Mechanistic Investigations Research Articles

Genetically determined gut microbiota associates with pulmonary arterial hypertension: a Mendelian randomization study

BackgroundEmerging evidences have demonstrated that gut microbiota composition is associated with pulmonary arterial hypertension (PAH). However, the underlying causality between intestinal dysbiosis and PAH remains unresolved.MethodAn analysis using the two-sample Mendelian randomization (MR) approach was conducted to examine the potential causal relationship between gut microbiota and PAH. To assess exposure data, genetic variants associated with 196 bacterial traits were extracted from the MiBioGen consortium, which included a sample size of 18,340 individuals. As for the outcomes, summary statistics for PAH were obtained from the NHGRI-EBI GWAS Catalog, which conducted a meta-analysis of four independent studies comprising a total of 11,744 samples. Causal effects were estimated employing various methods, including inverse variance weighted (IVW), MR-Egger, weighted median, weight mode and simple mode, with sensitivity analyses also being implemented with Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots.ResultsFollowing false discovery rate (FDR) correction, the genetically predicted genus Eubacterium fissicatena group (odds ratio (OR) 1.471, 95% confidence interval (CI) 1.178–1.837, q = 0.076) exhibited a causal association with PAH. In addition, the genus LachnospiraceaeUCG004 (OR 1.511, 95% CI 1.048–2.177) and genus RuminococcaceaeUCG002 (OR 1.407, 95% CI 1.040–1.905) showed a suggestive increased risk of PAH, while genus Eubacterium eligens group (OR 0.563, 95% CI 0.344–0.922), genus Phascolarctobacterium (OR 0.692, 95% CI 0.487–0.982), genus Erysipelatoclostridium (OR 0.757, 95% CI 0.579–0.989) and genus T–yzzerella3 (OR 0.768, 95% CI 0.624–0.945) were found to have nominal protective effect against PAH.ConclusionThe findings from our MR study have revealed a potential causal relationship between gut microbiota and PAH. Specifically, we have identified four types of gut microbiota that exhibit a protective effect on PAH, as well as three types that have a detrimental impact on PAH, thereby offering valuable insights for future mechanistic and clinical investigations in the field of PAH.

Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome.

High-impact genetic variants associated with neurodevelopmental disorders provide biologically-defined entry points for mechanistic investigation. The 3q29 deletion (3q29Del) is one such variant, conferring a 40-100-fold increased risk for schizophrenia, as well as high risk for autism and intellectual disability. However, the mechanisms leading to neurodevelopmental disability remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in individuals with 3q29Del (N = 24) and neurotypical controls (N = 1608) using structural MRI. Given prior radiology reports of posterior fossa abnormalities in 3q29Del, we focused our investigation on the cerebellum and its tissue-types and lobules. Additionally, we compared the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del and controls and examined the association between neuroanatomical findings and quantitative traits to probe gene-brain-behavior relationships. 3q29Del participants had smaller cerebellar cortex volumes than controls, before and after correction for intracranial volume (ICV). An anterior-posterior gradient emerged in finer grained lobule-based and voxel-wise analyses. 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction and displayed elevated rates of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Cerebellar white matter and subregional gray matter volumes were associated with visual-perception and visual-motor integration skills as well as IQ, while cystic/cyst-like malformations yielded no behavioral link. In summary, we find that abnormal development of cerebellar structures may represent neuroimaging-based biomarkers of cognitive and sensorimotor function in 3q29Del, adding to the growing evidence identifying cerebellar pathology as an intersection point between syndromic and idiopathic forms of neurodevelopmental disabilities.

Synergistic Influence of Fibrous Pattern Orientation and Modulus on Cellular Mechanoresponse.

The fibrous extracellular matrix (ECM) is vital for tissue regeneration and impacts implanted device treatments. Previous research on fibrous biomaterials shows varying cellular reactions to surface orientation, often due to unclear interactions between surface topography and substrate elasticity. Our study addresses this gap by achieving the rapid creation of hydrogels with diverse fibrous topographies and varying substrate moduli through a surface printing strategy. Cells exhibit heightened traction force on nanopatterned soft hydrogels, particularly with randomly distributed patterns compared with regular soft hydrogels. Meanwhile, on stiff hydrogels featuring an aligned topography, optimal cellular mechanosensing is observed compared to random topography. Mechanistic investigations highlight that cellular force-sensing and adhesion are influenced by the interplay of pattern deformability and focal adhesion orientation, subsequently mediating stem cell differentiation. Our findings highlight the importance of combining substrate modulus and topography to guide cellular behavior in designing advanced tissue engineering biomaterials.

Stereodivergent Synthesis of 1,4-Dicarbonyl Compounds through Sulfonium Rearrangement: Mechanistic Investigation, Stereocontrolled Access to γ-Lactones and γ-Lactams, and Total Synthesis of Paraconic Acids.

Although simple γ-lactones and γ-lactams have received considerable attention from the synthetic community, particularly due to their relevance in biological and medicinal contexts, stereoselective synthetic approaches to more densely substituted derivatives remain scarce. The in-depth study presented herein, showcasing a straightforward method for the stereocontrolled synthesis of γ-lactones and γ-lactams, builds on and considerably expands the stereodivergent synthesis of 1,4-dicarbonyl compounds by a ynamide/vinyl sulfoxide coupling. A full mechanistic and computational study of the rearrangement was conducted, uncovering the role of all of the reaction components and providing a rationale for stereoselection. The broad applicability of the developed tools to streamlining synthesis is demonstrated by concise enantioselective total syntheses of (+)-nephrosteranic acid, (+)-rocellaric acid, and (+)-nephromopsinic acid.

Investigating the Mechanism of Aluminum Fluoride Chelation.

Aluminum fluoride (AlF) complexes have been used over the past decade to incorporate [18F]fluoride into large biomolecules in a highly selective fashion by using relatively facile conditions. However, despite their widespread usage, there are a large number of variations in the reaction conditions, without a definitive discussion provided on the mechanism to understand how these changes would alter the end result. Herein, we report a detailed mechanistic investigation of the reaction, using a mixture of theoretical studies, fluorine-19 and fluorine-18 chemistry, and the consequences it has on the efficient clinical translation of AlF-containing imaging agents.

A Phosphine-Oxide Cobalt(II) Complex and Its Catalytic Activity Studies toward Alcohol Dehydrogenation Triggered Direct Synthesis of Imines and Quinolines.

Herein, a new pincer-like amino phosphine donor ligand, H2L1, and its phosphine-oxide analog, H2L2, were synthesized. Subsequently, cobalt(II) complexes 1 and 2 were synthesized by the reaction of anhydrous Co(II)Cl2 with ligands H2L1 and H2L2, respectively. The ligands and complexes were fully characterized by various physicochemical and spectroscopic characterization techniques. Finally, the identity of the complexes 1 and 2 was confirmed by single crystal X-ray structure determination. The phosphine ligand containing complex 1 was converted to the phosphine oxide ligand containing complex 2 in air in acetonitrile solution. Both complexes 1 and 2 were investigated as precatalysts for alcohol dehydrogenation-triggered synthesis of imines in air. The phosphine-oxide complex 2 was more efficient than the phosphine complex 1. A wide array of alcohols and amines were successfully reacted in a mild condition to result in imines in good to excellent yields. Precatalyst 2 was also highly efficient for the synthesis of varieties of quinolines in air. As H2L2 in 2 has side arms that can be deprotonated, we investigated complex 2 for its base (KOtBu) promoted deprotonation events by various spectroscopic studies and DFT calculations. These studies have shown that mono deprotonation of the amine side arm attached to the pyridine is quite feasible, and deprotonation of complex 2 leads to a dearomatized pyridyl ring containing complex 2a. The mechanistic investigations of the catalytic reaction, by a combination of experimental and computational studies, have suggested that the dearomatized complex, 2a acted as an active catalyst. The reaction proceeded through the hydride transfer pathway. The activation barrier of this step was calculated to be 26.5 kcal/mol, which is quite consistent with the experimental reaction temperature under aerobic conditions. Although various pincer-like complexes are explored for such reactions, phosphine oxide ligand-containing complexes are still unexplored.

Elucidating the Origin of Regioselectivity in Palladium-Catalyzed Aromatic Fluorination: Mechanistic Investigation and Microkinetic Analysis

Elucidating the Origin of Regioselectivity in Palladium-Catalyzed Aromatic Fluorination: Mechanistic Investigation and Microkinetic Analysis

Merging of Palladium and Organocatalysis Enabled Asymmetric Decarboxylative (2+1) Cycloadditions toward Cyclopropanes.

A cascade reaction enabling enantio- and diastereoselective construction of strained cyclopropanes is described. This asymmetric (2+1) annulation process uses vinyl methylene carbonate and 2-cyanoacrylate as reaction partners in the presence of Pd(PPh3)4 as a precatalyst and an enantioenriched phosphoramidite ligand featuring a morpholine functionality. Mechanistic investigations unveil that the PPh3 derived from the Pd(PPh3)4 and the morpholine-containing phosphoramidite work as cooperative phosphorus and Brønsted base catalysts to promote the reaction.

Removal of Methylene blue dye from contaminated wastewater using lignocellulosic biomasses: A comparative study

In this study, lupine seed (Lu-SP) and pumpkin seed shells (PSSP) biomasses were used to create alternative and effective adsorbents. Methylene blue (MB) dye was removed from wastewater using the as-prepared adsorbents at variables solution pH 2.0 –11.0, contact period (0–180 min), and adsorbent mass (0.2–2.0 g/L). The solution pH had a synergistic effect on the improved removal of MB and the optimal adsorption removal for both adsorbents occurred at pH 8.0 and 120 min. The adsorption isotherm modelling results showed a good fit with the Langmuir model, with a maximum monolayer adsorption capacity of 48.98 and 77.48 mg/g for PSSP and Lu-SP, respectively. Similarly, the pseudo-first-order (PFO) model is regarded as the best-fit kinetic model for both adsorbents and suggests the predominance of physisorption via interfacial diffusion. Mechanistic investigation of the present system suggests that both intraparticle diffusion and surface sorption mechanisms control the adsorption rate. Notably, the Lu-SP with a lower surface area (54.013 m2/g) outperformed the PSSP (235.992 m2/g) in terms of adsorption capacity under varying pH. Therefore, in addition to electrostatic interaction, adsorption into the micropores via volume filling is considered one of the adsorption mechanisms. This study, therefore, revealed that the PSSP and Lu-SP may be very helpful for removing cationic MB dye from contaminated wastewater.

Recent Developments in the Ruthenium‐Catalyzed Azide Alkyne Cycloaddition (RuAAC) Reaction

The ruthenium‐catalyzed azide alkyne cycloaddition (RuAAC) gives access to 1,5‐disubstitued triazoles in a single atom‐economical step and offers advantages compared to its copper‐catalyzed counterpart in that both terminal and internal alkynes can be employed. This review summarized recent findings in this field during the last eight years, covering mechanistic investigations, synthetic developments, as well as applications in medicinal chemistry, polymer synthesis and physical organic chemistry

Dynamic color‐tunable ultra‐long room temperature phosphorescence polymers with photo‐chromism and water‐stimuli response for multilevel anti‐counterfeiting

AbstractDeveloping dynamic color‐tunable ultra‐long room temperature phosphorescence (URTP) polymers with afterglow of over 1 s, photo‐chromism, and multi‐stimuli response for practical anti‐counterfeiting and information security applications is attractive but very challenging. Herein, by doping multicolor phosphorescence pyridinium bromide L block or viologen‐based photo‐chromic V block into polyvinyl alcohol matrixes, the water‐stimuli‐responsive color‐tunable URTP polymer films with afterglow of up to 8 s and the reversible viologen‐based photochromic polymer films have been developed. More significantly, a series of dynamic color‐tunable URTP polymer films with ultra‐long afterglow of over 6 s, photo‐chromism, and water‐stimuli response have been successfully exploited by integrating L and V blocks into one polymer system. Mechanistic investigations have revealed that their photo‐chromism mainly comes from the photo‐generated viologen free radicals. Furthermore, their dynamic multilevel anti‐counterfeiting applications have been demonstrated. These results pave the way to develop smarter multifunctional URTP materials for anti‐counterfeiting and optical sensing.

The Clinical Translation of α-humulene - A Scoping Review.

α-humulene, a sesquiterpene found in essential oils of various plant species, has garnered interest due to its potential therapeutic applications. This scoping review aims to consolidate α-humulene's evidence base, informing clinical translation, and guiding future research directions. A scoping review was conducted of EMBASE, MEDLINE, and PubMed databases up to 14th July 2023. All studies describing original research on α-humulene extraction, as well as pre-clinical and clinical research, were included for review. Three hundred and forty articles were analysed. α-humulene yields ranged from negligible to 60.90% across plant species. In vitro experiments demonstrated cytotoxicity against adenocarcinomas (such as colorectal, pulmonary, breast, prostatic, lung, and ovarian), with varying responses in other cell models. Mechanistic insights revealed its involvement in mitochondrial dysfunction, diminished intracellular glutathione levels, and the induction of oxidative stress. In rodent studies, oral administration of α-humulene at 50 mg/kg reduced inflammation markers in paw oedema and ovalbumin-induced airway inflammation. Intraperitoneal administration of α-humulene (50 - 200 mg/kg) exhibited cannabimimetic properties through cannabinoid 1 and adenosine A2a receptors. α-humulene also exhibited a multitude of properties with potential scope for therapeutic utilisation. However, there is a paucity of studies that have successfully translated this research into clinical populations with the associated disease. Potential barriers to clinical translation were identified, including yield variability, limited isolation studies, and challenges associated with terpene bioavailability. Consequently, rigorous pharmacokinetic studies and further mechanistic investigations are warranted to effectively uncover the potential of α-humulene.

Sustainable deep eutectic solvents induced the polymorph selectivity and high purification efficiency

Deep eutectic solvents (DESs), as modern green solvents, have been examined as sustainable crystallization media in recent years. Nevertheless, their roles in affecting nucleation and polymorph control of crystal materials are still poorly understood. Herein, we report the use of DES for controlling polymorph crystallization and investigate systematically the mechanism of DES solvent characteristics on polymorph selectivity. Concomitant crystallization of sulfathiazole (STZ) polymorphs has been widely reported in organic solvents, while we found DES can improve its polymorph selectivity significantly. Pure forms II and IV were selectively and rapidly obtained from solvents containing [thymol][fatty acid] and [thymol][coumarin] DESs, respectively. The microstructural changes of DES exhibited dynamic regulatory effect on STZ polymorph selectivity. Analysis of 1H NMR, viscosity and computational simulations revealed that the DES hydrogen-bonding network structures were preserved for DES contents above 50 wt% in binary solvents, which affected the nucleation kinetics of STZ and its molecular assembly during crystallization process. Further mechanistic investigations suggested that DES hydrogen-bonding network structures exerted confinement effect and nucleation-templating effect through DES-solute interactions (hydrogen-bonding and π-π stacking interactions for [thymol][fatty acid] and [thymol][coumarin] systems, respectively), which limited the motion of solute molecules and delayed nucleation rate as well as induced the STZ nucleation toward specific orientations, thus achieving polymorph selectivity. In addition, DESs could be recycled and exhibited good reproducibility in achieving STZ polymorph purification. This study offers a sustainably effective strategy for polymorph purification of crystalline materials and promotes advance the fundamental understanding of DES solvent characteristics on polymorph control.

Unusual Stability of an end-on Superoxido Copper(II) Complex under Ambient Conditions.

Superoxido copper complexes play an important role as usually short-lived intermediates in biology and chemistry. The unusual stability of anend-onsuperoxido copper complex observed in an oxygen-enhanced atom transfer radical polymerization (ATRP) led to a detailed mechanistic investigation of the formation of [CuII(Me6tren)(O2•-)]+(Me6tren = tris(2-dimethyl-aminoethyl)amine) under ambient conditions. The persistence of the superoxido copper complex could be explained by a reaction cycle including the peroxido complex[(Me6tren)2CuII2(O2)]2+together with [CuI(Me6tren)(DMSO)]+and [CuII(Me6tren)(OH)]+in the overall reaction.

Fabrication of porous biochar supported Bi2MoO6 photocatalyst for efficient degradation of ciprofloxacin in seawater under visible light irradiation: Mechanistic investigation and intermediates analysis

Efficient separation of photocarriers is a critical approach for advancing high-performance photocatalyst systems to effectively remove environmental contaminants. In this investigation, a hydrothermal technique was employed to synthesize composites of Bi2MoO6 and porous biochar derived from banana peels (BPB). The samples underwent various characterization methods to assess their composition, morphology, and photoelectrochemical properties. The BPB/Bi2MoO6 composite exhibited a synergistic adsorption and photocatalytic impact in eliminating the antibiotic ciprofloxacin (CIP) from pure water and seawater. The optimized BPB/Bi2MoO6 sample displayed a significant degradation efficiency of 98.7 % for CIP after 90 min of visible-light exposure in pure water. In artificial seawater, the degradation efficiency for CIP remained high at 93.6 %, which was 12.2 times greater than that of pure Bi2MoO6. The study also explored the impact of various factors such as catalyst dosage, solution pH, and pollutant concentration on the photocatalytic performance of BPB/Bi2MoO6. Moreover, the catalyst exhibited enhanced efficiency in the adsorption-photocatalytic degradation of CIP within a continuous flow reaction system. The enhanced photocatalytic performance was attributed to the composite's exceptional adsorption capacity, enhanced response to visible light, and efficient separation of photoinduced electron-hole pairs. Furthermore, the BPB/Bi2MoO6 photocatalyst displayed good stability and recyclability over five consecutive photodegradation cycles. Radical trapping and electron spin resonance (ESR) experiments verified that the degradation of CIP was mainly driven by •OH and h+ radicals. A thorough investigation employing density functional theory (DFT), radical trapping and ESR tests, and liquid chromatography mass spectrometry (LC-MS) was conducted to elucidate the degradation mechanism and pathways. Furthermore, toxicity assessment software was utilized to illustrate the progressive reduction in toxicity of the intermediate products. In conclusion, this study provides valuable insights into the role of biochar in enhancing the photocatalytic degradation of pollutants and offers guidance for the future development of environmentally friendly photocatalysts.

Decarboxylative stereoretentive C–N coupling by harnessing aminating reagent

In recent decades, strategies involving transition-metal catalyzed carbon-carbon or carbon-heteroatom bond coupling have emerged as potent synthetic tools for constructing intricate molecular architectures. Among these, decarboxylative carbon-nitrogen bond formation using abundant carboxylic acids or their derivatives has garnered notable attention for accessing alkyl- or arylamines, one of key pharmacophores. While several decarboxylative amination methods have been developed, the involvement of a common carboradical intermediate currently poses challenges in achieving stereospecific transformation toward chiral alkylamines. Herein, we present a base-mediated, stereoretentive decarboxylative amidation by harnessing 1,4,2-dioxazol-5-one as a reactive and robust amidating reagent under transition-metal-free ambient conditions, encompassing all types of primary, secondary and tertiary carboxylic acids, thereby providing access to the important pharmacophore, α-chiral amines. This method exhibits high functional group tolerance, convenient scalability, and ease of applicability for 15N-isotope labeling, thus accentuating its synthetic utilities. Experimental and computational mechanistic investigations reveal a sequence of elementary steps: i) nucleophilic addition of carboxylate to dioxazolone, ii) rearrangement to form a dicarbonyl N-hydroxy intermediate, iii) conversion to hydroxamate, followed by a Lossen-type rearrangement, and finally, iv) reaction of the in situ generated isocyanate with carboxylate leading to C–N bond formation in a stereoretentive manner.

Sustained Secretion of CCL21 via an Implantable Cell Reservoir Hydrogel Enhances the Systemic Antitumor Effect of Radiotherapy.

The combination of radiotherapy (RT) and immunotherapy shows promise in improving the clinical treatment of solid tumors; however, it faces challenges of low response rates and systemic toxicity. Herein, an implantable alginate/collagen hydrogel encapsulating C-C motif ligand 21 (CCL21)-expressing dendritic cells (CCL21-DCs@gel) was developed to potentiate the systemic antitumor effects of RT. The hydrogel functioned as a suitable reservoir for in vivo culture and proliferation of CCL21-DCs, thereby enabling sustained CCL21 release. The local CCL21 gradient induced by CCL21-DCs@gel significantly enhanced the efficacy of RT in suppressing primary tumor growth and inhibiting distant metastasis across several mouse models. Furthermore, the combination of RT with CCL21-DCs@gel provided complete prophylactic protection to mice. Mechanistic investigations revealed that CCL21-DCs@gel potentiated RT by promoting tumor lymphangiogenesis and attracting immune cell infiltration into the tumor. Collectively, these results suggest that CCL21-DCs@gel is a promising adjunct to RT for effectively eradicating tumors and preventing tumor recurrence.

Assessment of the Developmental Neurotoxicity of Environmental Chemicals: Investigating the Mechanisms & Identifying Potential Biomarkers

Background: Developmental neurotoxicity resulting from exposure to environmental chemicals is a significant public health concern. Understanding the mechanisms underlying such neurotoxicity and identifying potential biomarkers are essential for early detection and effective risk assessment. Objective: This study aimed to assess the developmental neurotoxicity of selected environmental chemicals and investigate the underlying mechanisms. Additionally, the study sought to identify potential biomarkers for early detection and monitoring of developmental neurotoxicity. Methods: In vitro neurodevelopmental models were established, including neuronal cell cultures and organoid systems, to evaluate the neurotoxic effects of environmental chemicals. Key endpoints, such as neuronal viability, morphology, neurite outgrowth, synaptogenesis, and synaptic activity, were assessed using appropriate assays and imaging techniques. Mechanistic investigations involved exploring oxidative stress, inflammation, disruption of neurotransmitter systems, and interference with neurodevelopmental processes through gene expression analysis, protein profiling, and signaling pathway investigations. Results: Exposure of the in vitro models to selected environmental chemicals resulted in significant neurotoxic effects, including impaired neuronal viability, disrupted morphological development, and altered synaptic activity. Mechanistic investigations revealed the involvement of oxidative stress and disruption of neurotransmitter systems in the observed neurotoxicity. Furthermore, several potential biomarkers, including gene expression changes and epigenetic modifications, showed significant correlations with developmental neurotoxicity. Conclusion: This study demonstrates the developmental neurotoxicity of environmental chemicals in in vitro neurodevelopmental models. The findings highlight the role of oxidative stress and neurotransmitter disruption as key mechanisms underlying neurotoxic effects. Moreover, the identification of potential biomarkers provides promising avenues for early detection and monitoring of developmental neurotoxicity. These results contribute to a better understanding of the risks associated with environmental chemical exposure during neurodevelopment and have implications for risk assessment and regulatory guidelines.

Stereoselective Synthesis of Polysubstituted Conjugated Dienes Enabled by Photo‐Driven Sequential Sigmatropic Rearrangement

AbstractWe here reported a highly stereoselective method for the synthesis of polysubstituted conjugated dienes from α‐aryl α‐diazo alkynyl ketones and pyrazole‐substituted unsymmetric aminals under mild conditions, which was promoted by photo‐irridation and involved with 1,6‐dipolar intermediate and quadruple sigmatropic rearrangements, was successfully developed. In this transformation, the cleavage of four bonds and the recombination of five bonds were implemented in one operational step. This protocol provided a modular tool for constructing dienes from amines, pyrazoles and α‐alkynyl‐α‐diazoketones in one‐pot manner. The results of mechanistic investigation indicated that the plausible reaction path underwent the 1,6‐sigmatropic rearrangement instead of the 1,5‐sigmatropic rearrangement.

Oroxin A alleviates early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation

BackgroundSubarachnoid hemorrhage (SAH), a severe subtype of stroke, is characterized by notably high mortality and morbidity, largely due to the lack of effective therapeutic options. Although the neuroprotective potential of PPARg and Nrf2 has been recognized, investigative efforts into oroxin A (OA), remain limited in preclinical studies.MethodsSAH was modeled in vivo through filament perforation in male C57BL/6 mice and in vitro by exposing HT22 cells to hemin to induce neuronal damage. Following the administration of OA, a series of methods were employed to assess neurological behaviors, brain water content, neuronal damage, cell ferroptosis, and the extent of neuroinflammation.ResultsThe findings indicated that OA treatment markedly improved survival rates, enhanced neurological functions, mitigated neuronal death and brain edema, and attenuated the inflammatory response. These effects of OA were linked to the suppression of microglial activation. Moreover, OA administration was found to diminish ferroptosis in neuronal cells, a critical factor in early brain injury (EBI) following SAH. Further mechanistic investigations uncovered that OA facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus, thereby activating the Nrf2/GPX4 pathway. Importantly, OA also upregulated the expression of FSP1, suggesting a significant and parallel protective effect against ferroptosis in EBI following SAH in synergy with GPX4.ConclusionIn summary, this research indicated that the PPARg activator OA augmented the neurological results in rodent models and diminished neuronal death. This neuroprotection was achieved primarily by suppressing neuronal ferroptosis. The underlying mechanism was associated with the alleviation of cellular death through the Nrf2/GPX4 and FSP1/CoQ10 pathways.