Organ Crosstalk Research Articles

Role and mechanism of myonectin in severe acute pancreatitis: a crosstalk between skeletal muscle and pancreas

BackgroundSevere acute pancreatitis (SAP) is characterized by high mortality rates and various complications, including skeletal muscle atrophy, which significantly exacerbates its outcomes. Despite its clinical relevance, the mechanistic understanding of the relationship between skeletal muscle and the pancreas in SAP remains limited. Our study aimed to elucidate this “organ crosstalk” and its potential implications.MethodsWe established an SAP mouse model through pancreatic duct ligation (PDL) and evaluated pancreatic necrosis, skeletal muscle atrophy, and myonectin expression levels. Recombinant myonectin protein was administered in vivo and in vitro to assess its effects on acinar cell necrosis. Mechanistic insights were gained through RNA-seq data analysis and experimental validation. Serum samples from AP patients and healthy controls were collected to investigate the correlation between serum myonectin levels and disease severity.ResultsThe mouse model exhibited severe pancreatic necrosis, skeletal muscle atrophy, and elevated myonectin levels, with myonectin administration exacerbating model severity. We identified iron accumulation-induced ferroptosis as a key pathway contributing to myonectin-mediated acinar cell necrosis. A total of 22 healthy controls and 52 patients with varying degrees of AP were included in the serum samples and clinical data (36.5% females, age 49.79 ± 16.53). Analysis of serum samples revealed significantly higher myonectin levels in AP patients, correlating with disease severity (R = 0.28, P = 0.041).ConclusionsOur findings underscore the significant role of myonectin in SAP progression and its potential as a prognostic marker for disease severity in AP patients. This study contributes to a deeper understanding of the pathophysiology of SAP and highlights potential therapeutic targets for intervention.

Proceedings of the 5th Meeting of Translational Hepatology, organized by the Spanish Association for the Study of the Liver (AEEH)

This is the summary report of the 5th Translational Hepatology Meeting, endorsed by the Spanish Association for the Study of the Liver (AEEH) and held in Seville, Spain, in October 2023. The meeting aimed to provide an update on the latest advances in the field of basic and translational hepatology, covering different molecular, cellular, and pathophysiological aspects of the most relevant clinical challenges in liver pathologies. This includes the identification of novel biomarkers and diagnostic tools, the understanding of the relevance of immune response and inflammation in liver diseases, the characterization of current medical approaches to reverse liver diseases, the incorporation of novel molecular insights through omics techniques, or the characterization of the impact of toxic and metabolic insults, as well as other organ crosstalk, in liver pathophysiology.

Organ Crosstalk: The Role of Spleen

Organ Crosstalk: The Role of Spleen

Abstract 4119213: A Novel Animal Model for Pulmonary Hypertension: Lung Endothelial Specific Deletion of Egln1 in Mice

Background: Pulmonary arterial hypertension (PAH) is a disastrous disease that is characterized by high blood pressure in the pulmonary arteries which has the potential to lead to heart failure over time. Previously, our lab found that endothelial-specific knockout of Egln1 , encoding prolyl 4-hydroxylase-2 (PHD2), induced spontaneous pulmonary hypertension (PH). Recently, we elucidated that Tmem100 is a lung-specific endothelial gene using Tmem100 CreERT2 mice. We reason that lung endothelial-specific deletion of Egln1 could lead to the development of PH without affecting other organs’ Egln1 gene expression and defect. Methods: Tm em100-CreERT2 mice were crossed with Egln1 flox/flox mice to generate Egln1 f/f ; Tmem100 CreERT2 (LiCKO) mice. Western blot and immunofluorescent staining were performed to verify the knockout efficacy of Egln1 in multiple organs of LiCKO mice. PH phenotypes including hemodynamics, right heart size and function, and pulmonary vascular remodeling were evaluated by right heart catheterization and echocardiography measurement. Results: Tamoxifen treatment induced Egln1 deletion in the lung ECs but no other organs in adult LiCKO mice. LiCKO mice exhibited an increase in right ventricular systolic pressure (RVSP, ~35 mmHg) and right heart hypertrophy. Echocardiography measurement showed right heart hypertrophy and cardiac and pulmonary arterial dysfunction. Pulmonary vascular remodeling including pulmonary wall thickness and muscularization of distal pulmonary arterials was enhanced in LiCKO mice compared to wild-type mice. Conclusions: Tmem100 promoter-mediated lung endothelial knockout of Egln1 in mice develops spontaneous PH. LiCKO mice could be a novel mouse model for PH to study lung and other organ crosstalk.

Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis

Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1/THY1+ myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP-related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting.

Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis.

Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1/THY1+ myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP-related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting.

Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives.

Steatotic liver diseases (SLD) are the principal worldwide cause of cirrhosis and end-stage liver cancer, affecting nearly a quarter of the global population. SLD includes metabolic dysfunction-associated alcoholic liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), resulting in asymptomatic liver steatosis, fibrosis, cirrhosis and associated complications. The immune processes include gut dysbiosis, adiposeliver organ crosstalk, hepatocyte death and immune cell-mediated inflammatory processes. Notably, various immune cells such as B cells, plasma cells, dendritic cells, conventional CD4+ and CD8+ T cells, innate-like T cells, platelets, neutrophils and macrophages play vital roles in the development of MetALD and MASLD. Immunological modulations targeting hepatocyte death, inflammatory reactions and gut microbiome include N-acetylcysteine, selonsertib, F-652, prednisone, pentoxifylline, anakinra, JKB-121, HA35, obeticholic acid, probiotics, prebiotics, antibiotics and fecal microbiota transplantation. Understanding the immunological mechanisms underlying SLD is crucial for advancing clinical therapeutic strategies.

The Interplay between Liver and Adipose Tissue in the Onset of Liver Diseases: Exploring the Role of Vitamin Deficiency.

The deficiency of vitamins, a condition known as "hidden hunger", causes comprehensive pathological states. Research over the years has identified a relationship between liver diseases and hypovitaminosis or defects in vitamin metabolism. The exact mechanisms remain elusive; however, the crucial involvement of specific vitamins in metabolic functions, alongside the reclassification of liver disease as metabolic dysfunction-associated steatotic liver disease (MASLD), has prompted researchers to investigate the potential cause-effect dynamics between vitamin deficiency and liver disease. Moreover, scientists are increasingly investigating how the deficiency of vitamins might disrupt specific organ crosstalk, potentially contributing to liver disease. Although the concept of a dysmetabolic circuit linking adipose tissue and the liver, leading to liver disease, has been discussed, the possible involvement of vitamin deficiency in this axis is a relatively recent area of study, with numerous critical aspects yet to be fully understood. In this review, we examine research from 2019 to July 2024 focusing on the possible link between liver-adipose tissue crosstalk and vitamin deficiency involved in the onset and progression of non-alcoholic fatty liver disease (NAFLD). Studies report that vitamin deficiency can affect the liver-adipose tissue axis, mainly affecting the regulation of systemic energy balance and inflammation.

Multi‐Organ Microphysiological Systems Targeting Specific Organs for Recapitulating Disease Phenotypes via Organ Crosstalk

Various systemic metabolic diseases arise from prolonged crosstalk across multiple organs, triggering serious impairments in various physiological systems. These diseases are intricate systemic pathologies characterized by complex mechanisms and an unclear etiology, making the treatment challenging. Efforts have been made to develop in vitro models to understand these diseases and devise new treatments. However, there are limitations in reconstructing the causal relationships between diseases and interorgan crosstalk, including the tissue‐specific microenvironment. Alternatively, multi‐organ microphysiological systems (MOMPS) present new possibilities for capturing the complexity of systemic metabolic diseases by replicating human microphysiology and simulating diverse interorgan crosstalk. Controlled interactions and scalable representations of biological complexity in MOMPS offer a more accurate portrayal of organ interactions, enabling the identification of novel relationships between organ crosstalk, metabolism, and immunity. This, in turn, can yield valuable insights into disease mechanisms and drug development research and enhance the efficiency of preclinical studies. In this review, the examples and technical capabilities of MOMPS pathological modeling for various diseases are discussed, leveraging state‐of‐the‐art biofabrication technology of MOMPS. It evaluates the current opportunities and challenges in this field.

Inter-organ cross-talk in human cancer cachexia revealed by spatial metabolomics

BackgroundCancer cachexia (CCx) presents a multifaceted challenge characterized by negative protein and energy balance and systemic inflammatory response activation. While previous CCx studies predominantly focused on mouse models or human body fluids, there's an unmet need to elucidate the molecular inter-organ cross-talk underlying the pathophysiology of human CCx. MethodsSpatial metabolomics were conducted on liver, skeletal muscle, subcutaneous and visceral adipose tissue, and serum from cachectic and control cancer patients. Organ-wise comparisons were performed using component, pathway enrichment and correlation network analyses. Inter-organ correlations in CCx altered pathways were assessed using Circos. Machine learning on tissues and serum established classifiers as potential diagnostic biomarkers for CCx. ResultsDistinct metabolic pathway alteration was detected in CCx, with adipose tissues and liver displaying the most significant (P ≤ 0.05) metabolic disturbances. CCx patients exhibited increased metabolic activity in visceral and subcutaneous adipose tissues and liver, contrasting with decreased activity in muscle and serum compared to control patients. Carbohydrate, lipid, amino acid, and vitamin metabolism emerged as highly interacting pathways across different organ systems in CCx. Muscle tissue showed decreased (P ≤ 0.001) energy charge in CCx patients, while liver and adipose tissues displayed increased energy charge (P ≤ 0.001). We stratified CCx patients by severity and metabolic changes, finding that visceral adipose tissue is most affected, especially in cases of severe cachexia. Morphometric analysis showed smaller (P ≤ 0.05) adipocyte size in visceral adipose tissue, indicating catabolic processes. We developed tissue-based classifiers for cancer cachexia specific to individual organs, facilitating the transfer of patient serum as minimally invasive diagnostic markers of CCx in the constitution of the organs. ConclusionsThese findings support the concept of CCx as a multi-organ syndrome with diverse metabolic alterations, providing insights into the pathophysiology and organ cross-talk of human CCx. This study pioneers spatial metabolomics for CCx, demonstrating the feasibility of distinguishing cachexia status at the organ level using serum.

Immune mediators in heart-lung communication.

It is often the case that serious, end-stage manifestations of disease result from secondary complications in organs distinct from the initial site of injury or infection. This is particularly true of diseases of the heart-lung axis, given the tight anatomical connections of the two organs within a common cavity in which they collectively orchestrate the two major, intertwined circulatory pathways. Immune cells and the soluble mediators they secrete serve as effective, and targetable, messengers of signals between different regions of the body but can also contribute to the spread of pathology. In this review, we discuss the immunological basis of interorgan communication between the heart and lung in various common diseases, and in the context of organ crosstalk more generally. Gaining a greater understanding of how the heart and lung communicate in health and disease, and viewing disease progression generally from a more holistic, whole-body viewpoint have the potential to inform new diagnostic approaches and strategies for better prevention and treatment of comorbidities.

Abstract P146: Sex-Dependent Regulation of the Endothelin System in Multi-End Organ Inflammation in Lupus-Associated Cardiovascular Disease

Lupus is a chronic autoimmune disease characterized by IgG deposition, Toll-like receptor 7 (TLR7) overactivation, and autoantibody production resulting in end organ inflammation. SLE disproportionally affects women, SLE disproportionally affects women to men (9:1 ratio), with a high prevalence in African American women. Highly vascularized organs are severely impacted by lupus, specifically the kidneys and brain. Recent literature has shown that cardiovascular disease (CVD) has significant detrimental impacts on organ crosstalk. Endothelin-1 (ET-1), a potent vasoconstricting peptide, has been shown elevated in patients with CVD and in patients with lupus independent of disease severity. However, the extent to which ET-1 promotes lupus-associated CVD and end organ cross talk remains to be elucidated. Therefore, we hypothesized that TLR7 overactivation in a murine model of SLE-associated CVD would lead to a sex-dependent regulation of the renal and cerebral ET systems. Female and male lupus-prone B6.Nba2 mice were subjected to bi-weekly treatment with the Resiquimod (R848; TLR7/8 agonist; 100ug/30ul) or vehicle control (Acetone) for one month and subsequently studied for 12 weeks. At 16 weeks, the kidneys and brains were collected for histology and ET system (ET-1, ET A, and ET B ) analysis. Exploration of specific end organ damage demonstrates a profound increase in renal and cerebral IgG complex deposition as well as renal macrophages and T cells in both females and males receiving R848. Renal ET-1 levels displayed no time nor treatment-dependent effects in females, while males exhibited a significant time-dependent increase in expression at the 4 and 16-week timepoints. Interestingly, at the receptor level, neither sex demonstrated differences in ET A nor ET B levels in the kidney. While renal ET-1 level did not change, females demonstrated a significant increase in cerebral ET-1 at the 16-week timepoint, while males trended for increased cerebral ET-1. At the receptor level, females had a trend for increased cerebral ET A expression, while there was no change in males, and neither sex displayed a change in ET B receptor expression. These findings suggest a potential shift towards a pro-inflammatory state via the cerebral ET-1/ET A signaling axis in the R848-treated females. These findings warrant further exploration into the end-organ specific pathophysiological role ET-1/ET A signaling in multiorgan crosstalk in lupus-associated CVD.

Abstract Or117: JNK2-mediated gut-heart crosstalk in aging-associated AF pathogenesis.

Introduction: Aging is an independent risk factor for atrial fibrillation (AF). We recently revealed a critical role of activated cardiac stress kinase JNK2 in AF risk. Yet, the mechanisms underlying JNK2 activation in the aged heart remain unclear. Emerging evidence suggests that organ crosstalk critically contributes to the development of heart diseases. Interestingly, increased AF episodes were clinically observed in patients with active gastrointestinal (GI) diseases (with a hallmark of enhanced intestinal epithelial barrier permeability (‘leaky gut’), but reduced AF during remission. While both GI dysfunction and enhanced AF risk are seen in aged humans and animal models, whether aging-associated leaky gut leads to AF pathogenesis through activated JNK2 remains unknown. Methods: To assess the leaky gut and AF link, young (Yg, 2 mo) wildtype (WT) and JNK2dn mice (cardiac-specific overexpression of inactive dominant negative (dn) JNK2) were used for aged fecal matter transplant (FMT), while aged (Ag, 24 mo) mice were transplanted with Yg fecal matter to rescue aging-associated AF. Atrial tachycardia/fibrillation (AT/AF) incidence was measured using our well-established protocol, and GI permeability was measured using a serum dextran (4-kDa) FITC fluorescence assay 7 days post-FMT. Results: Aged WT mice had an elevated FITC level (4.9±1.5 µg/ml vs 0.98±0.04 µg/ml; n=11,8; p<0.01) with increased AT/AF inducibility compared to Yg mice (n=7,10; p<0.05). Interestingly, Yg WT recipients subjected to aged FMT (Ag-to-Yg) exhibited an ~3-fold increase in GI permeability (n=14; p<0.01) and significantly enhanced AT/AF inducibility relative to Yg sham controls (8 of 13 vs 0 of 10; p<0.05), while Yg-to-Yg FMT did not alter GI permeability and AT/AF inducibility in Yg recipients (0 of 5, p=NS). Strikingly, cardiac-specific JNK2 inhibition prevented aged-FMT-caused AT/AF in Yg JNK2dn recipient mice (0 of 10; p<0.01), suggesting that activated cardiac JNK2 underlies leaky gut-evoked AF in aging. Further, Yg-to-Ag FMT eliminated aged-associated AT/AF inducibility in aged recipients (0 of 6). Conclusion: Aging-associated GI dysfunction enhances cardiac JNK2 activation, which in turn drives AF risk. Targeting cardiac JNK2 could be a novel anti-AF therapeutic strategy.

Cystic fibrosis-related metabolic defects: crosstalk between ion channels and organs.

Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic mutation ΔF508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein have dramatically increased the lifespan of patients with this mutation. This development has led to major changes in the field and has pushed research beyond the ion transport nature of cystic fibrosis and toward multiorgan physiological reprogramming. In this issue of the JCI, Bae, Kim, and colleagues utilized a large animal pig model prior to the onset of disease. They revealed metabolic reprogramming and organ crosstalk that occurred prior to disease progression. These findings provide paradigm-shifting insight into this complex disease.

#2334 Elevated serum admission creatinine in acute heart failure hospitalizations: lifting the veil to understand outcome differences

Abstract Background and Aims Organ crosstalk in heart failure and kidney dysfunction is prevalent and is associated to a high event rate. In this setting elevated serum creatinine (sCr) at acute decompensated heart failure (ADHF) admissions is a strong risk factor for poor outcomes. Current accepted cardiorenal syndrome (CRS) classification is based on timing and initial organ dysfunction and fails at capturing its nature and prognosis. We sought to describe patient (P) profile and outcomes in P hospitalized for ADHF with high admission sCr in function of current CRS classification and assess for stratifying predictors. Method We conducted an observational, analytical and cross-sectional study, with prospective and consecutive data acquisition. We included P over 18 years-old, who were admitted to the Intensive Care Telemetry Unit in our Hospital between July, 2011 and Dec, 2023 due to ADHF. P who received a heart transplant during index admission or those on chronic dialysis were excluded. Clinical, epidemiological and biochemical variables were registered. Renal dysfunction was defined under admission sCr >1.4 mg/dl and divided according to Ronco et al classification, as initially cardiac (type 2) or renal (type 4) origin. We constructed multivariate logistic and survival regression models, with selection of relevant predictors by resampling and regularization of a Lasso regression model. Statistical significance was considered with a 5% of alpha error level. Analysis was conducted using R (R Core Team, 2023). Results A total of 1868 consecutive P were included. P population consisted in type 2: 124 and type 4: 258 P, respectively. We found no differences in gender (p = 0.47), while type 4 were older (75 ± 12 vs 71 ± 12; p < 0.01). Ventricular dysfunction was more severe in type 2 (left ventricular ejection fraction 34 ± 17 vs 41 ± 16%; p < 0.001). While ischaemic heart disease was more prevalent in type 4 (32.8 vs 23.5%; p = 0.001), idiopathic cardiomyopathy was more frequent in type 2 (18.8 vs 7.2%; p = 0.001). Clinical phenotypes differed between groups, being clinical hypoperfusion more frequent in type 2 (32.4 vs 12.3%; p < 0.001). Admission sCr was higher in type 4 (1.9 [0.8] vs 1.6 [0.58] mg/dl; p < 0.001), as was 1st day natriuresis (81 vs 67 mEq; p = 0.01). Both groups experienced a similar diuretic resistance rate (21.2 vs 17.1%; p = 0.34), while type 4 received rescue ultrafiltration more frequently (11.3 vs 3.5%; p < 0.01). Type 2 received a higher inotropic support rate (47.1 vs 19.5%; p < 0.01) and had a longer length of stay (9 vs 7 days; p = 0.01). In-hospital (11.8 vs 11.3%; p = 0.99); 6-month and 1-year mortality rates (66.8 vs 72.8% and 55.1 vs 64.6% respectively; p = 0.3). In a similar way, 1-month (94.8 vs 94.7%), 6-month (72 vs 74.7%) and 1-year readmission rates (59.2 vs 60.9%; p = 0.6) were similar in both groups. A multiple logistic regression model (AUCROC 0.82) identified admission sCr (OR 2.6; CI 95% 2.2-3.2; p < 0.001), inotropic need (OR 1.87; CI 95% 1.4-2.6; p < 0.001), anasarca phenotype (OR 1.63; CI 95% 1.06-2.5; p = 0.02), moderate to severe right ventricular dysfunction (OR 1.4; CI 95% 1.03-1.9; p = 0.03) as independent predictors for a descending sCr behavior during hospitalization, while the lower T3 levels were associated with less probability for a descent of sCr (OR 0.21; CI 95% 0.1-0.46; p < 0.001). Conclusion Organ crosstalk in ADHF hospitalizations was associated with a high event rate. One-year mortality and readmission rates were similar in both groups. Renal support therapies were more frequent under lower kidney reserve conditions. Ventricular dysfunction and systemic congestion phenotype are relevant to a better understanding for potential reversibility at the admission time and may promote actions for outcome enhancing.

Proceedings of the 5th Meeting of Translational Hepatology, organized by the Spanish Association for the Study of the Liver (AEEH)

This is the summary report of the 5th Translational Hepatology Meeting, endorsed by the Spanish Association for the Study of the Liver (AEEH) and held in Seville, Spain, in October 2023. The meeting aimed to provide an update on the latest advances in the field of basic and translational hepatology, covering different molecular, cellular, and pathophysiological aspects of the most relevant clinical challenges in liver pathologies. This includes the identification of novel biomarkers and diagnostic tools, the understanding of the relevance of immune response and inflammation in liver diseases, the characterization of current medical approaches to reverse liver diseases, the incorporation of novel molecular insights through omics techniques, or the characterization of the impact of toxic and metabolic insults, as well as other organ crosstalk, in liver pathophysiology.

Distinguishing Molecular Properties of OAT, OATP, and MRP Drug Substrates by Machine Learning.

The movement of organic anionic drugs across cell membranes is partly governed by interactions with SLC and ABC transporters in the intestine, liver, kidney, blood-brain barrier, placenta, breast, and other tissues. Major transporters involved include organic anion transporters (OATs, SLC22 family), organic anion transporting polypeptides (OATPs, SLCO family), and multidrug resistance proteins (MRPs, ABCC family). However, the sets of molecular properties of drugs that are necessary for interactions with OATs (OAT1, OAT3) vs. OATPs (OATP1B1, OATP1B3) vs. MRPs (MRP2, MRP4) are not well-understood. Defining these molecular properties is necessary for a better understanding of drug and metabolite handling across the gut-liver-kidney axis, gut-brain axis, and other multi-organ axes. It is also useful for tissue targeting of small molecule drugs and predicting drug-drug interactions and drug-metabolite interactions. Here, we curated a database of drugs shown to interact with these transporters in vitro and used chemoinformatic approaches to describe their molecular properties. We then sought to define sets of molecular properties that distinguish drugs interacting with OATs, OATPs, and MRPs in binary classifications using machine learning and artificial intelligence approaches. We identified sets of key molecular properties (e.g., rotatable bond count, lipophilicity, number of ringed structures) for classifying OATs vs. MRPs and OATs vs. OATPs. However, sets of molecular properties differentiating OATP vs. MRP substrates were less evident, as drugs interacting with MRP2 and MRP4 do not form a tight group owing to differing hydrophobicity and molecular complexity for interactions with the two transporters. If the results also hold for endogenous metabolites, they may deepen our knowledge of organ crosstalk, as described in the Remote Sensing and Signaling Theory. The results also provide a molecular basis for understanding how small organic molecules differentially interact with OATs, OATPs, and MRPs.

WCN24-68 Impact of post-translational modifications of albumin and other biomolecules on the organ crosstalk

WCN24-68 Impact of post-translational modifications of albumin and other biomolecules on the organ crosstalk

Microphysiological Blood-Brain Barrier Systems for Disease Modeling and Drug Development.

The blood-brain barrier (BBB) is a highly controlled microenvironment that regulates the interactions between cerebral blood and brain tissue. Due to its selectivity, many therapeutics targeting various neurological disorders are not able to penetrate into brain tissue. Pre-clinical studies using animals and other in vitro platforms have not shown the ability to fully replicate the human BBB leading to the failure of a majority of therapeutics in clinical trials. However, recent innovations in vitro and ex vivo modeling called organs-on-chips have shown the potential to create more accurate disease models for improved drug development. These microfluidic platforms induce physiological stressors on cultured cells and are able to generate more physiologically accurate BBBs compared to previous in vitro models. In this review, different approaches to create BBBs-on-chips are explored alongside their application in modeling various neurological disorders and potential therapeutic efficacy. Additionally, organs-on-chips use in BBB drug delivery studies is discussed, and advances in linking brain organs-on-chips onto multiorgan platforms to mimic organ crosstalk are reviewed.

Pathogenesis of MASLD and MASH - role of insulin resistance and lipotoxicity.

Insulin resistance and lipotoxicity are extremely interconnected but fundamental in setting the stage for the development of MASLD/MASH. A comprehensive literature search was performed and key themes were synthesised to provide insight into the underlying molecular mechanisms of insulin resistance and lipotoxicity in the liver, muscle, pancreas and adipose tissue and how organ cross-talk is fundamental to driving disease pathogenesis. Classical thinking postulates that excess FFA load exceeds the storage capacity of adipose tissue, which is predicated upon both genetic and environmental factors. This results in insulin resistance and compensatory hyperinsulinaemia by pancreatic beta cells to overcome target organ insulin resistance. As adipocyte dysfunction worsens, not only are excess FFA delivered to other organs, including skeletal muscle, pancreas and liver but a pro-inflammatory milieu is established with increases in IL-6, TNF-α and changes in adipokine levels (increased leptin and decreased adiponectin). With increased intramuscular lipid accumulation, lipotoxic species decrease insulin signalling, reduce glucose uptake by downregulation of GLUT4 and decrease glycogen synthesis. With this additional reduced capacity, hyperglycaemia is further exacerbated and increased FFA are delivered to the liver. The liver has the largest capacity to oxidise fat and to adapt to these stressors and, therefore, has become the last line of defence for excess lipid storage and utilisation, the capacity of which may be impacted by genetic and environmental factors. However, when the liver can no longer keep up with increasing FFA delivery and DNL, lipotoxic species accumulate with ensuing mitochondrial dysfunction, increased ER stress, oxidant stress and inflammasome activation, all of which drive hepatocyte injury and apoptosis. The resulting wound healing response, marked by stellate cell activation, drives collagen accumulation, progressive fibrosis, and, ultimately, end organ failure and death. This vicious cycle and complex interplay between insulin resistance, hyperinsulinaemia, lipotoxicity and multi-directional cross-talk among different target organs are critical drivers of MASLD/MASH. Targeting tissue-specific insulin resistance and hyperinsulinaemia while decreasing FFA load (lipotoxicity) through dietary and lifestyle changes remain the best upstream interventions.