GABAergic inhibition in human hMT+ predicts visuo-spatial intelligence mediated through the frontal cortex.

The prevailing opinion emphasizes fronto-parietal network (FPN) is key in mediating general fluid intelligence (gF). Meanwhile, recent studies show that human MT complex (hMT+), located at the occipito-temporal border and involved in 3D perception processing, also plays a key role in gF. However, the underlying mechanism is not clear, yet. To investigate this issue, our study targets visuo-spatial intelligence, which is considered to have high loading on gF. We use ultra-high field magnetic resonance spectroscopy (MRS) to measure GABA/Glu concentrations in hMT+ combining resting-state fMRI functional connectivity (FC), behavioral examinations including hMT+ perception suppression test and gF subtest in visuo-spatial component. Our findings show that both GABA in hMT+ and frontal-hMT+ functional connectivity significantly correlate with the performance of visuo-spatial intelligence. Further, serial mediation model demonstrates that the effect of hMT+ GABA on visuo-spatial gF is fully mediated by the hMT+ frontal FC. Together our findings highlight the importance in integrating sensory and frontal cortices in mediating the visuo-spatial component of general fluid intelligence.

Sex differences in the metabolic activation of and platelet response to vicagrel in mice: Androgen as a key player.

As a biological variable, sex influences the metabolism of and/or response to certain drugs. Vicagrel is being developed as an investigational new drug in China; however, it is unknown whether sex could affect its metabolic activation and platelet responsiveness. This study aimed to determine whether such differences could exist, and to elucidate the mechanisms involved. Orchiectomized (ORX) or ovariectomized (OVX) mouse models were used to investigate the effects of androgen or estrogen on the metabolic activation of and platelet response to vicagrel. Plasma vicagrel active metabolite H4 concentrations, platelet inhibition of vicagrel, and protein levels of intestinal hydrolases Aadac and Ces2 were measured, respectively. Further, p38-MAPK signaling pathway was enriched, whose role was determined using SB202190. Results showed that female mice exhibited significantly elevated systemic exposure of H4 and enhanced platelet responses to vicagrel than males, and protein expression levels of Aadac and Ces2 differed by sex. OVX mice exhibited less changes than sham mice. ORX mice exhibited increases in protein levels of intestinal hydrolases, systemic exposure of H4, and platelet inhibition of vicagrel, but dihydrotestosterone (DHT) reversed these changes in ORX mice and suppressed these changes in OVX mice. Phosphorylated p38 levels were reduced in female or ORX mice but increased in ORX mice by DHT. SB202190 reversed DHT-induced changes observed in ORX mice. We concluded that sex differences exist in metabolic activation of and platelet response to vicagrel in mice through elevation of p38 phosphorylation by androgen, suggesting sex-based vicagrel dosage adjustments for patient care.

Exploring the clinical implications of novel SRD5A2 variants in 46,XY disorders of sex development.

This study was conducted retrospectively on a cohort of 68 patients with steroid 5 α-reductase 2 (SRD5A2) deficiency and 46,XY disorders of sex development (DSD). Whole-exon sequencing revealed 28 variants of SRD5A2, and further analysis identified seven novel mutants. The preponderance of variants was observed in exon 1 and exon 4, specifically within the nicotinamide adenine dinucleotide phosphate (NADPH)-binding region. Among the entire cohort, 53 patients underwent initial surgery at Sichuan Provincial People's Hospital (Chengdu, China). The external genitalia scores (EGS) of these participants varied from 2.0 to 11.0, with a mean of 6.8 (standard deviation [s.d.]: 2.5). Thirty patients consented to hormone testing. Their average testosterone-to-dihydrotestosterone (T/DHT) ratio was 49.3 (s.d.: 23.4). Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome; and their T/DHT ratios were below the diagnostic threshold. Furthermore, assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants. These mechanisms include interference with NADPH binding (c.356G>C, c.365A>G, c.492C>G, and c.662T>G) and destabilization of the protein structure (c.727C>T). The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts. Seven novel variations were identified, and the variant database for the SRD5A2 gene was expanded. These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.

Exploring the efficacy of laser speckle contrast imaging in the stratified diagnosis of rosacea: a quantitative analysis of facial blood flow dynamics across varied regions.

Background: Rosacea has a high incidence, significantly impacts quality of life, and lacks sufficient diagnostic techniques. This study aimed to investigate the feasibility of laser speckle contrast imaging (LSCI) for measuring facial blood perfusion in patients with rosacea and to identify differences in blood flow among various facial regions associated with different rosacea subtypes. Methods: From June to December 2023, 45 patients were recruited, with 9 excluded, leaving 36 subjects: 12 with erythematotelangiectatic rosacea (ETR), 12 with papulopustular rosacea (PPR), and 12 healthy controls. The Think View multispectral imaging analyzer assessed inflammation via gray reading values across the full face and five facial areas: forehead, nose, cheeks, and chin. LSCI measured and analyzed blood perfusion in the same areas. Plasma biomarkers interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) were tested in different groups. Results: Both ETR and PPR groups showed increased average blood perfusion and facial inflammation intensity by gray values compared to controls, with statistically significant differences. Average blood perfusion of ETR and PPR groups showed increased values in the forehead, cheeks, and nose, compared to controls, and the values in the cheeks were statistically different between ETR and PPR. The facial inflammation intensity of the ETR group showed increased values in the forehead and cheeks, and the PPR group showed increased gray values in the forehead, cheeks, nose, and chin compared to controls, and the values for the cheeks, nose, and chin were statistically significantly different between ETR and PPR. Plasma biomarkers IL-6, IL-1ß, and TNF-α were significantly elevated in both ETR and PPR groups compared to controls. Conclusion: LSCI is a valuable, non-invasive tool for assessing blood flow dynamics in rosacea, providing a data foundation for clinical research. Different rosacea subtypes exhibit distinct lesion distribution and blood flow patterns, and both ETR and PPR could affect all facial areas, particularly the cheeks in ETR and the forehead, nose, and chin in PPR.

Correlation between the Systemic Immunoinflammatory Index and Platelet-Lymphocyte Ratio in Patients with Adenomyosis.

Background: The chronic inflammatory immune response is a significant factor in the pathogenesis of benign gynecological diseases. The systemic immunoinflammatory index (SII) and the platelet-to-lymphocyte ratio (PLR) are commonly available biomarkers of inflammation. However, evidence of the relationship between SII and PLR in patients with adenomyosis is limited. This study aimed to investigate the relationship between SII and PLR in patients with adenomyosis. Methods: This cross-sectional study included 483 patients with adenomyosis who were first diagnosed at our institution between January 2019 and December 2021. Basic patient clinical information and inflammatory factors were collected for univariate analysis, smoothed curve fitting, and multivariate segmented linear regression. Results: The results of the univariate analysis showed a significant positive correlation between PLR levels and SII (P < 0.001). In addition, a nonlinear relationship between PLR and SII was tested using a smoothed curve fit after adjusting for potential confounders. Multiple segmented linear regression models showed a significant relationship between SII and PLR in both SII < 1,326.47 (ß 0.14, 95% CI: 0.12, 0.16; P < 0.0001) and >1,326.47 (ß 0.02, 95% CI: -0.01, 0.05; P = 0.2461). Conclusions: In conclusion, this study showed a nonlinear relationship between SII and PLR in patients with uterine adenomyosis. An increase in serum PLR levels correlates with an increase in SII before SII levels reach an inflection point.

Abnormal activation patterns in MT+ during visual motion perception in major depressive disorder.

Objective: Previous studies have found that patients with Major Depressive Disorder (MDD) exhibit impaired visual motion perception capabilities, and multi-level abnormalities in the human middle temporal complex (MT+), a key brain area for processing visual motion information. However, the brain activity pattern of MDD patients during the perception of visual motion information is currently unclear. In order to study the effect of depression on the activity and functional connectivity (FC) of MT+ during the perception of visual motion information, we conducted a study combining task-state fMRI and psychophysical paradigm to compare MDD patients and healthy control (HC). Methods: Duration threshold was examined through a visual motion perception psychophysical experiment. In addition, a classic block-design grating motion task was utilized for fMRI scanning of 24 MDD patients and 25 HC. The grating moved randomly in one of eight directions. We examined the neural activation under visual stimulation conditions compared to the baseline and FC. Results: Compared to HC group, MDD patients exhibited increased duration threshold. During the task, MDD patients showed decreased beta value and percent signal change in left and right MT+. In the sample comprising MDD and HC, there was a significant negative correlation between beta value in right MT+ and duration threshold. And in MDD group, activation in MT+ were significantly correlated with retardation score. Notably, no such differences in activation were observed in primary visual cortex (V1). Furthermore, when left MT+ served as the seed region, compared to the HC, MDD group showed increased FC with right calcarine fissure and surrounding cortex and decreased FC with left precuneus. Conclusion: Overall, the findings of this study highlight that the visual motion perception function impairment in MDD patients relates to abnormal activation patterns in MT+, and task-related activity are significantly connected to the retardation symptoms of the disease. This not only provides insights into the potential neurobiological mechanisms behind visual motion perception disorder in MDD patients from the aspect of task-related brain activity, but also supports the importance of MT+ as a candidate biomarker region for MDD.

Cynbungenins A-K, structurally diverse steroids with cytotoxic activity from the roots of Cynanchum bungei Decne.

Chemical investigation of the acid hydrolysate of Cynanchum bungei roots led to the isolation of eleven undescribed steroids, namely cynbungenins A-K (1-11), and seven previously described analogues (12-18). The complete structures of these compounds were elucidated using the comprehensive spectroscopic analyses and reference data. Structurally, compounds 1 and 2 represent the first example of androstane-type steroids found in the Cynanchum plants, and compounds 3-6 and 12 are characterized as pregnane-type steroids with a rare 8,14-seco-steroid core. In the cytotoxic activity assay, compound 16 displayed the strongest cytotoxic effect against MCF-7, HCT-116, HeLa, and HepG2 cancer cell lines, with IC50 values of 9.98-16.42 µM, and further research indicated that it induced both apoptosis and cell cycle arrest in the G0/G1 phase in a dose-dependent manner toward HepG2 cells.

The kynurenine pathway regulated by intestinal innate lymphoid cells mediates postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) expression and activity, which shifts intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1-KYN pathway in the intestine could be a promising therapeutic target for POCD.

Erratum: Triptolide Suppresses Glomerular Mesangial Cell Proliferation in Diabetic Nephropathy Is Associated with Inhibition of PDK1/Akt/mTOR Pathway: Erratum.

[This corrects the article DOI: 10.7150/ijbs.20485.].

MARCH8 Mediates K27-Linked Polyubiquitination of IL-7 Receptor α to Negatively Regulate IL-7-Triggered T Cell Homeostasis.

IL-7 is a cytokine produced by stromal cells, which binds to IL-7Rα and plays an important role for homeostasis of T lymphocytes. Excessive activities of IL-7-triggered signaling pathways causes autoimmune diseases. How IL-7-triggered signaling and immune effects are regulated is not fully understood. In this study, we show that the membrane-associated RING-CH (MARCH) E3 ligase family member MARCH8 mediates K27-linked polyubiquitination of IL-7Rα, leading to its lysosomal degradation. Site-directed mutagenesis suggests that MARCH8 meditates polyubiquitination of IL-7Rα at K265/K266, and mutation of these residues renders IL-7Rα resistance to MARCH8-mediated polyubiquitination and degradation. MARCH8 deficiency increases IL-7-triggered activation of the downstream transcription factor STAT5 and transcriptional induction of the effector genes in human T lymphoma cells. MARCH8 deficiency also promotes IL-7-triggered T cell proliferation and splenic memory CD8+ T cell differentiation in mice. Our findings suggest that MARCH8 negatively regulates IL-7-triggered signaling by mediating K27-linked polyubiquitination and lysosomal degradation of IL-7Rα, which reveals a negative regulatory mechanism of IL-7-triggered T cell homeostasis.

Brassica rapa BrICE1 and BrICE2 Positively Regulate the Cold Tolerance via CBF and ROS Pathways, Balancing Growth and Defense in Transgenic Arabidopsis.

Winter rapeseed (Brassica rapa) has a good chilling and freezing tolerance. inducer of CBF expression 1 (ICE1) plays a crucial role in cold signaling in plants; however, its role in Brassica rapa remains unclear. In this study, we identified 41 ICE1 homologous genes from six widely cultivated Brassica species. These genes exhibited high conservation, with evolutionary complexity between diploid and allotetraploid species. Cold stress induced ICE1 homolog expression, with differences between strongly and weakly cold-tolerant varieties. Two novel ICE1 paralogs, BrICE1 and BrICE2, were cloned from Brassica rapa Longyou 6. Subcellular localization assays showed that they localized to the nucleus, and low temperature did not affect their nuclear localization. The overexpression of BrICE1 and BrICE2 increased cold tolerance in transgenic Arabidopsis and enhanced reactive oxygen species' (ROS) scavenging ability. Furthermore, our data demonstrate that overexpression of BrICE1 and BrICE2 inhibited root growth in Arabidopsis, and low temperatures could induce the degradation of BrICE1 and BrICE2 via the 26S-proteasome pathway. In summary, ICE1 homologous genes exhibit complex evolutionary relationships in Brassica species and are involved in the C-repeat/DREB binding factor (CBF) pathway and ROS scavenging mechanism in response to cold stress; these regulating mechanisms might also be responsible for balancing the development and cold defense of Brassica rapa.

Irregularity of visual motion perception and negative symptoms in schizophrenia.

Schizophrenia (SZ) is a severe psychiatric disorder characterized by perceptual, emotional, and behavioral abnormalities, with cognitive impairment being a prominent feature of the disorder. Recent studies demonstrate irregularity in SZ with increased variability on the neural level. Is there also irregularity on the psychophysics level like in visual perception? Here, we introduce a methodology to analyze the irregularity in a trial-by-trial way to compare the SZ and healthy control (HC) subjects. In addition, we use an unsupervised clustering algorithm K-means + + to identify SZ subgroups in the sample, followed by validation of the subgroups based on intraindividual visual perception variability and clinical symptomatology. The K-means + + method divided SZ patients into two subgroups by measuring durations across trials in the motion discrimination task, i.e., high, and low irregularity of SZ patients (HSZ, LSZ). We found that HSZ and LSZ subgroups are associated with more negative and positive symptoms respectively. Applying a mediation model in the HSZ subgroup, the enhanced irregularity mediates the relationship between visual perception and negative symptoms. Together, we demonstrate increased irregularity in visual perception of a HSZ subgroup, including its association with negative symptoms. This may serve as a promising marker for identifying and distinguishing SZ subgroups.

Impact of social, familial and personal factors on depressive symptoms in middle-aged and older adults from the national CHARLS cohort.

BACKGROUND: This study aimed to evaluate whether social, familial and personal factors can predict incident and prevalent depressive symptoms in Chinese adults aged ≥ 45 years using data from the China Health and Retirement Longitudinal Study (CHARLS). METHODS: Study subjects without depressive symptoms from CHARLS at baseline were enrolled. Depressive symptoms were defined by the 10-item Center for Epidemiologic Studies Depression Scale. Statistical adjustment, subgroup exploration and unmeasured confounding assessment were undertaken to derive reliable estimates. RESULTS: 1681 (27.04%) of 6215 subjects who had no depressive symptoms in 2011, suffered one or more depressive symptoms in 2018. Multivariate analyses showed that number of grandchildren (odds ratio [95% confidence interval]: 1.06 [1.02, 1.10]), social activity score (0.95 [0.91, 0.98]), instrumental activities of daily living (IADL) (1.35 [1.11, 1.65]) and number of comorbidities (1.16 [1.10, 1.22]) were independently and significantly associated with the presence of incident depressive symptoms. Further categorization revealed significance for social activity score (odds ratio [95% confidence interval]: 0.78 [0.69, 0.89] and 0.71 [0.53, 0.95] for 1-5 and > 5 vs. 0), IADL (1.35 [1.11, 1.65] for yes vs. no) and number of comorbidities (1.38 [1.20, 1.58], 1.44 [1.16, 1.81] and 2.42 [1.54, 3.80] for 1-2, 3-4 and > 4 vs. 0) associated with incident depressive symptoms. Restricting analysis to wave IV data in 2018 observed significant association of number of grandchildren, social activity score, IADL and number of comorbidities with prevalent depressive symptoms. CONCLUSIONS: The present study findings support the marked contribution of social activity score, IADL and number of comorbidities to incident and prevalent depressive symptoms in Chinese middle-aged and older adults.

PLK2-mediated phosphorylation of SQSTM1 S349 promotes aggregation of polyubiquitinated proteins upon proteasomal dysfunction.

Dysregulation in protein homeostasis results in accumulation of protein aggregates, which are sequestered into dedicated insoluble compartments so-called inclusion bodies or aggresomes, where they are scavenged through different mechanisms to reduce proteotoxicity. The protein aggregates can be selectively scavenged by macroautophagy/autophagy called aggrephagy, which is mediated by the autophagic receptor SQSTM1. In this study, we have identified PLK2 as an important regulator of SQSTM1-mediated aggregation of polyubiquitinated proteins. PLK2 is upregulated following proteasome inhibition, and then associates with and phosphorylates SQSTM1 at S349. The phosphorylation of SQSTM1 S349 strengthens its binding to KEAP1, which is required for formation of large SQSTM1 aggregates/bodies upon proteasome inhibition. Our findings suggest that PLK2-mediated phosphorylation of SQSTM1 S349 represents a critical regulatory mechanism in SQSTM1-mediated aggregation of polyubiquitinated proteins.

Abnormal T Cells Function Associated With Intraspinal Cold Abscess Caused by Macrolide-resistant Mycoplasma pneumoniae in a Patient With X-linked Agammaglobulinemia.

Intraspinal cold abscesses caused by macrolide-resistant Mycoplasma pneumoniae in patients with X-linked agammaglobulinemia have not yet been described to our knowledge. Here we describe a patient with X-linked agammaglobulinemia who developed an intraspinal cold abscess caused by macrolide-resistant M. pneumoniae . Genetic analysis revealed a hemizygous c.1566 + 1G > C (IVS15 + 1G > C) mutation in BTK gene. The patient showed relatively naive T cells and a significant proliferative defect.

Omadacycline in the treatment of scrub typhus: Three case reports.

BACKGROUND: Scrub typhus is a naturally occurring acute infectious disease that is primarily transmitted through the bites of chiggers or larval mites infected by Orientia tsutsugamushi (O. tsutsugamushi). Omadacycline, a novel tetracycline, exhibits potent antibacterial efficacy against both typical bacteria and atypical pathogens. However, omadacycline application in the treatment of scrub typhus remains limited. CASE SUMMARY: In the present work, we report several cases of scrub typhus, with the main clinical symptoms being fever, the formation of eschars or ulcers, local or systemic lymphadenopathy, headache, myalgia and rash. Blood samples were collected before omadacycline was administered, and O. tsutsugamushi infection was confirmed through targeted next-generation sequencing (tNGS). After two days of treatment, the patients' symptoms, including fever, were alleviated, with no adverse drug reactions. CONCLUSION: tNGS is an effective method for diagnosing scrub typhus. Omadacycline can be considered an alternative option for antiinfective therapy in patients with O. tsutsugamushi infections.

Resveratrol Protects Müller Cells Against Ferroptosis in the Early Stage of Diabetic Retinopathy by Regulating the Nrf2/GPx4/PTGS2 Pathway.

The aim of this study was to investigate the anti-ferroptotic effect of resveratrol (RSV) on retinal Müller cells (RMCs) in the early stages of diabetic retinopathy (DR) via the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4)/prostaglandin-endoperoxide synthase 2 (PTGS2). The retina was obtained from normal and diabetic Sprague-Dawley rats or wild-type and Nrf2 knockout (KO) diabetic mice, with or without RSV (10 mg/kg/d) treatment for 12 weeks. RMCs transfected with or without SiNrf2 were cultured with high glucose and RSV (20 mM). The retinal neurofunctional changes were measured by electroretinogram (ERG). The retinal inner nuclear layer cell mitochondrial morphological changes were detected by transmission electron microscopy. The cell viabilities were measured by cell counting kit-8 (CCK-8) assay. The levels of Fe2+, malonic dialdehyde (MDA), and glutathione (GSH) were measured by colorimetric method. The expression of Nrf2, GPx4, and PTGS2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunocytochemistry. In vivo, RSV inhibited retinal neurofunctional changes and mitochondrial morphological changes; decreased Fe2+, MDA, and PTGS2; and increased GSH, Nrf2, and GPx4 in retina of DM rats. In vitro, RSV decreased MDA and PTGS2 and increased cell viability, GSH, Nrf2, and GPx4. In vivo and vitro, the role of Nrf2-regulated signaling pathway in anti-ferroptosis by RSV was further confirmed using Nrf2 KO mice and pre-transfected SiNrf2 in RMCs. These findings indicated that RSV is a potential therapeutic option for DR and that Nrf2/GPx4/PTGS2 plays a role in the anti-ferroptosis mechanism of RSV on RMCs.

Taraxasterol attenuates zearalenone-induced kidney damage in mice by modulating oxidative stress and endoplasmic reticulum stress.

Taraxasterol is one of the bioactive ingredients from traditional Chinese herb Taraxacum, which exhibits multiple pharmacological activities and protective effects. However, the underlying influence and mechanism of its use against kidney damage caused from zearalenone (ZEA) remain unexplored. The ZEA-induced kidney damage model of mice was established by feeding diets containing ZEA (2 mg/kg), and taraxasterol (5 and 10 mg/kg) was administered by gavage for 28 days. Results demonstrated taraxasterol increased average daily gain (ADG) and average daily feed intake (ADFI), reduced feed-to-gain ratio (F/G) and kidney index of mice induced by ZEA. Taraxasterol alleviated histopathological changes of kidney, reduced ZEA residue and the levels of blood urea nitrogen (BUN), uric acid (UA), and creatinine (CRE). Concurrently, taraxasterol reduced the contents of oxidative stress indicator reactive oxygen species (ROS) and malondialdehyde (MDA), and increased the activities of antioxidant enzymes catalase (CAT), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px). Further, taraxasterol up-regulated the mRNA and protein expression of nuclear factor erythroid-2-related factor 2 (Nrf2), GSH-Px, NAD(P)H quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1), and down-regulated the mRNA and protein expression of KELCH like ECH associated protein (Keap1) in Nrf2/Keap1 pathway. Taraxasterol down-regulated the mRNA and protein expression of immunoglobulin binding protein (Bip), C/EBP homologous protein (CHOP), Bcl-2 associated X (Bax), cysteine protease (Caspase)-12, and Caspase-3, and up-regulated B-cell lymphoma 2 (Bcl-2) expression in endoplasmic reticulum stress pathway. This study suggests that taraxasterol attenuates ZEA-induced mouse kidney damage through the modulation of Nrf2/Keapl pathway to play antioxidant role and endoplasmic reticulum stress pathway to enhance anti-apoptotic ability. It will provide a basis for taraxasterol as a potential drug to prevent and treat ZEA-induced kidney damage.

Elucidating the role of 4-hydroxy-2(3H)-benzoxazolone in chronic alcoholic liver disease via transcriptomics and metabolomics.

Background: Chronic alcoholic liver disease (CALD) is a global health problem which includes multiple pathological processes such as immune inflammation and oxidative stress. 4-hydroxy-2(3H)-benzoxazolone (HBOA), an alkaloid isolated from Acanthus ilicifolius L, has been shown to exert hepatoprotective and immunomodulatory effects. However, its effects on CALD remain unclear. This study aimed to investigate the effects and underlying mechanisms of HBOA on CALD. Methods: Rats were administered alcohol by gavage continuously for 12 weeks to establish the CALD model, and then treated with HBOA by gavage for 4 weeks. Transcriptomics and metabolomics were used to predict the potential mechanisms of the effects of HBOA on CALD. Liver histology and function, oxidative stress, inflammatory cytokines, and the TLR4/NF-κB pathway components were evaluated. Results: HBOA significantly improved alcohol-induced liver injury and steatosis. It decreased the expression levels of pro-inflammatory cytokines (tumour necrosis factor-α [TNF-α], interleukin (IL)-1ß, and IL-6), and increased the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH], and glutathione peroxidase [GSH-Px]). Western blotting confirmed that HBOA treatment largely diminished NF-κBp65 nuclear translocation. Comprehensive transcriptomics and metabolomics analyses indicated that HBOA regulated the glycerophospholipid metabolism pathway to achieve therapeutic effects in rats with CALD. Conclusion: HBOA has a therapeutic effect on rats with CALD. Its mechanism of action mainly affects the glycerophospholipid metabolic pathway to promote lipid metabolism homeostasis by regulating the expression of Etnppl, Gpcpd1, and Pla2g4c. In addition, it may also inhibit the TLR4/NF-κB signaling pathway, thereby reducing the immune-inflammatory response.