Edwin Nash Broyles, MD. 1894--1977.
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History, 20th Century↗
SEARCH · PubMed Health
Results for “NASH”
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Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis through extracellular vesicles.
BACKGROUND AND AIMS: Immune system activation, along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver, are key drivers of NASH. Extracellular vesicles (EVs) released by cells that carry biological signals contribute to intercellular communication. However, the roles of immune cell-derived EVs in the pathogenesis of NASH are unclear. APPROACH AND RESULTS: Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with nonalcoholic fatty liver disease of different severity as well as 20 healthy subjects, a rat model, and an in vitro cell-based assay. There was increased platelet activation, accompanied by pEVs release, in NASH patients/rat model, and palmitate-treated cells. The mitochondria in the platelets and pEVs from NASH patients/rats were increased but dysfunctional, including a reduction in fatty acid β-oxidation, inactivated acetyl-CoA carboxylase 2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes through pEVs to increase the number of lipid droplet-bound mitochondria. An increase in dysfunctional lipid droplet-bound mitochondria in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial reactive oxygen species production, and apoptosis. CONCLUSIONS: We offer a novel molecular mechanism that connects platelets, pEVs, and excessive LD accumulation to the development of NASH. Our results suggest that NASH progression may be alleviated by specifically inhibiting the production and release of pEVs, or by targeting pEV components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.
Non-alcoholic Fatty Liver Disease↗
A DUAL MTOR/NAD+ ACTING GEROTHERAPY.
The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it's largely unclear how they might talk to each other in aging. In genome-wide CRISPRa screening with a novel class of N-O-Methyl-propanamide-containing compounds we named BIOIO-1001, we identified lipid metabolism centering on SIRT3 as a point of intersection of the mTOR/insulin and NAD+ pathways. In vivo testing indicated that BIOIO-1001 reduced high fat, high sugar diet-induced metabolic derangements, inflammation, and fibrosis, each being characteristic of non-alcoholic steatohepatitis (NASH). An unbiased screen of patient datasets suggested a potential link between the anti-inflammatory and anti-fibrotic effects of BIOIO-1001 in NASH models to those in amyotrophic lateral sclerosis (ALS). Directed experiments subsequently determined that BIOIO-1001 was protective in both sporadic and familial ALS models. Both NASH and ALS have no treatments and suffer from a lack of convenient biomarkers to monitor therapeutic efficacy. A potential strength in considering BIOIO-1001 as a therapy is that the blood biomarker that it modulates, namely plasma triglycerides, can be conveniently used to screen patients for responders. More conceptually, to our knowledge BIOIO-1001 is a first therapy that fits the geroscience hypothesis by acting on multiple core aging pathways and that can alleviate multiple conditions after they have set in.
Preprint↗
Clinical Trial: Phase 3 Trial of Resmetirom Versus Placebo in Metabolic Dysfunction-Associated Steatohepatitis-Reanalysis of Fibrosis Stage 2-3 Subset.
BACKGROUND: Resmetirom is an oral thyroid hormone receptor beta agonist clinically used to treat metabolic dysfunction-associated steatohepatitis (MASH) among adults with stage F2 or F3 fibrosis. AIMS: Because the pivotal, 52-week, randomized, controlled, phase 3 MAESTRO-NASH trial (once-daily oral resmetirom 80 or 100 mg or placebo) included patients with F1, F2, or F3 fibrosis, we conducted a post hoc analysis aimed at assessing treatment response in the subset of patients with stages F2 and F3 fibrosis, consistent with the approved label population. METHODS: Co-primary end points were MASH resolution (hepatocellular ballooning score 0, lobular inflammation score ≤ 1, and ≥ 2-point nonalcoholic fatty liver disease activity score [NAS] reduction from baseline) with no fibrosis worsening, and ≥ 1-stage fibrosis improvement with no NAS worsening at Week 52. RESULTS: Among 917 patients with F2 or F3 fibrosis, metabolic risk factor prevalence was high (hypertension, 78.0%; dyslipidemia, 71.1%; type 2 diabetes, 67.0%). MASH resolution was achieved by 25.7% in the 80-mg group, 29.9% in the 100-mg group, and 9.5% in the placebo group (p < 0.0001 for both comparisons with placebo). Respective percentages with fibrosis improvement were 26.5%, 28.9%, and 17.3% (p < 0.01 for both comparisons). From baseline to Week 24, low-density lipoprotein cholesterol decreased by 11.7% and 13.7% in the 80- and 100-mg resmetirom groups, respectively, and increased by 2.3% with placebo (p < 0.0001 for both comparisons). No new safety signals emerged. CONCLUSION: Results among patients with F2 and F3 fibrosis were consistent with the primary MAESTRO-NASH analysis population, demonstrating efficacy and safety of resmetirom after 52 weeks.
Humans↗
Integrative pan-cancer analysis of transferrin reveals context-dependent prognostic associations and links to immune and metabolic disease-related programs.
BACKGROUND: Iron metabolism is closely linked to tumor biology, yet the pan-cancer significance of transferrin (TF), the major circulating iron-transport protein, remains insufficiently defined. Although TF has been implicated in cancer-related processes, its prognostic relevance, immune associations, and broader disease-related transcriptional context have not been systematically characterized across tumor types. OBJECTIVE: This study aimed to perform an integrative pan-cancer analysis of TF to characterize its expression patterns, clinical associations, immune context, pathway features, and pharmacogenomic correlations, and to explore whether TF-related signals extend to selected metabolic and chronic organ injury settings. METHODS: We used multiple public databases, including The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Gene Expression Omnibus (GEO), and Cancer Cell Line Encyclopedia (CCLE), to integrate transcriptomic, proteomic, and clinical data across 33 tumor types and selected non-malignant conditions. TF expression was evaluated across normal tissues, tumors, and cell lines, followed by survival analysis, immune infiltration analysis, TMB/MSI and methylation assessment, pathway enrichment, and drug-response correlation. Independent GEO cohorts of non-alcoholic steatohepatitis (NASH), heart failure (HF), and liver cirrhosis (LC) were used for cross-disease extension. Selected findings were further explored in OA/PA-treated hepatocytes, 786-O renal carcinoma cells, and AC16 cardiomyocytes. RESULTS: TF showed pronounced tissue specificity and cancer-type-dependent dysregulation. Across pan-cancer cohorts, the most consistent adverse survival associations were observed in kidney renal clear cell carcinoma (KIRC) and stomach adenocarcinoma (STAD), where TF remained associated with overall survival (OS) in multivariable analyses. TF expression was also correlated with cancer-type-specific immune infiltration patterns and selected drug-response profiles. Across independent NASH, HF, and LC datasets, TF expression was elevated and TF-associated pathways partially overlapped with those observed in cancer. In vitro experiments provided preliminary support that TF modulation is associated with proliferative phenotypes in KIRC cells and stress- and metabolism-related phenotypes in hepatocyte and cardiomyocyte models. CONCLUSION: These findings support TF as a context-dependent biomarker candidate in cancer, with the most consistent prognostic relevance observed in KIRC and STAD. Rather than establishing a unified mechanism across diseases, this study provides an integrative framework suggesting that TF is associated with malignant behavior, immune context, and selected metabolic stress-related programs, and warrants further mechanistic investigation.
Iron metabolism↗
2' Derivatives of guanosine and inosine cyclic 3',5'-phosphates. Synthesis, enzymic activity, and the effect of 8-substituents.
A series of representative derivatives of guanosine cyclic 3',5'-phosphate (cGMP) and inosine cyclic 3',5'-phosphate (cIMP) which contained modifications in either the 2' position or the 8 and 2' positions were synthesized. Three types of derivatives were investigated: (1) derivatives in which the 2' position has been altered to produce a 2'-deoxynucleoside cyclic 3',5'-phosphate or a 9-beta-D-arabinofuranosylpurine cyclic 3',5'-phosphate; (2) 2'-omicron-acyl derivatives; and (3) doubly modified derivatives containing a 2' modification [as in (1) and (2)] and an 8-substitution. 2'-Deoxyinosine cyclic 3',5'-phosphate and 9-beta-D-arabinofuranosylhypoxanthine cyclic 3',5'-phosphate were obtained by HNO2 deamination of 2'-deoxyadenosine cyclic 3',5'-phosphate and 9-beta-D-arabinofuranosyladenine cyclic 3',5'-phosphate (ara-cAMP), respectively. Treatment of 8-bromo-2'-omicron-(p-toluenesulfonyl) adenosine cyclic 3',5'-phosphate with NaSH yielded the intermediate 8,2'-anhydro-9-beta-D-arabinofuranosyl-8-mercaptoadenine cyclic 3',5-phosphate, which was converted directly to 2'-deoxyadenosine cyclic 3',5'-phosphate (dcAMP) by treatment with Raney nickel. 8-Bromo-2'-omicron-(p-toluenesulfonyl) guanosine cyclic 3',5'-phosphate was converted to 8,2'-anhydro-9-beta-D-arabinofuranosyl-8-mercaptoguanine cyclic 3',5'-phosphate, and the latter was desulfurized with Raney nickel to give 2-deoxyguanosine cyclic 3',5'-phosphate. Ara-cAMP, 9-beta-D-arabinofuranosylguanine cyclic 3',5'-phosphate, and 9-beta-D-arabinofuranosyl-8-mercaptoguanine cyclic 3',5'-phosphate have been previously reported (Mian et al. (1974), J. Med. Chem. 17, 259). 8-Bromo-2'-omicron-acetylinosine cyclic 3',5'-phosphate and 8-[(p-chlorophenyl)thio]-2'-omicron-acetylinosine cyclic 3',5'-phosphate were produced by acylation of 8-bromoinosine cyclic 3',5'-phosphate and 8-[(p-chlorophenyl)thio]inosine cyclic 3',5'-phosphate, respectively; while 8-bromo-2'-omicron-butyrylguanosine cyclic 3',5'-phosphate was synthesized by bromination of 2'-omicron-butyrylguanosine cyclic 3',5'-phosphate.
Animals↗
Role of DNA gyrase in phiX replicative-form replication in vitro.
Preparations containing DNA gyrase activity Gellert, M., Mizuchi, K., O'Dea, M.H. & Nash, H.A. (1976) Proc. Natl. Acad. Sci. USA 73, 3872-3876] have been extensively purified from Escherichia coli. Such fractions, in the presence of ATP and Mg2+, catalyze supertwisting of relaxed circular double-stranded DNA replicative forms of a number of DNAs that results in the formation of superhelical replicative forms. Relaxed phiX174 replicative form (phiX RFIV) is not attacked by the A protein endonuclease coded for by the phiX DNA genome. After exposure to preparations of DNA gyrase, the relaxed phiX174 replicative form is converted to phiX RFI which can then be attacked by the phiX gene A protein and participate in replication of duplex phiX DNA.
Adenosine Triphosphate↗
A genetic and biochemical analysis of the temperature sensitive, normal-winged alleles of the rudimentary locus of Drosophila melanogaster.
The genetic and biochemical characteristics of a particular class of mutants at the rudimentary locus are described. The mutants are pyrimidine auxotrophs, like classical rudimentary alleles, but they are unique in that they do not alter the size or shape of the wing (Falk and Nash 1974b). Aspartate transcarbamylase and dihydroorotase activities have been measured in seven different normal-winged mutants, and the results indicate that these strains are enzymologically "leaky" mutants. Previous studies have shown that three genetic functions (corresponding to the first three enzymes of pyrimidine synthesis) are associated with the rudimentary locus. Four of the seven mutants appear to affect all three of these functions. Each of the four is temperature sensitive, and a biochemical analysis of the temperature sensitivity of one of these mutants, (r)pyr1-3, suggests that a process affecting the synthesis or assembly of these enzymes is altered at high temperatures.
Alleles↗
Reduced R-loop abundance at proinflammatory loci: a shared epigenetic mechanism in inflammatory and metabolic diseases.
INTRODUCTION: R-loops, RNA-DNA hybrid structures with a displaced single-stranded DNA loop, are key regulators of transcriptional control, chromatin architecture, and genome stability and have emerging roles in inflammatory signaling. However, the relationship between R-loop abundance and strongly modulated inflammatory effector genes in metabolic inflammation and influenza virus infection remains underexplored. METHODS: We performed a locus-centric integrative analysis combining robust differentially expressed genes (DEGs) from multiple inflammatory and infection-related murine and human transcriptomic disease models with experimentally validated multi-cell R-loop annotations from the reference atlas RLoopBase. Our correlation framework evaluated the directional relationship between R-loop abundance and inflammatory gene expression rather than assuming disease-sample-matched R-loop measurements. We further analyzed R-loop regulatory proteins, NRF2-associated R-loop regulators, and overlaps between R-loop regulators and CRISPRi-identified mitochondrial and cellular reactive oxygen species (ROS) regulators. RESULTS: In angiotensin II-infused apolipoprotein E-deficient (ApoE-/-) mice, a model of abdominal aortic aneurysm (AAA), genomic regions encoding the top significantly upregulated genes exhibited significantly fewer R-loops than those encoding downregulated genes at days 14 and 28. Similarly, in atherosclerotic ApoE-/- mice fed a high-fat diet for 32 and 78 weeks, upregulated genes were associated with fewer R-loops than downregulated genes. Reduced R-loop abundance was also observed in genomic regions encoding the top significantly upregulated genes in liver tissues from patients with non-alcoholic steatohepatitis (NASH), as well as in monosodium urate (MSU)-stimulated lymphatic endothelial cells (LECs) and influenza virus-infected human umbilical vein endothelial cells (HUVECs). R-loop regulatory proteins upregulated during metabolic inflammation were enriched in immune and inflammatory pathways. NRF2 was identified as a regulator of 27 R-loop regulatory proteins, including 10 positively and 17 negatively regulated proteins. Furthermore, 54 R-loop regulatory proteins overlapped with CRISPRi-identified mitochondrial and cellular ROS regulators, suggesting potential reciprocal regulation between R-loop homeostasis and ROS signaling. Disease-associated changes in pro-ROS and anti-ROS R-loop regulatory proteins further linked R-loop regulation to inflammatory and oxidative stress pathways. DISCUSSION: These findings identify reduced R-loop abundance at genomic regions encoding strongly upregulated inflammatory genes as a shared feature across multiple models of metabolic inflammation and influenza virus infection. The results further suggest that immune-associated R-loop regulatory proteins and the NRF2-ROS axis may contribute to R-loop remodeling during inflammatory disease. This integrative framework provides new insight into the potential role of R-loops and ROS-sensitive R-loop regulators in inflammatory and metabolic diseases and identifies candidate pathways for future mechanistic investigation and therapeutic targeting.
R-loop regulatory proteins↗
AI-driven diagnostic and prognostic models for metabolic dysfunction-associated steatotic liver disease: insights from clinical, imaging, and multi-omics studies-a scoping review.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common chronic liver disease around the world, affecting 33.6% of the adult population (95% CI: 28.1%-39.5%; I 2 = 99.9%), or roughly one in three. The extent of the liver damage is variable, from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), cirrhosis and hepatocellular carcinoma (HCC). Early diagnosis is essential to prevent serious liver damage. Traditional diagnostic techniques such as liver biopsy, imaging, and biomarker testing are all invasive, costly, reduced sensitive to early-stage disease, and they also have variability among observers. Modern diagnostic and prognostic approaches based on the principles of Artificial Intelligence (AI) and specifically on machine learning (ML) and deep learning (DL) have enabled multimodal approaches integrating clinical, imaging and molecular data. This scoping review conducted per PRISMA-ScR guidelines, synthesizes findings from 73 studies (search window 2020-2026) across three dimensions: clinical data driven models, imaging-based classifiers (ultrasound, CT and MRI), and multi-omics (genomics, transcriptomics and proteomics) techniques. Moreover, emergence of models such as U-Net and LiverNet 2.x, classification models like DeepLiverNet and BiLSTM models, as well as transformer frameworks and the identification of biomarkers models are also described. This study also investigates challenges such as data heterogeneity, data interpretability, fairness and real-world clinical application. Finally, important areas of research opportunities and future directions are highlighted to present a developing clinically applicable, explainable and ethical AI solutions to manage MASLD.
MASLD↗
The Triad of NF-κB, HIF-1α, and Oxidative Stress in Hepatocellular Carcinoma: Pathogenesis, Clinical Challenges, and Therapeutic Potential of CIGB-552 in Liver Transplantation.
Hepatocellular carcinoma (HCC) represents a formidable oncological challenge characterized by complex molecular pathogenesis and limited therapeutic outcomes, particularly in the context of liver transplantation. As the sixth most commonly diagnosed cancer and the third leading cause of cancer-related mortality worldwide, HCC poses significant clinical challenges that demand innovative therapeutic approaches. Central to HCC development and progression is a pathogenic triad comprising nuclear factor-kappa B (NF-κB), hypoxia-inducible factor-1α (HIF-1α), and oxidative stress-three interconnected pathways that drive inflammation, angiogenesis, metabolic reprogramming, and cell survival. This comprehensive review examines the molecular mechanisms underlying this triad in HCC pathogenesis across different etiological contexts, including viral hepatitis and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). We critically analyse the unique clinical challenges posed by HCC in liver transplantation recipients, particularly the paradoxical requirement for immunosuppression alongside antitumor immunity, and constraints surrounding immunotherapy application. Furthermore, we present CIGB-552, a novel peptide therapeutic targeting COMMD1 (Copper Metabolism MURR1 Domain-containing protein 1), as a promising dual-function agent capable of simultaneously disrupting the pathogenic triad through NF-κB inhibition, HIF-1α suppression, and strategic modulation of oxidative stress via SOD1 regulation. The multimodal mechanism of CIGB-552 offers a theoretically rational therapeutic approach for HCC management in both pre-transplant and post-transplant settings. Clinical validation in the transplantation setting is required.
Humans↗
Talcosis and coronary artery disease.
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Adult↗
Risk of Relapse and Efficacy of Adjuvant Chemotherapy in Localized Appendiceal Adenocarcinoma.
IMPORTANCE: Relapse risk and benefit of adjuvant chemotherapy after resection of appendiceal adenocarcinoma (AA) are uncertain. OBJECTIVE: To identify clinicopathologic and genomic factors associated with relapse and assess efficacy of adjuvant chemotherapy in localized AA. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study (January 2000 through February 2024; median follow-up, 62.6 months) used Kaplan-Meier and Cox proportional hazards modeling. It took place at the University of Texas MD (UT MD) Anderson Cancer Center with validation from Memorial Sloan Kettering Cancer Center (MSKCC). Participants included a complete localized cohort of 439 patients with stage I to III AA from UT MD Anderson, of whom 202 underwent surgery at UT MD Anderson and also included a validation cohort of 128 patients with stage II AA from MSKCC. EXPOSURES: Surgical resection with or without adjuvant chemotherapy. MAIN OUTCOMES AND MEASURES: Rate of recurrence, recurrence-free survival (RFS), and overall survival (OS). RESULTS: There were 439 patients with localized AA (median age, 56.5 [IQR, 22.2-83.7] years; 50% female and 50% male) managed at MD Anderson between January 2000 and February 2024. Of 202 MDA surgical patients, 19 (9.4%) had a relapse including 9 (6%) patients with stage II and 8 (19.5%) of patients stage III disease. Five-year OS was 95.7% without vs 77.2% with relapse (hazard ratio [HR], 5.50; 95% CI, 3.07-9.83; P < .001). Relative to goblet cell tumors, mucinous (HR, 5.60; 95% CI, 2.1-15; P < .001) and enteric-type (HR, 6.60; 95% CI, 2.9-15; P < .001) histologies were independently associated with relapse, as was pathologic T4 (HR, 3.30; 95% CI, 1.9-5.7; P < .001). Importantly, poor differentiation, perforation, lymphovascular invasion, and perineural invasion, known risk factors in colorectal cancer, were not significantly associated with relapse. For the complete localized cohort, adjuvant chemotherapy was not associated with improved RFS (univariate HR, 2.06; 95% CI, 1.36-3.13; P = .001 and multivariable HR, 0.98; 95% CI, 0.43-2.28; P = .90) or OS (univariate HR, 1.80; 95% CI, 1.0-3.2; P = .04 and multivariable HR, 0.71; 95% CI, 0.24-2.1; P = .53). TP53 mutation in goblet cell tumors (HR, 6.93; 95% CI, 1.50-31.00; P = .01) and GNAS mutation in nongoblet tumors (HR, 17.0; 95% CI, 3.09-93.3; P = .001) were associated with greater risk of relapse. CONCLUSIONS AND RELEVANCE: These results demonstrate that relapse after resection of localized AA is uncommon. Molecular profiling and histopathologic subtype refine risk. Adjuvant chemotherapy were not associated with benefit.
Journal Article↗
Wound infection following appendicectomy: the effect of extraperitoneal wound drainage and systemic antibiotic prophylaxis.
The value of extraperitoneal wound drainage and a 3-day course of prophylactic systemic cephaloridine used both separately and together have been assessed in a prospective controlled randomized trial involving 246 patients undergoing appendicectomy at the Leicester Royal Infirmary. Extraperitoneal wound drainage was shown to reduce significantly the incidence of postoperative wound infection in patients with a gangrenous or perforated appendix (P less than 0-025). Prophylactic cephaloridine significantly reduced the overall incidence of wound infection (P less than 0-02) and was also effective when the appendix was gangrenous or perforated (P less than 0-01). A highly significant reduction in wound infection was achieved when the appendix was gangrenous or perforated by the addition of wound drainage to the antibiotic regimen (P less than 0-001).
Adolescent↗
Laparoscopy for the confirmation and prognostic evaluation of pelvic inflammatory disease.
A presumptive diagnosis of pelvic inflammatory disease (PID) is usually made in our gynecologic clinics when obscure, acute lower abdominal pain is accompained by fever and abnormal vaginal discharge, urinary and rectal discomfort, marked tenderness of the pelvic organs to palpation, or pelvic masses. In the present study, during a 2-year period, 223 women underwent laparoscopy to confirm this diagnosis. PID was confirmed in 103 (46.2%) of the cases; other serious conditions were diagnosed in 69 (30.9%) of the cases; and no evidence of disease was found in 51 (22.9%) of the cases. The authors conclude that laparoscopy is a valuable tool in the diagnosis of PID.
Diagnosis, Differential↗
Cinoxacin in female mongrel dogs: effect of urine pH on urinary drug excretion and correlation of in vitro characteristics of oral dosage forms with bioavailability.
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Administration, Oral↗
Biochemical studies of purine auxotrophs of Drosophila melanogaster.
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Animals↗
Integration and excision of bacteriophage lambda.
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Chromosomes, Bacterial↗