resist pathogens. Furthermore, diverse bioactive compounds derived from plants can modulate core mechanisms of ferroptosis, demonstrating potential for antitumor therapy and other diseases. Furthermore, plant-derived bioactive compounds exhibit broad pharmacological properties and can modulate the core mechanisms of ferroptosis, thereby showing great potential in the treatment of ferroptosis-related diseases such as tumors, autoimmune disorders, and neurodegenerative diseases. This review comprehensively elaborates on the primary regulatory mechanisms of ferroptosis, systematically analyzes iron-dependent cell death in plants, and explores the crosstalk between plant ferroptosis and stress adaptation. It also focuses on the regulatory effects of plant bioactive compounds on ferroptosis and their therapeutic potential, aiming to provide innovative strategies for crop protection in agricultural production and novel approaches for combating human diseases associated with ferroptosis.

Aim: This study aimed to repurpose FDA-approved drugs for the treatment of mitochondrial complex I diseases.

Materials and methods: The NUO-51 protein of the filamentous fungus Podospora anserina is the homolog of the human key catalytic subunit of complex I, NDUFV1. By introducing a pathogenic mutation into P. anserina NUO-51 we created a novel model of complex I deficiency targeting the NDUFV1 subunit. The thermosensitive phenotype of the fungal mutant enabled us to screen a library of nearly one thousand FDA-approved molecules. We have implemented various techniques such as growth analysis, oxygen consumption measurements, complex I activity assays and western blotting on Podospora, Caenorhabditis elegans and human on equivalent NDUFV1 mutant models, treated or untreated with the most effective drugs found during the screen.

Key findings: We isolated a series of compounds able to rescue the growth defect of the Podospora nuo-51 mutant, including ligands of serotonin receptors or transporters. Among the selected drugs, alverine citrate (ALV) and dapoxetine hydrochloride (DAP) emerged as the most active drugs. Both drugs enhanced respiration and complex I activity, not only in the Podospora mutant, but also in Caenorhabditis elegans worms deficient for the NDUFV1 ortholog and in fibroblasts from patient carrying NDUFV1 mutations.

Significance: Together, our work demonstrates the usefulness of Podospora anserina as fungal model for identifying promising therapeutic candidates for complex I diseases, paving the way for future clinical trials.

Background: Dysregulation of the wound remodeling phase can lead to excessive scar formation, which may cause functional impairment and aesthetic distress. However, effective strategies to improve tissue repair outcomes remain limited. Stanniocalcin-1 (STC-1), a secreted glycoprotein, has recently attracted attention for its roles in tissue repair and inflammation, yet its involvement in skin scar remodeling remains unknown.

Methods: A combination of clinical sample analysis, in vitro experiments using NIH-3T3 fibroblasts and macrophage co-culture models, RNA sequencing, and an in vivo murine full-thickness wound model was employed. The effects of recombinant STC-1 protein and STC-1 overexpression were evaluated on fibroblast function, extracellular matrix (ECM) remodeling, inflammatory response, and scar remodeling.

Results: STC-1 was highly expressed in keloid tissues, primarily in fibroblasts, and its expression was elevated under hypoxic conditions in a HIF-1α-associated manner. In vitro, STC-1 suppressed fibroblast proliferation, migration, and LPS-induced inflammation, while alleviating oxidative stress and mitochondrial dysfunction. STC-1 promoted angiogenesis and M2-like macrophage polarization. In vivo, STC-1 treatment reduced scar size, improved collagen organization, and modulated immune cell infiltration, accompanied by enhanced PI3K/AKT signaling.

Conclusions: During scar formation, STC-1 modulates fibroblast activity, immune responses, angiogenesis, and ECM remodeling through coordinated regulation of multiple signaling pathways. Collectively, these effects may contribute to STC-1's ability to improve the quality of tissue repair and scar remodeling in vivo. The PI3K/AKT pathway represents one downstream pathway associated with STC-1 activity. However, its efficacy in treating established pathological scars, including keloids, remains to be validated in future studies using more clinically relevant models.

Background: SGLT2 inhibitor dapagliflozin (Dapa) has gained increasing attention in the treatment of myocardial ischemia-reperfusion injury (IRI). However, the mechanism of action of the cardiovascular benefits of Dapa is unclear. The present study aimed to investigate the effects of Dapa on myocardial IRI and the underlying molecular mechanisms.

Methods: The effects of Dapa on myocardial IRI were investigated using the in vitro perfusion Langendorf model and the in vitro hypoxia/reoxygenation (H/R) cell model. Histological changes, myocardial enzymes, oxidative stress and mitochondrial structure/function were assessed. Mechanistic studies involved various molecular biology methods such as ELISA, immunoprecipitation, western blot, immunofluorescence and Bioinformatics.

Results: Our findings demonstrate that Dapa upregulates EGFR phosphorylation, suppresses NHE1 expression in myocardial tissues, modulates NCOA4-mediated ferritinophagy to enhance mitochondrial function, reduces ROS expression, and mitigates myocardial IRI. In the Langendorf model, Dapa effectively attenuates cardiac dysfunction, myocardial injury, mitochondrial damage, and oxidative imbalance induced by ischemia-reperfusion. In vitro experiments revealed that blocking EGFR or autophagy with inhibitors (AG and Baf, respectively) or inducing ferroptosis with Era promotes ROS release, exacerbates mitochondrial injury, and diminishes the protective effects of Dapa. Notably, Era did not affect NCOA4-mediated ferritinophagy. Conversely, the EGFR agonist NSC counteracted these effects, underscoring that Dapa confers cardioprotection by modulating mitochondrial function through EGFR-mediated regulation of NCOA4-mediated ferritinophagy.

Conclusion: In summary, Dapa activates EGFR phosphorylation, regulates NCOA4-mediated ferritinophagy, modulates mitochondrial function, and effectively mitigates myocardial IRI. These findings provide a robust theoretical foundation for the clinical application of Dapa in treating cardiovascular conditions.