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Critical illness causes disturbances in lipid metabolism. Here, we investigated the levels of apolipoprotein A-IV (apoA-IV), a regulator of triglyceride and cholesterol metabolism, in human sepsis. ApoA-IV (analyzed in 156 patients with systemic inflammatory response syndrome (SIRS)/sepsis) and cholesteryl ester (CE) (analyzed in 121 of these patients) were lower in patients compared to 43 healthy controls. In contrast, triglyceride (TG) levels were elevated in patients. ApoA-IV levels in plasma of the patients did not correlate with these lipids. Patients with SIRS, sepsis or septic shock had comparable apoA-IV, TG, CE and free cholesterol (FC) levels. Patients on dialysis had significantly lower CE levels, whereas apoA-IV levels did not change much. CE levels were elevated in patients with viral sepsis due to SARS-CoV-2 infection in comparison to SIRS/sepsis patients not infected by this virus. CE levels correlated negatively with procalcitonin, interleukin-6 and bilirubin, while TGs were positively associated with bilirubin and C-reactive protein. ApoA-IV, TG, CE and FC levels were not associated with bacterial infection or survival. In conclusion, this analysis suggests that CE levels decline in sepsis-related renal failure and also shows that plasma apoA-IV and CE levels are early biomarkers of sepsis.

SARS-CoV-2 infection was shown to induce proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels in sepsis. Here, we investigate the association between serum PCSK9 levels and disease severity. PCSK9 was measured in serum of 55 controls, 40 patients with moderate and 60 patients with severe COVID-19 disease. Serum PCSK9 was elevated in moderate COVID-19 compared to controls and further increased in severe cases. PCSK9 levels were not associated with C-reactive protein, bacterial superinfections, interventions, or survival in patients with severe COVID-19. PCSK9 regulates circulating cholesterol levels, and 15 cholesteryl ester (CE) species and free cholesterol (FC) were quantified by direct flow injection analysis using a high-resolution hybrid quadrupole-Orbitrap mass spectrometer. Most CE species with shorter fatty acid chains were decreased in severe compared to moderate COVID-19, and none of the CE species were correlated with PCSK9 in patients with severe COVID-19. Levels of all CE species negatively correlated with C-reactive protein in severe COVID-19 patients. Notably, FC was induced in severe compared to moderate COVID-19. The FC/CE ratio correlated positively with inflammatory markers and was associated with non-survival. The current study suggests that the imbalance between CE and FC levels is associated with disease severity and mortality in patients with COVID-19.

Predicting responses and monitoring the severity of inflammatory bowel disease (IBD) is challenging due to a lack of specific biomarkers. This study identifies urinary hydroxyproline, a marker of collagen turnover elevated in experimental colitis, as independent of conventional biomarkers like creatinine, glomerular filtration rate, C-reactive protein, and fecal calprotectin. Among 71 IBD patients, urinary hydroxyproline levels were significantly higher compared with 36 controls, with an area under the receiver operating characteristic curve of 0.814, highlighting its potential as a diagnostic tool. No significant difference in hydroxyproline levels was observed between the 50 Crohn’s disease and 21 ulcerative colitis patients, nor was there a correlation with kidney function markers, gastrointestinal symptom severity, or stool consistency. Disease localization was not associated with urinary hydroxyproline levels. Interestingly, 14 patients with primary sclerosing cholangitis and IBD also exhibited elevated urinary hydroxyproline levels, comparable to IBD patients but higher than healthy controls. This underscores the role of urinary hydroxyproline as an independent biomarker for IBD diagnosis, without association with disease severity or established markers like fecal calprotectin.

Abstract Background Metastatic Crohn’s disease is a rare disorder characterized by various granulomatous skin lesions that occur independently of gastrointestinal tract involvement. However, currently there is no standardized care or specific treatment. Therapeutic approaches include immunosuppressive agents, such as corticosteroids, azathioprine, and monoclonal antibodies targeting inflammatory cytokines like tumor necrosis factor (TNF). Case presentation We present a case of a 29-year-old western European woman with significant blind ending abdominal subcutaneous fistulas and abscesses, who sought evaluation in the dermatology department. Histological examination revealed multiple epithelioid cell granulomas. There was no evidence of infectious or rheumatologic diseases such as sarcoidosis. The tentative diagnosis was metastatic Crohn’s disease, which was not related to an intestinal manifestation of the disease. The patient responded to infliximab but had to discontinue it due to an allergic reaction. Subsequent adalimumab treatment failed to induce clinical remission; thus, therapy was switched to ustekinumab, resulting in a positive response. Written informed consent for publication of their clinical details and clinical images was obtained from the patient. For our study more than 1600 publications were screened for cases of metastatic Crohn’s disease on PubMed database. 59 case reports with 171 patients were included in the analysis and evaluated for localization, diagnostic and therapeutic approaches, and complications and were summarized in this review. Conclusion The successful ustekinumab treatment of a patient with metastatic Crohn's disease underscores the potential of this minimally investigated therapeutic option, highlighting the need for future treatment guidelines given the increasing prevalence of such cases.

Abstract Direct air capture has gained traction as a method for carbon dioxide removal. How and whether direct air capture can be deployed requires securing social license to operate, and increasingly demands environmental justice and just transition principles. Here we use a nationally representative survey to evaluate public perceptions of direct air capture, paired with focus groups to assess community perceptions across four communities in the United States: Houston, Texas; Monaca, Pennsylvania; Bakersfield, California; and Rock Springs, Wyoming. We find conditional support for direct air capture deployment among focus group participants, and majority support for direct air capture deployment among national survey respondents. The most important determinants of project support were procedural justice elements—in particular community involvement in planning and implementation—and anticipated community benefits in the forms of local infrastructure and workforce development, supporting the need to center environmental justice and just transition principles into project planning and implementation. Where concerns over environmental and health implications are strong, direct air capture may not gain local social license to operate, especially in communities with previous negative experiences with industry.

Fibroblasts are mesenchymal cells that are responsible for creating and maintaining tissue architecture through the production of extracellular matrix. These cells also play critical roles in processes such as wound repair and immune modulation in normal tissues and various disease states including fibrosis, autoimmunity, and cancer. Fibroblasts have a complex repertoire of functions that vary by organ, inflammatory state, and the developmental stage of an organism. How fibroblasts manage so many functions in such a context-dependent manner represents a gap in our understanding of these cells. One possibility is that a tissue-resident precursor cell state exists that provides the fibroblast lineage with flexibility during growth, inflammation, or other contexts that require dynamic tissue changes. Recent work has suggested that a precursor fibroblast cell state is marked by expression of Peptidase inhibitor 16 ( Pi16). This review aims to concatenate and compare studies on fibroblasts that express Pi16 to clarify the roles of this cell state in fibroblast lineage development and other functions.

Hydroxychloroquine (HCQ) is an antimalarial agent that is commonly used in the management of rheumatic skin disease. Few reports exist documenting exacerbation of dermatomyositis (DM) related to HCQ. Herein, we describe three adult patients with worsening DM cutaneous disease after starting HCQ and resolution or improvement with cessation. The time to exacerbation ranged from two weeks to nine months after the initiation of HCQ 400mg/day. Two of the three patients had antibodies to transcription intermediary factor 1γ (TIF1γ) and the other had antibodies to anti-nuclear matrix protein 2 (NXP2). After discontinuation of HCQ, the time to improvement or resolution of cutaneous symptoms ranged from six weeks to six months. Hydroxychloroquine may be associated with worsening cutaneous features in DM. In patients who are not improving despite escalation of immunosuppressive medications, or are worsening, we recommend a trial of discontinuing HCQ.

Fibroblasts are mesenchymal cells that are responsible for creating and maintaining tissue architecture through the production of extracellular matrix. These cells also play critical roles in processes such as wound repair and immune modulation in normal tissues and various disease states including fibrosis, autoimmunity, and cancer. Fibroblasts have a complex repertoire of functions that vary by organ, inflammatory state, and the developmental stage of an organism. How fibroblasts manage so many functions in such a context-dependent manner represents a gap in our understanding of these cells. One possibility is that a tissue-resident precursor cell state exists that provides the fibroblast lineage with flexibility during growth, inflammation, or other contexts that require dynamic tissue changes. Recent work has suggested that a precursor fibroblast cell state is marked by expression of Peptidase inhibitor 16 (Pi16). This review aims to concatenate and compare studies on fibroblasts that express Pi16 to clarify the roles of this cell state in fibroblast lineage development and other functions.

IntoductionIdentification of specific metabolome and lipidome profile of patients with primary sclerosing cholangitis (PSC) is crucial for diagnosis, targeted personalized therapy, and more accurate risk stratification.MethodsNuclear magnetic resonance (NMR) spectroscopy revealed an altered metabolome and lipidome of 33 patients with PSC [24 patients with inflammatory bowel disease (IBD) and 9 patients without IBD] compared with 40 age-, sex-, and body mass index (BMI)-matched healthy controls (HC) as well as 64 patients with IBD and other extraintestinal manifestations (EIM) but without PSC.ResultsIn particular, higher concentrations of pyruvic acid and several lipoprotein subfractions were measured in PSC in comparison to HC. Of clinical relevance, a specific amino acid and lipid profile was determined in PSC compared with IBD and other EIM.DiscussionThese results have the potential to improve diagnosis by differentiating PSC patients from HC and those with IBD and EIM.

Este trabalho tem como objetivo, a partir da experiência e do testemunho de um Coletivo de Mulheres, propor uma leitura do que nomeamos como o Real da violência por meio do ensino de Lacan e comentadores. Diferente do Real enquanto fundamento ausente ou falta-a-ser, o Real da violência se insere historicamente no dia a dia e na vida de determinados corpos brasileiros, precisamente os corpos negros, femininos e periféricos. Em vista do cenário de impasses socio-políticos do Brasil, mas também de potentes vozes e ações que têm surgido das comunidades atravessadas por estruturas de violência, a experiência do Coletivo ilustra o presente trabalho, a fim de demonstrar caminhos possíveis para um saber-fazer com esse Real ao qual seus filhos e a comunidade estão mais expostos. À luz de conceitos da Teoria Feminista, como, por exemplo, a noção de interseccionalidade e a categoria corpo-território, endossamos essa discussão que demanda à Psicanálise conversar com outros campos do saber. Empreitada que exige engajamento ético e político dos psicanalistas, em especial dos que exercem a práxis analítica no Brasil.

Background/Objectives: Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is an antagonist of transforming growth factor (TGF)-β type 1 signaling. BAMBI functions as an anti-fibrotic protein and exerts pro- as well as anti-cancerogenic activities. Our study aimed to correlate hepatocyte BAMBI protein levels in hepatocellular carcinoma (HCC) with T stage, lymph node invasion, vessel invasion, grading, tumor size and Union for International Cancer Control (UICC) stage, as well as with liver inflammation and fibrosis stages. Methods: Hepatocyte BAMBI protein expression was assessed by immunohistochemistry in HCC tissues of 320 patients and non-tumor tissues of 51 patients. Results: In the HCC tissues of the whole cohort and sex-specific analysis, BAMBI protein was not related to T stage, vessel invasion, lymph node invasion, histologic grade, UICC stage and tumor size. Accordingly, BAMBI was not associated with overall survival, recurrence-free and metastasis-free survival. BAMBI protein levels in tumor and non-tumor tissues were not related to inflammation and fibrosis grade. BAMBI protein levels in HCC tissues and non-tumor tissues from HCC patients, which were analyzed by immunoblot in a small cohort and by immunohistochemistry in the tissues of patients described above, were similar. Notably, BAMBI protein was low-abundant in HCC tissues of hepatitis C virus (HCV) compared to hepatitis B virus (HBV)-infected patients with comparable disease severity. Immunoblot analysis revealed reduced BAMBI protein in non-tumor tissues of patients with HCV in comparison to patients with HBV and normal human liver tissues. Conclusions: In summary, this analysis showed that hepatocyte BAMBI protein levels of patients with HCC are related to HCV infection rather than the severity of the underlying liver disease and cancer staging.

Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 2019 (COVID-19), a disease with very heterogeneous symptoms. Dyslipidaemia is prevalent in at least 20% of Europeans, and dyslipidaemia before SARS-CoV-2 infection increases the risk for severe COVID-19 and mortality by 139%. Many reports described reduced serum cholesterol levels in virus-infected patients, in particular in those with severe disease. The liver is the major organ for lipid homeostasis and hepatic dysfunction appears to occur in one in five patients infected with SARS-CoV-2. Thus, SARS-CoV-2 infection, COVID-19 disease severity and liver injury may be related to impaired cholesterol homeostasis. These observations prompted efforts to assess the therapeutic opportunities of cholesterol-lowering medications to reduce COVID-19 severity. The majority of studies implicate statins to have beneficial effects on disease severity and outcome in COVID-19. Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies have also shown potential to protect against COVID-19. This review describes the relationship between systemic cholesterol levels, liver injury and COVID-19 disease severity. The potential effects of statins and PCSK9 in COVID-19 are summarised. Finally, the relationship between cholesterol and lung function, the first organ to be affected by SARS-CoV-2, is described.

Background/Objectives: Chemerin is an adipokine involved in inflammatory and metabolic diseases, and its circulating levels have been associated with inflammatory parameters in various patient cohorts. Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, which causes COVID-19, triggers inflammatory pathways. However, the association between serum chemerin levels and COVID-19 disease severity and outcomes has not been definitively established. Methods: In this study, serum chemerin levels were analyzed in 64 patients with moderate COVID-19 and 60 patients with severe disease. Results: The results showed that serum chemerin levels were comparable between these two groups and slightly higher than in healthy controls. Notably, COVID-19 patients with hypertension exhibited elevated serum chemerin levels, while those with liver cirrhosis had lower levels. When patients with these comorbidities were excluded from the analyses, serum chemerin levels in COVID-19 patients were similar to those in healthy controls. Positive correlations were observed between serum chemerin levels and markers such as alkaline phosphatase, C-reactive protein, eosinophils, and lymphocytes in the entire cohort, as well as in the subgroup excluding patients with hypertension and cirrhosis. Additionally, urinary chemerin levels were comparable between COVID-19 patients and controls, and neither hypertension nor dialysis significantly affected urinary chemerin levels. Both survivors and non-survivors had similar serum and urinary chemerin levels. Conclusions: In conclusion, this study suggests that comorbidities such as arterial hypertension and liver cirrhosis do have a more significant impact on serum chemerin levels than SARS-CoV-2 infection itself.

Fibroblasts are cells of mesenchymal origin that are found throughout the body. While these cells have several functions, their integral roles include maintaining tissue architecture through the production of key extracellular matrix components, and participation in wound healing after injury. Fibroblasts are also key mediators in disease progression during fibrosis, cancer, and other inflammatory diseases. Under these perturbed states, fibroblasts can activate into inflammatory fibroblasts or contractile myofibroblasts. Fibroblasts require various growth factors and mitogenic molecules for survival, proliferation, and differentiation. While the activity of mitogenic growth factors on fibroblasts in vitro was characterized as early as the 1970s, the proliferation and differentiation effects of growth factors on these cells in vivo are unclear. Recent work exploring the heterogeneity of fibroblasts raises questions as to whether all fibroblast cell states exhibit the same growth factor requirements. Here, we will examine and review existing studies on the influence of fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptors (PDGFRs), and transforming growth factor β receptor (TGFβR) on fibroblast cell states.

Fibroblasts are cells of mesenchymal origin that are found throughout the body. While these cells have several functions, their integral roles include maintaining tissue architecture through the production of key extracellular matrix components, and participation in wound healing after injury. Fibroblasts are also key mediators in disease progression during fibrosis, cancer, and other inflammatory diseases. Under these perturbed states, fibroblasts can activate into inflammatory fibroblasts or contractile myofibroblasts. Fibroblasts require various growth factors and mitogenic molecules for survival, proliferation, and differentiation. While the activity of mitogenic growth factors on fibroblasts in vitro was characterized as early as the 1970s, the proliferation and differentiation effects of growth factors on these cells in vivo are unclear. Recent work exploring the heterogeneity of fibroblasts raises questions as to whether all fibroblast cell states exhibit the same growth factor requirements. Here, we will examine and review existing studies on the influence of fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptors (PDGFRs), and transforming growth factor β receptor (TGFβR) on fibroblast cell states.

Abstract Background Disturbed bile acid homeostasis associated with a rise of primary and a decline of secondary bile acids is a consistent finding in inflammatory bowel diseases (IBDs). Whether fecal bile acids may emerge as biomarkers for IBD diagnosis and disease severity is less clear. Our study aimed to identify associations of 18 fecal bile acid species with IBD entity and disease activity. Methods Stool samples of 62 IBD patients and 17 controls were collected. Eighteen fecal bile acid species were quantified by LC–MS/MS using stable isotope dilution. Lipid levels normalized to a dry weight of the fecal homogenates and ratios of single bile acid species to total bile acid levels were used for calculations. Results IBD patients exhibited altered primary and secondary bile acid ratios in stool, with notable distinctions between ulcerative colitis (UC) compared to Crohn’s disease (CD) and healthy controls. Fecal calprotectin was negatively correlated with glycolithocholic acid (GLCA) and hyodeoxycholic acid (HDCA) in UC. These bile acids were reduced in stool of UC patients with fecal calprotectin levels > 500 µg/g compared to UC patients with low calprotectin levels. Moreover, negative associations of six secondary bile acids with C-reactive protein (CRP) existed in UC. In CD patients, fecal bile acids did not correlate with CRP or fecal calprotectin. Diarrhoea is common in IBD, and UC patients with diarrhoea had reduced deoxycholic acid (DCA), glycine conjugated DCA (GDCA) and lithocholic acid in stool in contrast to patients with normal stool consistency. Fecal bile acid levels were not associated with diarrhoea in CD patients. UC patients treated with mesalazine had increased levels of fecal GDCA whereas no such changes were observed in CD patients. Bile acid levels of CD and UC patients treated with biologicals or corticosteroids did not change. Relative levels of GHDCA (specificity: 79%, sensitivity: 67%) and glycochenodeoxycholic acid (specificity: 74%, sensitivity: 63%) were the most specific to distinguish UC from CD. Conclusion Disrupted fecal bile acid homeostasis is associated with disease severity and disease symptoms in UC but not in CD, potentially aiding in distinguishing IBD subtypes and classifying the pathophysiology of diarrhoea in UC.

Abstract Background Urinary 3-indoxyl sulfate levels as well as fecal short chain fatty acid (SCFA) concentrations are surrogate markers for gut microbiota diversity. Patients with inflammatory bowel diseases (IBDs) and patients with primary sclerosing cholangitis (PSC), a disease closely associated with IBD, have decreased microbiome diversity. In this paper, the fecal SCFAs propionate, acetate, butyrate and isobutyrate of patients with IBD and patients with PSC-IBD and urinary 3-indoxyl sulfate of IBD patients were determined to study associations with disease etiology and severity. Methods SCFA levels in feces of 64 IBD patients and 20 PSC-IBD patients were quantified by liquid chromatography with tandem mass spectrometry (LC–MS/MS). Urinary 3-indoxyl sulfate levels of 45 of these IBD patients were analysed by means of reversed-phase liquid chromatography-electrospray ionization-tandem mass spectrometry. Feces of 17 healthy controls and urine of 13 of these controls were analyzed in parallel. These cohorts had comparable sex distribution and age. Results Urinary 3-indoxyl sulfate concentrations (normalized to urinary creatinine levels) was increased (P = 0.030) and fecal isobutyrate levels (normalized to dry weight of the stool sample) of IBD patients were decreased (P = 0.035) in comparison to healthy controls. None of the analyzed metabolites differed between patients with Crohn´s disease (CD) and patients with ulcerative colitis (UC). Fecal acetate and butyrate positively correlated with fecal calprotectin (P = 0.040 and P = 0.005, respectively) and serum C-reactive protein (P = 0.024 and P = 0.025, respectively) in UC but not CD patients. UC patients with fecal calprotectin levels above 150 µg/g, indicating intestinal inflammatory activity, had higher fecal acetate (P = 0.016), butyrate (P = 0.007) and propionate (P = 0.046) in comparison to patients with fecal calprotectin levels

Fibroblasts are mesenchymal cells that are responsible for creating and maintaining tissue architecture through the production of extracellular matrix. These cells also play critical roles in processes such as wound repair and immune modulation in normal tissues and various disease states including fibrosis, autoimmunity, and cancer. Fibroblasts have a complex repertoire of functions that vary by organ, inflammatory state, and the developmental stage of an organism. How fibroblasts manage so many functions in such a context-dependent manner represents a gap in our understanding of these cells. One possibility is that a tissue-resident precursor cell state exists that provides the fibroblast lineage with flexibility during growth, inflammation, or other contexts that require dynamic tissue changes. Recent work has suggested that a precursor fibroblast cell state is marked by expression of Peptidase inhibitor 16 ( Pi16). This review aims to concatenate and compare studies on fibroblasts that express Pi16 to clarify the roles of this cell state in fibroblast lineage development and other functions.

Fibroblasts are cells of mesenchymal origin that are found throughout the body. While these cells have several functions, their integral roles include maintaining tissue architecture through the production of key extracellular matrix components, and participation in wound healing after injury. Fibroblasts are also key mediators in disease progression during fibrosis, cancer, and other inflammatory diseases. Under these perturbed states, fibroblasts can activate into inflammatory fibroblasts or contractile myofibroblasts. Fibroblasts require various growth factors and mitogenic molecules for survival, proliferation, and differentiation. While the activity of mitogenic growth factors on fibroblasts in vitro was characterized as early as the 1970s, the proliferation and differentiation effects of growth factors on these cells in vivo are unclear. Moreover, recent work exploring the heterogeneity of fibroblasts raises questions as to whether all fibroblast cell states exhibit the same growth factor requirements. Here, we will examine and review existing growth factors known to influence fibroblast homeostasis to begin unpacking the potential growth factors that may influence in vivo fibroblast cell states.

Fibroblasts, non-hematopoietic cells of mesenchymal origin, are tissue architects which regulate the topography of tissues, dictate tissue resident cell types, and drive fibrotic disease. Fibroblasts regulate the composition of the extracellular matrix (ECM), a 3-dimensional network of macromolecules that comprise the acellular milieu of tissues. Fibroblasts can directly and indirectly regulate immune responses by secreting ECM and ECM-bound molecules to shape tissue structure and influence organ function. In this review, we will highlight recent studies which elucidate the mechanisms by which fibroblast-derived ECM factors (e.g., collagens, fibrillar proteins) regulate ECM architecture and subsequent immune responses, with a focus on macrophages. As examples of fibroblast-derived ECM proteins, we examine Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Transforming Growth Factor-β-inducible protein (TGFBI), also known as BIGH3. We address the need for investigation into how diverse fibroblast populations coordinate immune responses by modulating ECM, including the fibroblast-ECM-immune axis and the precise molecular mediators and pathways which regulate these processes. Finally, we will outline how novel research identifying key regulators of ECM deposition is critical for therapeutic development for fibrotic diseases and cancer.

Bacterial and fungal superinfections are common in COVID-19, and early diagnosis can enable timely intervention. Serum calprotectin levels increase with bacterial, fungal, and viral infections. This study evaluated serum calprotectin as a diagnostic and prognostic tool for microbial superinfections in COVID-19. Serum samples from adult patients with moderate and severe COVID-19 were collected during hospitalization from 2020 to 2024. Calprotectin levels were measured using an enzyme-linked immunosorbent assay in 63 patients with moderate COVID-19, 60 patients with severe COVID-19, and 34 healthy individuals. Calprotectin serum levels were elevated in patients with moderate COVID-19 compared with controls, and these levels were further increased in the severe cases. Patients with severe COVID-19 and vancomycin-resistant enterococci (VRE) bacteremia had elevated calprotectin levels, but their C-reactive protein and procalcitonin levels were not increased. Fungal superinfections and herpes simplex virus reactivation did not change the calprotectin levels. A calprotectin concentration of 31.29 µg/mL can be used to diagnose VRE bloodstream infection with 60% sensitivity and 96% specificity. These data suggest that serum calprotectin may be a promising biomarker for the early detection of VRE bloodstream infections in patients with COVID-19.

Amyloid beta (Aβ) plays a major role in the pathogenesis of Alzheimer’s disease and, more recently, has been shown to protect against liver fibrosis. Therefore, we studied Aβ-42 levels and the expression of genes involved in the generation, degradation, and transport of Aβ proteins in liver samples from patients at different stages of metabolic dysfunction-associated liver disease (MASLD) and under steatotic conditions in vitro/in vivo. Amyloid precursor protein (APP), key Aβ-metabolizing proteins, and Aβ-42 were analyzed using RT-PCR, Western blotting, Luminex analysis in steatotic in vitro and fatty liver mouse models, and TaqMan qRT-PCR analysis in hepatic samples from patients with MASLD. Hepatocytes loaded with palmitic acid induced APP, presenilin, and neprilysin (NEP) expression, which was reversed by oleic acid. Increased APP and NEP, decreased BACE1, and unchanged Aβ-42 protein levels were found in the steatotic mouse liver compared to the normal liver. Aβ-42 concentrations were low in MASLD samples of patients with moderate to severe fibrosis compared to the livers of patients with mild or no MASLD. Consistent with the reduced Aβ-42 levels, the mRNA expression of proteins involved in APP degradation (ADAM9/10/17, BACE2) and Aβ-42 cleavage (MMP2/7/9, ACE) was increased. In the steatotic liver, the expression of APP- and Aβ-metabolizing proteins is increased, most likely related to oxidative stress, but does not affect hepatic Aβ-42 levels. Consistent with our previous findings, low Aβ-42 levels in patients with liver fibrosis appear to be caused by the reduced production and enhanced non-amyloidogenic processing of APP.

Infectious diseases are associated with low iron levels and the induction of hepcidin, the primary protein regulating cellular iron export. Bone morphogenetic protein 6 (BMP6), a key regulator of hepcidin expression, has not yet been analyzed in the plasma of patients with systemic inflammatory response syndrome (SIRS) or sepsis. An analysis of 38 SIRS, 39 sepsis, and 78 septic shock patients revealed similar levels of BMP6 in sepsis and septic shock, which were lower compared to patients with SIRS and healthy controls. Plasma BMP6 levels did not correlate with procalcitonin and C-reactive protein levels in patients with SIRS or sepsis/septic shock. Neither bacterial nor SARS-CoV-2 infections affected plasma BMP6 levels. There was no difference in BMP6 levels between ventilated and non-ventilated patients, or between patients with and without dialysis. Vasopressor therapy did not alter BMP6 levels. Survivors had plasma BMP6 levels similar to non-survivors. Due to the high variability of plasma BMP6 levels, these analyses have limited clinical relevance. Iron, ferritin, and transferrin levels were known in at least 50% of patients but did not correlate with plasma BMP6 levels. In conclusion, this study showed normal BMP6 plasma levels in SIRS, which are reduced in patients with sepsis and septic shock. This suggests that the commonly observed increase in hepcidin levels and the decline in iron levels in SIRS, sepsis, and septic shock are not due to higher BMP6.

Phosphatidylcholine (PC) is an essential lipid for liver health and lipoprotein metabolism, but its circulating levels have rarely been studied in patients with cirrhosis. Chronic hepatitis C virus (HCV) infection causes lipid abnormalities and is a major cause of cirrhosis. Effective HCV elimination with direct-acting antivirals (DAAs) is associated with the normalization of serum low-density lipoprotein cholesterol levels. Since PC is abundant in all lipoprotein particles, this study analyzed the association between serum PC species levels and liver cirrhosis before and after HCV eradication. Therefore, 27 PC species were measured by Fourier Transform Mass Spectrometry in the serum of 178 patients with chronic HCV infection at baseline and in 176 of these patients at the end of therapy. The PC species did not correlate with viral load, and the levels of 13 PC species were reduced in patients infected with genotype 3a compared to those affected with genotype 1. Four PC species were slightly elevated 12 weeks after DAA initiation, and genotype-related changes were largely normalized. Patients with HCV and cirrhosis had higher serum levels of PC 30:0 and 32:0 before and at the end of therapy. PC species containing polyunsaturated fatty acids were mostly decreased in cirrhosis. The levels of polyunsaturated, but not saturated, PC species were inversely correlated with the model of the end-stage liver disease score. A receiver operating characteristic curve analysis showed area under the curve values of 0.814 and 0.826 for PC 32:0 and 0.917 and 0.914 for % PC 32:0 (relative to the total PC levels) for the classification of cirrhosis at baseline and at the end of therapy, respectively. In conclusion, the specific upregulation of PC 32:0 in cirrhosis before and after therapy may be of diagnostic value in HCV-related cirrhosis.

Neutrophils are critical immune cells in severe coronavirus disease 2019 (COVID-19). S100 calcium-binding protein A12 (S100A12) is highly expressed in neutrophils during acute inflammation. The aim of this study was to evaluate serum S100A12 levels as a diagnostic and prognostic tool in COVID-19. Serum samples of patients with moderate and severe COVID-19 were collected during 2020 to 2024. Enzyme-linked immunosorbent assay was used to measure serum S100A12 levels in 63 patients with moderate COVID-19, 60 patients with severe disease and 33 healthy controls. Serum S100A12 levels were elevated in moderate COVID-19 compared to controls and were even higher in severe cases. In moderate disease, serum S100A12 levels positively correlated with immune cell counts. While C-reactive protein and procalcitonin are established inflammation markers, they did not correlate with serum S100A12 levels in either patient cohort. Patients with severe COVID-19 and vancomycin-resistant enterococcus (VRE) infection had increased S100A12 levels. Elevated S100A12 levels were also observed in patients with herpes simplex reactivation. Fungal superinfections did not alter S100A12 levels. These data show that serum S100A12 increases in moderate and severe COVID-19 and is further elevated by VRE bloodstream infection and herpes simplex reactivation. Therefore, S100A12 may serve as a novel biomarker for severe COVID-19 and an early diagnostic indicator for bacterial and viral infections.