Objective This investigation seeks to examine the involvement of Thrombospondin 1 (THBS1) in sepsis-related acute renal dysfunction, focusing specifically on how it influences macrophage phenotypic switching and programmed cell death through pyroptosis, while evaluating its potential as a novel treatment approach. Methods This study employed RNA sequencing technology for gene expression profiling to investigate transcriptomic alterations in patients with sepsis-associated acute kidney injury. An experimental murine sepsis model was established, and THBS1 gene expression was suppressed using small interfering RNA-mediated gene knockout technology. Methods such as immunofluorescence microscopy were employed to assess macrophage phenotypic transformation and renal injury. In vitro experiments involved the isolation and culture of primary macrophages, which were then polarized by lipopolysaccharide (LPS) and co-cultured with renal tubular epithelial cells (HK-2 cell line) to investigate the mechanisms underlying programmed cell death. Results THBS1 expression showed marked increases in both human sepsis cases and murine models, promoting polarization toward M1-type macrophages. Inhibition of THBS1 led to attenuated inflammatory responses, decreased oxidative stress, mitigated renal injury, and promoted macrophage differentiation toward the M2 phenotype. Macrophage-derived THBS1, stimulated by LPS exposure, triggered pyroptotic cell death in HK-2 renal tubular cells. Downregulation of THBS1 enhanced macrophage mitochondrial performance through multiple mechanisms: suppressing succinate dehydrogenase function, normalizing mitochondrial transmembrane potential, lowering reactive oxygen species production, and correcting metabolic abnormalities. Discussion The protein THBS1 has been identified as a critical mediator in sepsis-induced acute kidney injury, primarily through its ability to promote M1 macrophage polarization and trigger pyroptotic cell death. Experimental evidence demonstrates that suppressing THBS1 activity leads to significant attenuation of renal damage and enhancement of macrophage mitochondrial performance. These observations indicate THBS1's potential as a valuable intervention point for managing sepsis-associated kidney dysfunction, with its effects being mediated via macrophage phenotype modulation and pyroptosis regulation.

Epidemiological evidence suggests that developmental arsenic (As) exposure increases behavioral abnormalities in offspring. However, how placental neuroendocrine function and sex-specific responses contribute to these effects remains poorly understood. Here, we demonstrate that maternal As exposure induces trophoblastic damage, vascular disruption, and placental labyrinth thinning, leading to placental dysplasia, fetal growth restriction, and sex-specific behavioral outcomes in offspring. Integrated transcriptomic and neurobehavioral analyses revealed sex-dependent alterations primarily involving neurodevelopmental pathways and transporter dysfunction. Concurrently, neurotransmitter metabolomic profiling identified profound disturbances in tryptophan, tyrosine, and amino acid metabolism in the placenta and fetal brain. Bayesian benchmark dose (BMD) modeling revealed that points of departure (PoDs) followed the rank order, such that metabolomic (mPoDs) < neurobehavioral (nPoDs) < apical (aPoDs). Notably, alterations in the tryptophan pathway were the most sensitive early perturbations observed, with BMDL10 values for 5-hydroxy-l-tryptophan of 3.73 μg/L in females and 4.17 μg/L in males, respectively. Overall, this exploratory framework provides evidence for placental neuroendocrine toxicity of As and highlights its potential relevance for refined environmental risk assessment.

Adolescent depression has rapidly emerged as a critical public health concern, driven by its soaring prevalence, profound functional impairment, and heightened suicide risk. However, the underlying mechanisms remain poorly understood. A growing body of evidence highlights the gut microbiota-brain axis as a key modulator of host emotional function, acting through interconnected immune, metabolic, and neural pathways. In the current work, a clinical study involving first-diagnosed adolescent depression patients was conducted and significant reductions in Roseburia intestinalis (R.i.) and its metabolite butyrate were identified. Therefore, we hypothesized that alterations in R.i. and butyrate may be involved in adolescent depression and may serve as novel therapeutic strategy. Intriguingly, transplantation of R.i. obviously retarded the chronic restraint stress (CRS)-induced depression in adolescent mice. Critically, this protective effect was completely abrogated by blocking the G protein-coupled receptor 43 (GPR43). Mechanistically, we delineated a novel “peripheral-central” regulatory cascade: R.i. robustly promoted the expansion of peripheral CD25⁺Foxp3⁺ regulatory T (Treg) cells, alleviating pathological inflammation in both of the colon (peripheral) and brain (central). Reciprocally, depletion of Treg cells completely abolished not only R.i.’s antidepressant effects but also its anti-inflammatory actions in the colon and brain in vivo. The in vitro study revealed that either the R.i. conditioned or heated culture medium obviously alleviated the LPS+corticosterone induced neuroinflammation in microglial cells, shifting reactive state toward a homeostatic state. Collectively, our study for the first time reveals that R.i. ameliorates adolescent depression-like changes through a GPR43-dependent, Treg-mediated mechanism. Given the unmet clinical need for clinical diagnosis and therapy of adolescent depression, the present study provided the potential translational values for the novel treatments, such as transplantation of R.i. or butyrate supplement, which represent promising therapeutic strategies.

BACKGROUND Anhedonia in major depressive disorder remains therapeutically challenging. Building on our prior randomized evidence of clinical benefit with Pediococcus acidilactici CCFM6432, we further investigated candidate peripheral immune and central reward correlates of treatment response. AIM To evaluate whether add-on CCFM6432 alleviates anhedonia through immune-inflammatory modulation and changes in reward-related electrophysiological measures. METHODS Adults with major depressive disorder and anhedonia received standard antidepressant therapy plus CCFM6432 or plus placebo for 30 days. Assessments comprised Hamilton Depression Scale; Temporal Experience of Pleasure Scale (total, anticipatory, consummatory); event-related potentials indexing reward anticipation and feedback - stimulus-preceding negativity and feedback-related negativity; and a 13-marker peripheral panel (immune-inflammatory, neurotrophic, neurotransmitter-related). Of 92 screened, 71 were randomized; 55 completed (CCFM6432 group: n = 27; Placebo group: n = 28). RESULTS CCFM6432 produced greater reductions in lipopolysaccharide, C-reactive protein, and interleukin-6 vs placebo (P < 0.05). Decreases in these markers were aligned with improvements in the Temporal Experience of Pleasure Scale (total and anticipatory subscales) and with increased stimulus-preceding negativity amplitude, although the latter association attenuated after adjustment for depressive and anxiety symptom changes. No between-group differences were observed for neurotrophic or neurotransmitter-related measures, and feedback-related negativity showed no treatment-related effects. CONCLUSION These findings provide preliminary clinical support that immune-inflammatory modulation may contribute to the anhedonia-relieving effects of CCFM6432, particularly in reward anticipation. Larger multicenter studies with multimodal endpoints are warranted to confirm these results and elucidate mechanistic pathways.

Nonalcoholic fatty liver disease (NAFLD) is fundamentally characterized by dysregulated hepatic lipid metabolism. Recent evidence suggests that peripheral neurotransmitter metabolism may be involved in NAFLD pathogenesis, yet the relationship between neurotransmitter and lipid metabolism remains incompletely understood. This study employed targeted serum metabolomics to simultaneously investigate alterations in the kynurenine (KYN) pathway and lipid metabolism. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified a concurrent reduction in serum levels of KYN pathway metabolites, including KYN, xanthurenic acid (XA), and its precursor tryptophan (TRP), in NAFLD patients. These changes were significantly accompanied by dysregulated levels of palmitic acid (PA), arachidonic acid (AA), and eicosapentaenoic acid (EPA). Method validation confirmed analytical reliability, with limit of detection (LOD) of 0.2-5 ng/mL and limit of quantification (LOQ) of 0.5-10 ng/mL for both KYN metabolites and fatty acids. Calibration curves displayed excellent linearity (R2 > 0.995), and both intra-day and inter-day precision was satisfactory, with recovery rates meeting validation criteria. To validate these associations, an HFD-induced NAFLD mouse model was used. Parallel reductions in KYN pathway metabolites and dysregulated fatty acid metabolism were observed in the liver. Logistic regression with false discovery rate (FDR) correction revealed that most KYN metabolite levels varied concordantly with fatty acid levels in mice. In summary, this study provides the first systematic demonstration of concurrent dysregulation of the KYN pathway and lipid metabolism in NAFLD, supported by robust chromatographic-mass spectrometric validation. The observed parallel metabolic disturbances offer new perspectives for therapeutic strategies targeting NAFLD.

Bisphenol F (BPF), a major bisphenol A substitute widely used in packaging and pharmaceuticals, poses emerging neuropsychiatric risks with unknown mechanisms. Here, we first linked elevated urinary BPF in newly diagnosed depressed patients to human depressive phenotypes. In mice, we found that BPF exposure resulted in depletion of Lactobacillus acidophilus (L. acidophilus), whose transplantation obviously reversed the depression-like behaviors. With the Multi-omics (16S rRNA sequencing, untargeted/targeted metabolomics) assays, we revealed the two key reduced target metabolites produced by L. acidophilus, indole-3-lactic acid (ILA) and indole-3-acetic acid (IAA). Exogenous supplementation of ILA/IAA strikingly rescued the BPF-induced depressive behaviors. Mechanistically, the molecular docking and microscale thermophoresis results showed that BPF serves as a novel exogenous aryl hydrocarbon receptor (AHR) ligand, competing with ILA/IAA at MET109/LEU110 to activate cytochrome P450 1B1 (CYP1B1) signaling; Critically, knockout of AHR in mice (AHR-/-) substantially impeded the BPF induced depression like behaviors, CYP1B1 activation and microglia mediated abnormal synaptic pruning.Collectively, the present study uncovers a novel "microbiota-indole metabolite-AHR-CYP1B1" axis mediating BPF-induced depressive changes, supporting targeted interventions (e.g., L.acidophilus) transplantation, ILA/IAA supplementation, AHR modulation) as potential therapies for neuropsychiatric disorders induced by BPF.

Methamphetamine (Meth) abuse leads to cognitive impairment, with the hippocampus being severely affected. However, the precise cellular mechanisms underlying Meth-induced hippocampal damage remain unclear. This study utilizes single-nucleus RNA sequencing (snRNA-seq) to investigate the transcriptional changes in mouse hippocampal neurons after acute Meth exposure. We analyze 36,376 nuclei isolated from the hippocampus of acute Meth-treated and control mice, revealing significant alterations in excitatory neuron transcriptomes. Notably, oxidative phosphorylation (OXPHOS) and peroxisome pathways were prominently activated. Five distinct excitatory neuron subtypes were identified across different hippocampal regions, with the dorsal-ventral (DG) region exhibiting the most pronounced changes in gene expression, inflammatory response, reactive oxygen species (ROS) signaling, and OXPHOS activity. High-dimensional weighted correlation network analysis (hdWGCNA) reveals five modules endowed with functional roles in recognizing-associated pathways. Furthermore, it provides insights into intercellular communication and transcriptional regulation patterns within the hippocampus after Meth exposure. In conclusion, this study offers a comprehensive understanding of Meth's impact on hippocampal transcriptomes and may guide the development of therapeutic strategies for acute Meth-induced neurotoxicity.

cGAMP-induced STING activation contributes to inflammatory and interferon-related signalling, making STING a relevant target for inhibitor development. In this study, a 59,319-sequence peptide library was screened against STING by molecular docking, and four top-ranked peptides were selected for evaluation. MST analysis demonstrated that Peptides 1-4 bound to recombinant STING, with Peptide-1 showing the highest affinity (Kd = 0.15 ± 0.01 μM). Docking and simulation analyses suggested that binding was mediated by hydrogen bonding and hydrophobic contacts. Molecular dynamics, MM/PBSA, and free energy landscape analyses suggested stable binding with favourable calculated energetics. Peptide-1 showed no apparent cytotoxicity up to 10 μM in RAW264.7 macrophages and primary BMDMs, while dose-dependently reducing cGAMP-induced IFN-β and IL-6 expression at both protein and mRNA levels. This inhibitory effect was accompanied by reduced STING and IRF3 phosphorylation. Collectively, these findings suggest that Peptide-1 may bind STING and attenuate cGAMP-induced IFN-β and IL-6 expression.

BackgroundMajor depressive disorder (MDD) exhibits pronounced age-related pathophysiological heterogeneity, yet the distinct signatures of the microbiota-gut-brain (MGB) axis between adolescent and adult patients remain inadequately characterized. This study aimed to elucidate age-specific MGB axis dysregulation by integrating gut microbiota profiling, plasma metabolomics, and their interactive networks in first-episode, drug-naïve MDD patients across these two developmental stages.MethodsWe enrolled 62 first-episode, drug-naïve MDD patients (28 adolescents, 34 adults) alongside 43 age- and sex-matched healthy controls (22 adolescents, 21 adults). Fecal samples underwent 16S rRNA gene sequencing, while plasma was analyzed via untargeted metabolomics. Comprehensive bioinformatics and network analyses were applied to map microbial compositional shifts, metabolic perturbations, and microbe-metabolite crosstalks.ResultsIntegrated multi-omics analysis revealed distinct age-specific gut microbiota and plasma metabolome signatures in TMDD and AMDD compared with their age-matched controls. ① Microbiota: Beyond shared depletion of Firmicutes and butyrate-producing genera (Anaerobutyricum, Blautia), TMDD exhibited more extensive remodeling. Characterized by increased (Chao1 index, p < 0.05) Bifidobacterium loss and enrichment of Bacteroidetes, Gemmatimonadetes, and Planctomycetes. ② Metabolome: TMDD perturbations targeted neurodevelopmental and oxidative pathways, such as arginine/proline metabolism, D-amino acid metabolism, and glutathione metabolism. Whereas AMDD focused on energy dysfunction and excitotoxicity, involving the TCA cycle, purine metabolism, and alanine/aspartate/glutamate metabolism. ③ Interactome: In AMDD, positive correlations with protective (lipids) were attenuated, while pathological links with pro-inflammatory sphingolipids and polyamines strengthened. The interactome in AMDD remained stable.ConclusionOur findings suggest that first-episode, drug-naïve MDD patients display distinct age-specific dysregulation of the microbiota-gut-plasma metabolome axis. The non-overlapping pathological signatures, a “development-nutrition-metabolic” disturbance pattern in adolescents versus an “energy metabolism-oxidative stress” pattern in adults, underscore the pronounced pathophysiological heterogeneity of MDD across the lifespan. These preliminary observations indicate that future diagnostic biomarkers and therapeutic interventions, particularly microbiota-targeted strategies, should be precisely tailored to the biological profiles of different age groups. However, given the exploratory nature of this subtyping, larger independent cohort studies are warranted to validate these findings before clinical translation.

Adolescent depression is undergoing a rapid surge and has become a severe global public health challenge. However, current therapeutic approaches are limited and often accompanied by significant side effects primarily due to the elusive underlying mechanisms. The gut-brain axis has recently gained growing attention for its pivotal roles in neuropsychiatric disorders, particularly the tryptophan (Trp) metabolism by the microbiota. With the 16S rRNA gene sequencing, the abundance of Bacteroidetes, a microbiota phylum that includes several taxa involved in tryptophan metabolism and indole derivative production was significantly reduced in unmedicated adolescents with depression. The in-depth analysis showed that levels of key indole derivatives, including IAA, IPA and IAld, were markedly decreased in depressed patients; crucially, these reductions showed a significant negative correlation with depression severity scores. Consistent with the clinical findings, a similar decline in IAA, IPA, and IAld levels was observed in adolescent mice with depression induced by chronic restraint stress (CRS). Notably, depression-like behaviors in these mice were substantially ameliorated by a high-Trp diet (CRS + 1.19% Trp) and direct supplementation with indole derivatives. In a reciprocal experiment, a low-Trp diet (0.09% Trp) was found to de novo induce depressive behaviors in otherwise healthy mice. Morphological analysis of brain tissue uncovered another critical insight, the microglial cells in CRS mice exhibited hallmark features of overactivation. Remarkably, both the high-Trp diet and indole derivative supplementation exerted consistent protective effects, shown as restored microglial morphology and neurogenesis. Mechanistically, the indole derivatives were shown to activate AhR signaling, which in turn balanced the expression of anti-inflammatory factors (e.g., IL-10, TGF-β) and pro-inflammatory factors (e.g., IL-1β, CD68), thereby remodeling microglial morphology and promoting neurogenesis in hippocampus. A series of loss-of-function and gain-of-function experiments further confirmed AhR’s essential role: the salutary effects of indole derivatives on anti-depression were substantially attenuated in AhR-/- mice; reciprocally, conditional microglia-specific overexpression of AhR in the hippocampus of CRS mice significantly ameliorated CRS-induced depressive-like changes, accompanied by suppression of microglial activation and upregulation of anti-inflammatory factors. Collectively, the present study revealed a previously unrecognized the microbiota-derived indole derivatives ameliorated CRS-induced adolescent depression via the AhR signaling pathway. These findings highlight that targeting the indole derivative-AhR signaling axis may represent a novel therapeutic strategy for adolescent depression, one with the potential to minimize side effects and address the unmet clinical needs of this vulnerable population.

Objective Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is extensively used in neurointerventional procedures to prevent thromboembolic events. Intracranial aneurysm (IA) and cerebral artery stenosis (CAS) might exhibit different responses to DAPT because they have different pathophysiologies. In the present study, we compared IA and CAS patients in terms of ischemic and hemorrhagic complications after endovascular treatment maintained with DAPT. Methods We conducted a retrospective analysis of patients undergoing neurointerventional procedures at our center between August 2023 and September 2024. Clinical data, including DAPT regimens, baseline characteristics, and complications (ischemic or hemorrhagic), were systematically reviewed. Propensity score matching (PSM) was used to adjust for baseline differences between groups. Results A total of 991 patients (556 IA and 435 CAS) were enrolled. While IA patients and CAS patients demonstrated comparable rates of ischemic complications (2.3% vs. 1.1%, P = 0.131), the former showed a significantly higher incidence of hemorrhagic complications than the latter, particularly nuisance bleeding (NB) (45.7% vs. 15.9%, P < 0.001). There were significant differences in the prevalence of atherosclerosis risk factors and baseline characteristics between the two groups. After PSM (232 matched pairs), ischemic event rates remained similar between groups, while hemorrhagic complications remained more frequent in IA patients. Conclusion Our findings indicate that standard DAPT (aspirin 100mg/day + clopidogrel 75mg/day) appears appropriate for CAS patients but may be associated with increased NB risk in IA patients. These results underscore the need for condition-specific antiplatelet strategies in neurointerventional practice.

Bisphenol F (BPF), a widely used substitute for bisphenol A (BPA), has raised growing concerns due to its potential metabolic toxicity. Recent studies suggest that BPF exposure is associated with lipid accumulation and non-alcoholic fatty liver disease (NAFLD‌)-like changes, however, the underlying mechanisms remain poorly understood. This study was performed to investigate the BPF-induced NAFLD-like changes through the lipid degradative pathway, which via an unrecognized defect of lipophagy mediated by Adipose Triglyceride Lipase (ATGL)-Sirtuin 1 (SIRT1)-Peroxisome proliferator-activated receptor α (PPARα) signaling axis. It showed that BPF significantly suppressed ATGL, SIRT1 and PPARα expression, both in vivo and in vitro study, inhibited lysosomal acidification, and disrupted autophagic flux. Reciprocally, overexpression of ATGL and pharmacological activation of PPARα effectively ameliorated the BPF induced lipid accumulation, defects of autophagic flux, and restored acidification of lysosomes via enhanced Vacuolar-type adenosine triphosphatases (V-ATPase, a proton pump) level. Mechanistically, BPF exposure significantly blocked the Transcription Factor EB (TFEB‌‌) nuclear translocation, and thereby impaired the lysosomal generation and acidification. Intriguingly, pharmacological activation of PPARα facilitated TFEB nuclear translocation and counteracted the BPF-induced lipid deposition. These findings reveal key roles of ATGL-SIRT1-PPARα axis in lipophagy in BPF induced NAFLD-like changes, during which TFEB nuclear translocation played the crucial roles, therefore, targeting lipid degradation pathways may offer potential therapeutic strategies for NAFLD prevention and treatment.

Major depressive disorder (MDD), one of the most prevalent mental illnesses, is characterized by anhedonia, the inability to experience pleasure from rewarding activities. This minireview examines the complex relationship between music, anhedonia, and neural activity from neuroimaging and neuroelectrophysiological perspectives. It synthesizes the latest advances in music neuroscience, exploring music's potential to modulate emotional responses and alleviate anhedonia in depressed individuals. Anhedonia has been linked to dysfunctional brain reward circuits. Functional magnetic resonance imaging studies have revealed that the potential mechanism by which music exerts its anti-depressive effect may involve the reactivation of the anterior cingulate cortex, while electroencephalographic studies have revealed that oscillatory network dysfunction significantly impairs music perception engagement in patients with MDD. Musical chills, representing intense emotional peaks during musical experiences, can evoke profound pleasure in healthy individuals and may offer a therapeutic modality for alleviating anhedonia in MDD. This review discusses how music therapy may support emotional regulation by activating these neural pathways and enhancing affective processing. Despite promising developments, this field remains understudied. A more nuanced research approach is urgently needed to better understand the mechanisms underlying music's effects on anhedonia and to develop effective interventions.

The aim of this research was to characterize changes in peripheral blood neurotransmitter metabolites in olanzapine-treated schizophrenia (SCZ) and to identify potential biomarkers for SCZ. Concurrently, the relationship between these differential neurotransmitters and cognitive function is explored. We recruited 40 SCZ treated with single-agent olanzapine and 40 healthy controls (HC). Cognitive function and psychopathology were assessed using the MCCB and PANSS, respectively. Neurotransmitter levels were determined by targeted metabolomics approach using liquid chromatography-mass spectrometry (LC/MS). SCZ showed cognitive impairment in all domains of the MCCB compared to HC. Interestingly, a 4-neurotransmitter panel consisting of 3-Methoxytyramine hydrochloride (3-MT), 3,4-Dihydroxyphenylacetate (DOPAC), arginine, and r-aminobutyric acid (GABA) illustrated the highest determinative score between SCZ and HC. Arginine was positively correlated with PANSS general psychopathology scores. 3-MT independently predicted the verbal learning scores only in SCZ, whereas GABA independently predicted the social cognition scores only. Furthermore, GABA independently predicted the working memory scores only in HC. The collective assessment of these four neurotransmitters (3-MT, DOPAC, arginine, and GABA) holds considerable promise as potential biomarkers for SCZ. Moreover, 3-MT and GABA may enhance our understanding of cognitive dysfunction in SCZ, particularly in areas of verbal learning and social cognitive dysfunction.

Methamphetamine (Meth), a psychostimulant drug of the amphetamine type, is widely abused and highly neurotoxic. Meth exposure leads to neuronal necroptosis, and the mitochondrial dysfunction may be involved. However, the underlying mechanisms remain poorly understood. Here, we found that Meth significantly elicited the formation of the RIPK1–RIPK3–MLKL necrosome complex. Intriguingly, the activated MLKL (p-MLKL) translocated to the mitochondrial membrane and displayed pore-forming activity, manifesting as the penetration of MLKL in the cell membranes of the mitochondria, which caused decreased mitochondrial membrane potential, ATP generation, and mitochondrial DNA (mtDNA) and increased mitochondrial ROS (mtROS) generation, which finalized neuronal necroptosis. Notably, MLKL activation and translocation seem to depend on the RIPK1–RIPK3 axis since these adverse effects can be substantially ameliorated by disruption of the necrosome complex formation by the necroptotic inhibitor 1 (Nec-1), which also markedly impeded the MLKL mitochondrial membrane translocation. Finally, to delineate the effects of pore formation-associated ROS generation, specific blockage of mtROS retarded the Meth-induced neuronal necroptosis. In conclusion, our study reveals for the first time that MLKL mitochondrial membrane translocation may be involved in Meth-induced neuronal necroptosis. Therefore, impeding MLKL translocation might provide a novel therapeutic strategy for Meth-induced neurotoxicity.

Sepsis can cause severe cardiac damage, and matrix metalloproteinase 9 (MMP9) is involved in the inflammatory response and tissue injury processes. Monotropein is a monoterpene glycoside with anti-inflammatory and antioxidant effects. This study aims to investigate whether monotropein can alleviate sepsis-induced cardiac injury by affecting the activity of MMP9. The correlation between MMP9 and septic cardiac injury was explored using differential expression gene analysis from the GEO database and an in vitro lipopolysaccharide (LPS)-stimulated H9c2 cell model. In a cecal ligation and puncture (CLP)-induced mouse sepsis model, the effects of monotropein on myocardial cell apoptosis, inflammatory factor expression, and antioxidant enzyme levels were validated through drug administration. The results showed that MMP9 was significantly upregulated in sepsis patients. In the H9c2 cell model, LPS-induced MMP9 activity was positively correlated with cell damage. Inhibition of MMP9 alleviates LPS-induced myocardial matrix disruption and apoptosis. Monotropein exerts anti-matrix degradation and anti-apoptotic effects through MMP9 in LPS-induced H9c2 cells. Monotropein also reduced the expression of LPS-induced inflammatory factors (TNF-α, IL-1β, IL-6).In the mouse model, monotropein decreased oxidative stress damage (lower MDA levels, increased GSH, T-AOC, CAT enzyme activity), and improved cardiac injury by inhibiting myocardial cell apoptosis-related proteins (Bax, Bcl-2, and Caspase-3 activation). Monotropein exerts a protective effect on septic cardiac injury by inhibiting MMP9 activity, reducing inflammatory response, and enhancing antioxidant capacity, thereby ameliorating myocardial cell damage and apoptosis.

The optimal timing of enteral nutrition for critically ill septic patients in the intensive care unit (ICU) who require invasive mechanical ventilation has not been determined, and the influence of early enteral nutrition on clinical outcomes is unclear. This retrospective observational study utilized data from the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2) database to investigate patients with sepsis who needed invasive mechanical ventilation post-ICU admission. Patients who had enteral nutrition (EN) initiated within 72 h of ICU were categorized into the early enteral nutrition (EEN) group, while those who began enteral nutrition after 72 h were placed in the delayed enteral nutrition (DEN) group. Propensity score matching analysis was performed to compare outcomes between these two groups, with the primary outcome being 28-day mortality. The final analysis included 2293 patients, 1546 (67.4

In addition to the high neurotoxicity, depression, and anxiety are the most prominent characteristics of methamphetamine (Meth) withdrawal. Studies to date on the issue of Meth-associated depression and anxiety are focused on the brain, however, whether peripheral homeostasis, especially the “microbiota-gut” axis participates in these adverse outcomes, remains poorly understood. In the current study, with the fecal microbiota transplantation (FMT) assay, the mice received microbiota from Meth withdrawal mice displayed marked depression and anxiety behaviors. The 16S rRNA sequencing results showed that Meth withdrawal contributed to a striking reduction of Akkermansia, Bacteroides, Faecalibaculum, Desulfovibrio, and Anaerostipes, which are known to be associated with tryptophan (TRP) metabolism. Noteworthily, the substantial decreases of the indole derivatives from the TRP metabolic pathway, including IAA, IPA, ILA, IET, IArA, IAld, and TRM were observed in the serum of both Meth abusing humans and mice during Meth withdrawal with the UHPLC-MS/MS analysis. Combining the high and low TRP diet mouse model, the mice with high TRP diet obviously impeded Meth-associated depression and anxiety behaviors, and these results were further strengthened by the evidence that administration of IPA, IAA, and indole dramatically ameliorated the Meth induced aberrant behaviors. Importantly, these protective effects were remarkably counteracted in aryl hydrocarbon receptor knockout (AhR KO) mice, underlining the key roles of microbiota-indoles-AhR signaling in Meth-associated depression and anxiety. Collectively, the important contribution of the present work is that we provide the first evidence that peripheral gut homeostasis disturbance but not limited to the brain, plays a key role in driving the Meth-induced depression and anxiety in the periods of withdrawal, especially the microbiota and the indole metabolic disturbance. Therefore, targeting AhR may provide novel insight into the therapeutic strategies for Meth-associated psychological disorders.