ABSTRACT Chronic low‐grade inflammation is implicated in obesity, type 2 diabetes, affective disorders, and neurodegeneration. Yet, most preclinical studies focused exclusively on males. Here, we conducted a comprehensive study of sex differences in the response to chronic low‐dose lipopolysaccharide (LPS) exposure in male and female rats using telemetric monitoring, behavioral testing, plasma and cecal metabolomics, fecal microbiome profiling, and hippocampal transcriptomics. LPS reduced food intake and slowed body weight gain in males but not females, with depot‐specific adipose tissue loss (inguinal in males, visceral in females) and increased liver weight in females only. Body temperature changes were small and had a distinct temporal and directional pattern in each sex. Males, but not females, displayed reduced locomotion. Plasma amino acids increased in males but decreased in females, while citrate and mannose were affected in both sexes. Cecal metabolomics revealed shifts in TCA cycle intermediates and short‐chain fatty acid precursors independent of sex. Taxon‐level, sex‐specific effects of chronic LPS were detected in the fecal microbiome. While circulating inflammatory factor changes were consistent with endotoxin tolerance in both sexes, hippocampal RNA sequencing revealed increased cytokine signaling and innate immune pathways in both sexes, with more robust changes in males. Anxiety‐like behavior was affected in males only. In females, LPS prolonged the estrous cycle through extended diestrus. These findings demonstrate that intermittent low‐dose LPS exposure produces widespread multi‐system sex‐divergent outcomes, with males showing greater central inflammatory and behavioral vulnerability and females exhibiting distinct peripheral metabolic, thermoregulatory, and reproductive consequences.
ABSTRACT A possible interaction between liver and lung in health and disease has attracted growing interest. From an anatomist's perspective, the liver and the lung share many morphological, physiological, and developmental analogies. Both organs supply the body with important substances from the environment (nutrients, oxygen). Even though the liver receives nutrients from the intestine via the portal vein and is therefore not in direct contact with the external environment, the three‐dimensional organ architecture is similar, as both organs need an inflow from external substances as well as a dual blood supply (vasa privata and vasa publica). The cellular architecture is linked to the anatomical location and function, and cells of both organs share comparable anatomical and functional characteristics. In addition, there are (patho‐)physiologic mechanisms including liver and lung such as the renin‐angiotensin system, lipid metabolism, regeneration, as well as bacterial translocation and acute phase response. Dysfunction of one organ can therefore influence the other organ as well. As a consequence, there are many different diseases affecting both organs, such as hepatopulmonary syndrome, obstructive sleep apnea, acute respiratory distress syndrome, portopulmonary hypertension, and others. Liver and lung are either both affected by a systemic stimulus, or one of the organs is causally diseased and secondarily affects the other. Nevertheless, detailed knowledge about pathomechanisms is mostly lacking. By analyzing and comparing the structural and functional characteristics of liver and lung, the present review article aims at providing the reader with a comprehensive overview about the anatomical basis of the liver‐lung axis.
ABSTRACT Background Prior studies established adipose‐derived extracellular vesicles, or adiposomes, as mediators of interorgan communication with lipidomic signatures linked to cardiometabolic health. Because adiposomes signal to distant organs via the circulation, we examined whether circulating adiposome lipidomes reflect matched subcutaneous adipose tissue adiposomes. Methods This cross‐sectional paired lipidomic study included 22 subjects with matched circulating and subcutaneous adipose tissue adiposome samples. Untargeted lipidomics quantified 773 lipid features across 18 detected broad classes. Spearman correlation was the primary across‐subject species‐level metric; pooled and within‐subject Pearson and Spearman correlations, principal component analysis, Bland–Altman analysis, class composition, and matched‐versus‐mismatched similarity were complementary measures. Additional analyses evaluated sex, cardiometabolic phenotypes, and focused species‐clinical associations. Results Across 770 species with valid across‐subject estimates, the median plasma‐subcutaneous Spearman ρ was 0.101 and no species survived Benjamini‐Hochberg false‐discovery‐rate correction, although 553 (71.8%) correlations were positive. Mean broad‐class composition was highly conserved (Spearman ρ = 0.996; Pearson r on log 2 percentages = 0.996). Matched whole‐profile similarity was not greater than mismatched similarity (median ρ = 0.818 vs. 0.811; p = 0.620), and the matched sample was the closest pair for 0 of 22 participants. Neither sex nor any prespecified cardiometabolic phenotype explained matched‐profile similarity after correction, and no focused species‐clinical association survived full‐screen FDR correction. Conclusions Circulating and subcutaneous adiposome lipidomes share a highly conserved mean class architecture, but individual species, subject‐specific matching, and clinical‐association patterns are not interchangeable. Plasma adiposomes may therefore serve as complementary circulating readouts of adipose‐derived interorgan lipid signaling rather than direct tissue substitutes.
Objective To investigate associations among sleep-related features, neuroendocrine alterations, and colorectal cancer (CRC)-related molecular programs, and to identify candidate genes involved in hypothalamus-tumor interactions.Methods NHANES data were analyzed to assess associations between sleep disorder status and mortality among cancer survivors. An orthotopic MC38 CRC mouse model was used to evaluate sleep-wake and neuroendocrine alterations. Integrative analyses of murine hypothalamic and colorectal tissue transcriptomes, TCGA data, and public hypothalamic single-cell datasets were performed to identify and characterize candidate genes. HVCN1 knockdown and overexpression were used for functional validation in MC38 cells.Results Sleep disorder status was inversely associated with cardiovascular mortality in NHANES cancer survivors (HR = 0.47, 95% CI: 0.29-0.74, p = 0.001), but not with all-cause or cancer-specific mortality. Tumor-bearing mice exhibited sleep fragmentation-like changes with increased corticosterone and norepinephrine levels. Transcriptomic integration identified 28 shared genes between hypothalamic and colorectal tissues, including HVCN1. TCGA analysis identified a sleep disturbance-related CRC subtype with poorer survival, while single-cell analysis revealed cell-type-dependent expression of HVCN1 across hypothalamic populations. HVCN1 was upregulated in hypothalamic and tumor tissues, and its overexpression promoted MC38 cell proliferation, migration, and invasion, whereas knockdown produced opposite effects.Conclusion Tumor-bearing status is associated with coordinated sleep-wake, neuroendocrine, and molecular alterations. HVCN1 is a candidate component of the hypothalamus-tumor interaction framework and regulates aggressive CRC cell behaviors in vitro, while its proposed pH-regulatory mechanism requires further validation.
ABSTRACT Preeclampsia (PE) is a life‐threatening pregnancy‐specific complication with complex pathogenesis, mainly involving poor placentation and endothelial dysfunction. Pyroptosis, an inflammatory regulated cell death mediated by gasdermin proteins and inflammatory caspases, has emerged as a key participant in PE pathogenesis. Excessive pyroptosis in trophoblasts impairs invasion and spiral artery remodeling, leading to placental ischemia/hypoxia, whereas aberrant pyroptosis in endothelial cells (ECs) exacerbates inflammatory responses and vascular dysfunction, with both processes contributing to PE progression. Notably, pyroptosis activation at the maternal‐fetal interface initiates a placenta‐to‐maternal interorgan communication axis, whereby pyroptosis‐associated mediators—including IL‐1β, IL‐18, HMGB1, and cellular debris are released into the maternal circulation, remotely perturbing vascular endothelial function and damaging distant maternal organs to trigger the systemic multiorgan manifestations of PE. This review summarizes the molecular mechanisms (canonical, non‐canonical, and other pathways) and key regulatory factors (reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, autophagy, and non‐coding RNAs) of pyroptosis, and focuses on its roles in trophoblast cells and ECs during PE development. Critically, we systematically categorize and highlight potential therapeutic agents targeting distinct nodes of the pyroptosis pathway, including direct inhibitors of the NLRP3 inflammasome, caspase‐1, gasdermin D, and the IL‐1β/IL‐1R axis, as well as their upstream regulators. In conclusion, this review identifies remaining research gaps and emphasizes that targeting pyroptosis, particularly the pyroptosis‐mediated interorgan communication axis, provides a promising novel strategy for the diagnosis and treatment of PE.
