Exploring the fate of phlorotannins from Laminaria digitata across the gastrointestinal tract: Insights into susceptibility and bioactivity prior and post gastrointestinal digestion.

Phlorotannins are phenolic compounds exclusive from brown macroalgae endowed with promising bioactive properties. However, considering that diet is their main route of entrance to our system, gastrointestinal digestion might affect such bioactive properties. Here, phlorotannin extracts obtained from Laminaria digitata were submitted to simulated gastrointestinal digestion to evaluate its impact on their antioxidant and anti-inflammatory properties. Overall, a reduction of the total phlorotannin content along the gastrointestinal tract was noticed, although the antioxidant activity measured in vitro via NO● and O2●- scavenging assays, maintained almost the same. The crude extract (70 % v/v acetone) exhibited superior inhibition of NO● release on lipopolysaccharide-stimulated cells after digestion. In contrast, the opposite occurred to the phlorotannin-purified extract, indicating that the digestive process favors the anti-inflammatory properties of the former but not the latter. Data collected from UHPLC-MS analysis revealed that the fuhalol and carmalol-type compounds were completely absent from the digested phlorotannin-purified extract, which could partly explain its lower anti-inflammatory activity compared with its non-digested counterpart. Overall, this study contributes to a better understanding of the impact of gastrointestinal digestion on the bioactivity profile of L. digitata phlorotannins, demonstrating that fuhalols and carmalols are particularly susceptible to the digestive process.

A Metastable Semiquinone Molecular Switch Modulated by Ascorbate/O2: a Study from a System Far-From-Equilibrium to Biological Assays in Mitochondria.

A molecular switch based on the metastable radical anion derived from a substituted heteroaryl quinone is described. Pyrrolil quinone thiocyanate (PQ 5) showed an interaction with the fluoride anion that was visible to the naked eye and quantified by UV/vis and 1H and 13C NMR. The metastable quinoid species formed by the interaction with F- ("ON" state) showed a molecular switching effect autocontrolled by the presence of ascorbate ("OFF" state) and back to the "ON" state by an autooxidation process, measured by visible and UV/vis spectroscopy. Due to its out-of-equilibrium properties and the exchange of matter and energy, a dissipative structural behaviour is proposed. Considering its similarity to the mechanism of coenzyme Q in oxidative phosphophorylation, PQ 5 was evaluated on Saccharomyces cerevisiae mitochondrial function for inhibition of complexes II, III and IV, reactive oxygen species (ROS) production, catalase activity and lipid peroxidation. The results showed that PQ 5 inhibited complex III activity as well as the activity of all electron transport chain (ETC) complexes. In addition, PQ 5 reduced ROS production and catalase activity in yeast. The results suggest that PQ 5 may have potential applications as a new microbicidal compound by inducing ETC dysfunction.

Difluorenoheteroles: topological control of π conjugation in diradicaloids and mixed-valence radical ions.

Two families of difluorenoheterole diradicaloids were synthesized, featuring isomeric ring systems with distinct conjugation topologies. The two types of difluorenoheteroles contain, respectively, a Chichibabin-like motif (CH) and a newly introduced heteroatom-linked triphenylmethyl dyad (TD-X). Combined experimental and theoretical investigations show that the TD-X systems have reduced quinoidal character but the interaction between formal spin centers is sufficiently strong to ensure a singlet ground state. The singlet-triplet energy gaps in the TD-X difluorenoheteroles are strongly affected by the heterocyclic ring, with values of -4.3 and -0.7 kcal mol-1 determined for the pyrrole- and thiophene-containing analogues, respectively. In cyclic voltammetry experiments, the TD-X systems show diminished energy gaps and superior reversibility in comparison with their CH counterparts. The radical anions and cations obtained from these diradicaloids show extremely red-shifted bands, occasionally with λ max > 3500 nm. Computational studies show that some of these ions adopt distonic structures and may be characterized as class-II mixed-valence species.

Degree of PEGylatation of Lumbricus terrestris Hemoglobin Improves Microcirculatory Blood Flow but Increases the Rate of Auto-Oxidation.

INTRODUCTION: The demand for red blood cells (RBCs) is on the rise due to the increasing diagnosis of chronic diseases such as sickle cell anemia, malaria, and thalassemia. Despite many commercial attempts, there are no U.S. FDA-approved artificial RBCs for use in humans. Existing RBC substitutes have employed various strategies to transport oxygen, extend the circulation time, and reduce organ toxicity, but none have replicated the natural protective mechanisms of RBCs, which prevent hemoglobin (Hb) dimerization and heme iron oxidation. Lumbricus terrestris (earthworm) erythrocruorin (LtEc) is a naturally occurring extracellular hemoglobin (Hb) with promising attributes: large molecular diameter (30 nm), high molecular weight (3.6 MDa), low auto-oxidation rate, and limited nitric oxide-scavenging properties. These characteristics make LtEc an ideal candidate as an RBC substitute. However, LtEc has a significant drawback, its short circulatory half-life. To address this issue, we explored thiol-mediated surface PEGylation of LtEc (PEG-LtEc) at varying polyethylene glycol (PEG) surface coverages. Increasing PEG surface coverage beyond 40% destabilizes LtEc into smaller subunits that are 1/12th the size of LtEc. Therefore, we evaluated two PEG surface coverage options: PEG-LtEc-0.2 (20% PEGylation) and PEG-LtEc-1.0 (100% PEGylation). METHODS: We conducted experiments using golden Syrian hamsters with dorsal window chambers and catheters to assess the efficacy of these solutions. We measured microvascular parameters, organ function, cerebral blood flow, circulation time, mean arterial pressure, heart rate, and blood gases and performed histology to screen for toxicity. CONCLUSION: Our findings indicate that both PEG-LtEc molecules offer significant benefits in restoring microvascular parameters, organ function, cerebral blood flow, and circulation time compared to LtEc alone. Notably, PEG-LtEc-1.0 showed superior microvascular perfusion, although it exhibited a higher rate of auto-oxidation compared to PEG-LtEc-0.2. These results underscore the advantages of PEGylation in terms of tissue perfusion and organ health while highlighting its limitations.

Methylene Blue, a Unique Topical Analgesic: A Case Report.

Background: Rectal prolapse is a circumferential, full-thickness protrusion of the rectum through the anus, which, if not properly managed, may become incarcerated and pose a risk of strangulation. This pathology is rarely a medical emergency unless a complication is encountered. Such complications include infection, necrosis, perforation, incarceration, and uncontrolled pain. Case Presentation: We report a case of an elderly patient with pain associated with chronic rectal prolapse. Surgical intervention had been ruled out, and there had been no pain relief after using systemic analgesics. Case Management: Based on increasing reports of analgesic properties, topical methylene blue (MB) 0.1% was applied externally at the prolapsed organ, obtaining pain relief. Case Outcome: The patient experienced immediate and long-lasting pain relief; MB applications were continued every 12 hours as needed. After this therapy, the patient was no longer in need of systemic analgesics. No side effects were reported. Conclusion: Topical MB may be an effective analgesic for the management of pain associated with chronic rectal prolapse. This treatment might be extrapolated to other clinical scenarios of tegumentary pain. Similar use has been shown to be safe and effective in other pathologies, including pain in oral mucositis associated with cancer therapy.

Sugar feeding in triatomines: a new perspective for controlling the transmission of Chagas disease.

Introduction: Triatomines are vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. Currently, there is no vaccine against this disease. Thus, control of the insect vector population is the main strategy available to reduce the number of cases. Triatomines are considered obligate hematophagous, but different alternative feeding behaviors were described, such as haemolymphagy or plant feeding. Methods: To determine the preference for sugar feeding in nymphs and adults of Rhodnius prolixus, the insects were exposed a piece of cotton containing bromophenol blue plus sucrose. In addition, we offered several sugars for different species of triatomines, and tested sugar meals as a route of delivery of insecticides in first-instar nymphs of R. prolixus. The effect of sugar feeding on the physiology of these different species of triatomines was recorded. Results: First instar nymphs ingested sucrose more strongly than other stages, and showed high mortality rates. In different species of triatomines, sucrose induced an ingestion, but engorgement varied according to the species. R. prolixus nymphs showed an indiscriminate intake of various sugars, with very different physiological effects. Furthermore, ingesting different combinations of insecticides + sugar significantly reduced insect survival. Discussion: In summary, we described for the first-time sugar feeding as a widespread behavior in several species of triatomines, and the possibility of the use of toxic sugar baits for the control of these vectors. The knowledge of feeding behavior in these insects can be fundamental for the development of new strategies to control Chagas disease.

Novel human recombinant N-acetylgalactosamine-6-sulfate sulfatase produced in a glyco-engineered Escherichia coli strain.

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), resulting in the accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). Previously, it was reported the production of an active human recombinant GALNS (rGALNS) in E. coli BL21(DE3). However, this recombinant enzyme was not taken up by HEK293 cells or MPS IVA skin fibroblasts. Here, we leveraged a glyco-engineered E. coli strain to produce a recombinant human GALNS bearing the eukaryotic trimannosyl core N-glycan, Man3GlcNAc2 (rGALNSoptGly). The N-glycosylated GALNS was produced at 100 mL and 1.65 L scales, purified and characterized with respect to pH stability, enzyme kinetic parameters, cell uptake, and KS clearance. The results showed that the addition of trimannosyl core N-glycans enhanced both protein stability and substrate affinity. rGALNSoptGly was capture through a mannose receptor-mediated process. This enzyme was delivered to the lysosome, where it reduced KS storage in human MPS IVA fibroblasts. This study demonstrates the potential of a glyco-engineered E. coli for producing a fully functional GALNS enzyme. It may offer an economic approach for the biosynthesis of a therapeutic glycoprotein that could prove useful for MPS IVA treatment. This strategy could be extended to other lysosomal enzymes that rely on the presence of mannose N-glycans for cell uptake.

Cardiac Tumors: Review.

Cardiac tumors are rare and encompass a variety of presentations. Clinica symptoms are usually nonspecific, but they can present as obstructive, embolic, or constitutional symptoms. Treatment options and prognosis vary highly depending on the subtype, tumor size, and location. Surgical resection is usually the first-line therapy, except for cardiac lymphomas, and provides favorable long-term prognosis in most benign tumors. Cardiac sarcomas, however, are usually diagnosed in advanced stages, and the treatment relies on a multimodal approach with chemotherapy and radiotherapy. Metastatic cardiac tumors are usually related to advanced disease and carry an overall poor prognosis.

Dynamics of ecosystem services along ecological network seascapes

Human societies depend on services provided by ecosystems, from local needs as clean water and pest control to global services like ozone layer and the ocean biological pump. Ecosystem services are intrinsically linked to the states of the ecosystem, which are, in turn, governed by a complex web of ecological interactions. These interactions and, consequently, the services they support, are increasingly under threat from environmental changes driven by human activities. Therefore, safeguarding these vital services require an understanding of how the structure and dynamics of ecological interactions are affected by environmental change. A critical step towards this goal is the development of an integrative theoretical framework that can elucidate how ecosystem services are sustained or impaired by interactions within these complex ecosystems in fluctuating environments. Recent years have seen significant progress in quantitatively characterizing the organization and the dynamics of ecological interactions through the study of ecological networks. However, linking temporally varying network structure in fluctuating environments, the seascapes of ecological networks, and their impact on ecosystem services remains a challenge. We propose an approach based upon merging empirical ecological network analysis with Boolean functions and modeling techniques accounting for fluctuating environments to tackle how ecosystem services are affected by the changing structure and dynamics of ecological networks. The approach aims to contribute to the study of how the organization of ecological interactions affects the persistence of ecosystem services. Specifically, we discuss how this approach can be used provide new insights into how environmental change affect the relationship between ecological networks and ecosystem services. The combination of information on ecosystem services, Boolean networks and fluctuating environments might allow to enhance the research around conservation strategies for preserving biodiversity and ecosystem services in the face of ongoing environmental change.

General Applicability of Existing College of American Pathologists Accreditation Requirements to Clinical Implementation of Machine Learning-Based Methods in Molecular Oncology Testing.

CONTEXT.­: The College of American Pathologists (CAP) accreditation requirements for clinical laboratory testing help ensure laboratories implement and maintain systems and processes that are associated with quality. Machine learning (ML)-based models share some features of conventional laboratory testing methods. Accreditation requirements that specifically address clinical laboratories' use of ML remain in the early stages of development. OBJECTIVE.­: To identify relevant CAP accreditation requirements that may be applied to the clinical adoption of ML-based molecular oncology assays, and to provide examples of current and emerging ML applications in molecular oncology testing. DESIGN.­: CAP accreditation checklists related to molecular pathology and general laboratory practices (Molecular Pathology, All Common and Laboratory General) were reviewed. Examples of checklist requirements that are generally applicable to validation, revalidation, quality management, infrastructure, and analytical procedures of ML-based molecular oncology assays were summarized. Instances of ML use in molecular oncology testing were assessed from literature review. RESULTS.­: Components of the general CAP accreditation framework that exist for traditional molecular oncology assay validation and maintenance are also relevant for implementing ML-based tests in a clinical laboratory. Current and emerging applications of ML in molecular oncology testing include DNA methylation profiling for central nervous system tumor classification, variant calling, microsatellite instability testing, mutational signature analysis, and variant prediction from histopathology images. CONCLUSIONS.­: Currently, much of the ML activity in molecular oncology is within early clinical implementation. Despite specific considerations that apply to the adoption of ML-based methods, existing CAP requirements can serve as general guidelines for the clinical implementation of ML-based assays in molecular oncology testing.

Triindenotriphenylenes: Spin-Frustrated Triskelion Triradicals with Excellent Ambient Stability.

A triskelion-shaped triradical triindeno[1,2-a:1',2'-g:1'',2''-m]triphenylen-7-yl (1) and its internally fused derivative obtained by oxidative cyclization (2) were prepared in a straightforward synthetic sequence. Both compounds were confirmed to be triradicals and to possess intramolecular antiferromagnetic exchange interactions between spins, displaying a spin-frustrated doublet ground state with doublet-quartet energy gaps of -0.14 kcal/mol for 1 and -0.06 kcal/mol for 2. Despite their open-shell character, they were sufficiently stable to be handled under ambient conditions on a timescale of days. Both compounds could be reversibly reduced to mono-, di-, and trianions and oxidized to 1+ and 22+, with strong NIR absorptions (1800 to over 3200 nm) observed for all open-shell ions.

Standardisation of the definition of the types of oncological colectomy. Delphi method for consensus of experts of the Spanish association of surgeons.

There is no international consensus on the definition of the type of oncological resection that corresponds to each of the colectomies existing in the current literature. The objective is to define for each colectomy described in the literature: embryological dissection plane, vascular pedicles in which to perform central ligation, the extent of the colectomy, and the need for resection of the greater momentum. A consensus of experts is carried out through the Delphi methodology through two rounds from the Coloproctology Section of the Spanish Association of Surgeons. Study period: November 2021-January 2023. 120 experts were surveyed. Degrees of consensus: Very strong: >90%, Strong: 80-90%, Moderate: 50-80%, No consensus: <50%. The definition for each oncological colectomy was established by very strong, and strong recommendations. Each oncological colectomy was established as Right hemicolectomy (RHC), RHC with D3 lymphadenectomy, Extended-RHC, transverse colon segmental colectomy, splenic flexure segmental colectomy, subtotal colectomy, total colectomy, left hemicolectomy (LHC), extended-LHC, sigmoidectomy.

Atherosclerotic Cardiovascular Disease Primary and Secondary Prevention in Latino Subgroups.

BACKGROUND: Studies assessing equity in the prevention of atherosclerotic cardiovascular disease (ASCVD) for Latinos living in the USA collectively yield mixed results. Latino persons are diverse in many ways that may influence cardiovascular health. The intersection of Latino nativity and ASCVD prevention is understudied. OBJECTIVE: To determine whether disparities in ASCVD screening, detection, and prescribing differ for US Latinos by country of birth. DESIGN: A retrospective cohort design utilizing 2014-2020 electronic health record data from a network of 320 community health centers across 12 states. Analyses occurred October 1, 2022, to September 30, 2023. PARTICIPANTS: Non-Hispanic White and Latino adults age 20-75 years, born in Cuba, Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, and the USA. EXPOSURES: Ethnicity and country of birth. MAIN MEASURES: Outcome measures included prevalence of statin eligibility, of having insufficient data to establish eligibility, odds of having a documented statin prescription, and rates of statin prescriptions and refills. We used covariate-adjusted logistic and generalized estimating equations logistic and negative binomial regressions to generate absolute and relative measures. KEY RESULTS: Among 108,672 adults, 23% (n = 25,422) were statin eligible for primary or secondary prevention of ASCVD using American College of Cardiology/American Heart Association guidelines. Latinos, born in and outside the USA were more likely eligible than Non-Hispanic White patients were (US-born Latino OR = 1.55 (95% CI = 1.37-1.75); non-US-born Latino OR = 1.63 (95% CI = 1.34-1.98)). The eligibility criteria that was met differed by ethnicity and nativity. Latinos overall were less likely missing data to establish eligibility and differences were again observed by specific non-US country of origin. Among those eligible, we observed no statistical difference in statin prescribing between US-born Latinos and non-Hispanic White persons; however, disparities varied by specific non-US country of origin. CONCLUSION: Efforts to improve Latino health in the USA will require approaches for preventing and reversing cardiovascular risk factors, and statin initiation that are Latino subgroup specific.

Molecular classification of metastatic and recurrent endometrial endometrioid carcinoma: prognostic relevance among low- and high-stage tumours.

AIMS: Molecular classification according to The Cancer Genome Atlas (TCGA) improves endometrial endometrioid carcinoma (EEC) prognostication and has specific treatment implications; however, original data were skewed towards low-grade and low-stage tumours. Herein, we molecularly classify EECs metastatic at the time of diagnosis or with subsequently documented recurrent/metastatic disease to examine correlation with clinical outcomes. METHODS: TCGA categories include POLE-mutated, microsatellite instability (MSI), p53 abnormal (p53 abnl) and no specific molecular profile (NSMP). POLE targeted sequencing at exons 9, 11, 13 and 14 and immunohistochemistry (IHC) for PMS2, MSH6 and p53 were performed to establish molecular classification. RESULTS: The distribution in our cohort of 141 EECs was similar to that generally reported in EEC, with nine POLE-mutated (6%), 45 MSI (32%), 16 p53 abnl (11%) and 71 NSMP (50%), with similar distributions between low- and high-stage cohorts. We demonstrate that when stratified by molecular subtype, disease-specific survival from the time of high-stage (stages III-IV) presentation or time of recurrence in low-stage (stages I-II) disease among metastatic and/or recurrent EEC is strongly associated with TCGA classification (high-stage P = 0.02, low-stage P = 0.017). Discordant molecular classification between primary and metastatic/recurrent tumours occurred in four of 105 (3.8%) patients, two related to PMS2/MSH6 IHC and two related to p53 IHC. CONCLUSIONS: We demonstrate that molecular classification is prognostically relevant not only at the time of diagnosis, but also at the time of recurrence and in the metastatic setting. Rare subclonal alterations occur and suggest a role for confirming TCGA classification in recurrent/metastatic tumours.

Multifractality approach of a generalized Shannon index in financial time series.

Multifractality is a concept that extends locally the usual ideas of fractality in a system. Nevertheless, the multifractal approaches used lack a multifractal dimension tied to an entropy index like the Shannon index. This paper introduces a generalized Shannon index (GSI) and demonstrates its application in understanding system fluctuations. To this end, traditional multifractality approaches are explained. Then, using the temporal Theil scaling and the diffusive trajectory algorithm, the GSI and its partition function are defined. Next, the multifractal exponent of the GSI is derived from the partition function, establishing a connection between the temporal Theil scaling exponent and the generalized Hurst exponent. Finally, this relationship is verified in a fractional Brownian motion and applied to financial time series. In fact, this leads us to proposing an approximation called local fractional Brownian motion approximation, where multifractal systems are viewed as a local superposition of distinct fractional Brownian motions with varying monofractal exponents. Also, we furnish an algorithm for identifying the optimal q-th moment of the probability distribution associated with an empirical time series to enhance the accuracy of generalized Hurst exponent estimation.

Structural Flexibility and Disassembly Kinetics of Single Ferritin Molecules Using Optical Nanotweezers.

Ferritin, a spherical protein shell assembled from 24 subunits, functions as an efficient iron storage and release system through its channels. Understanding how various chemicals affect the structural behavior of ferritin is crucial for unravelling the origins of iron-related diseases in living organisms including humans. In particular, the influence of chemicals on ferritin's dynamics and iron release is barely explored at the single-protein level. Here, by employing optical nanotweezers using double-nanohole (DNH) structures, we examined the effect of ascorbic acid (reducing reagent) and pH on individual ferritin's conformational dynamics. The dynamics of ferritin increased as the concentration of ascorbic acid approached saturation. At pH 2.0, ferritin exhibited significant structural fluctuations and eventually underwent a stepwise disassembly into fragments. This work demonstrated the disassembly pathway and kinetics of a single ferritin molecule in solution. We identified four critical fragments during its disassembly pathway, which are 22-mer, 12-mer, tetramer, and dimer subunits. Moreover, we present single-molecule evidence of the cooperative disassembly of ferritin. Interrogating ferritin's structural change in response to different chemicals holds importance for understanding their roles in iron metabolism, hence facilitating further development of medical treatments for its associated diseases.

Single-extracellular vesicle (EV) analyses validate the use of L1 Cell Adhesion Molecule (L1CAM) as a reliable biomarker of neuron-derived EVs.

Isolation of neuron-derived extracellular vesicles (NDEVs) with L1 Cell Adhesion Molecule (L1CAM)-specific antibodies has been widely used to identify blood biomarkers of CNS disorders. However, full methodological validation requires demonstration of L1CAM in individual NDEVs and lower levels or absence of L1CAM in individual EVs from other cells. Here, we used multiple single-EV techniques to establish the neuronal origin and determine the abundance of L1CAM-positive EVs in human blood. L1CAM epitopes of the ectodomain are shown to be co-expressed on single-EVs with the neuronal proteins ß-III-tubulin, GAP43, and VAMP2, the levels of which increase in parallel with the enrichment of L1CAM-positive EVs. Levels of L1CAM-positive EVs carrying the neuronal proteins VAMP2 and ß-III-tubulin range from 30% to 63%, in contrast to 0.8%-3.9% of L1CAM-negative EVs. Plasma fluid-phase L1CAM does not bind to single-EVs. Our findings support the use of L1CAM as a target for isolating plasma NDEVs and leveraging their cargo to identify biomarkers reflecting neuronal function.

Precision nutrition impact on metabolic health and quality of life in aging population after a 3-month intervention: A randomized intervention.

OBJECTIVES: Innovative precision dietary procedures are required to promote healthy aging. This study aimed to evaluate the effects of a personalised strategy based on the inclusion of individualised foods and digital tools on overall health status and quality of life within a follow-up of 3 months in older adults with overweight or obesity. METHODS: 127 men and women aged between 50 and 80 years with overweight/obesity participated in the study-between January 2020 and September 2020 at the Center for Nutrition Research-University of Navarra and IMDEA-ALIMENTACIÓN-and were randomly assigned to a usual-care group (standard recommendations) or precision group (precision nutrition strategy based on the inclusion of individualised foods and a mobile application). Anthropometry, body fat percentage, biochemical parameters, diet, and quality of life (SF-36 Health Survey) were assessed at baseline and after 3 months. RESULTS: Both strategies were found to improve overall metabolic health; however, the precision approach demonstrated significantly better outcomes. The precision strategy reduced body weight at 3 months (-4.3 kg; p < 0.001) with significant improvements in body fat percentage, blood pressure and general metabolic health (glycated haemoglobin; alanine aminotransferase; aspartate aminotransferase; hepatic steatosis index) in comparison with the standard recommendations. The precision approach significantly enhanced the quality of life (SF-36) of individuals, with additional improvements in emotional well-being (p = 0.024) and vitality (p = 0.008). Adherence to the Mediterranean diet was significantly associated with a higher quality of life and vitality. CONCLUSION: These results support the benefit of precision nutrition approaches for promoting healthy aging and emotional well-being, enhancing the quality of life in aging populations, during the COVID-19 pandemic.

Drug repurposing in MASLD and MASH-cirrhosis: Targets and treatment approaches based on pathways analysis.

Designing and predicting novel drug targets to accelerate drug discovery for treating metabolic dysfunction-associated steatohepatitis (MASH)-cirrhosis is a challenging task. The presence of superimposed (nested) and co-occurring clinical and histological phenotypes, namely MASH and cirrhosis, may partly explain this. Thus, in this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Here, we used gene/protein and set enrichment analysis to predict druggable pathways for the treatment of MASH-cirrhosis. Our findings indicate that the pathogenesis of MASH-cirrhosis can be explained by perturbations in multiple, simultaneous, and overlapping molecular processes. In this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Therefore, we used systems biology modeling to provide evidence that MASH and cirrhosis paradoxically present unique and distinct as well as common disease mechanisms, including a network of molecular targets. More importantly, pathway analysis revealed straightforward results consistent with modulation of the immune response, cell cycle control, and epigenetic regulation. In conclusion, the selection of potential therapies for MASH-cirrhosis should be guided by a better understanding of the underlying biological processes and molecular perturbations that progressively damage liver tissue and its underlying structure. Therapeutic options for patients with MASH may not necessarily be of choice for MASH cirrhosis. Therefore, the biology of the disease and the processes associated with its natural history must be at the forefront of the decision-making process.