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The enzyme acyl–coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol, and studies in animals suggest that inhibiting ACAT may reduce the progression of atherosclerosis. In this trial, the ACAT inhibitor pactimibe had no beneficial effect on the progression of coronary atherosclerosis and actually worsened some angioscopic measures of atherosclerosis. Contrary to expectations, ACAT inhibition may in fact promote atherogenesis. The ACAT inhibitor pactimibe had no beneficial effect on the progression of coronary atherosclerosis and actually worsened some angioscopic measures of atherosclerosis. Contrary to expectations, ACAT inhibition may in fact promote atherogenesis. The introduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) nearly two decades ago marked a turning point in the effort to develop pharmacologic agents to reduce morbidity and mortality from coronary disease. However, despite the development of increasingly potent statins capable of markedly lowering cholesterol levels, coronary disease remains the leading cause of death in Western societies. 1 Basic research has clarified the metabolic pathways underlying the accumulation and removal of lipids from the vascular wall. Accordingly, drug-discovery efforts have focused on targeted therapeutic approaches. One promising target is the enzyme acyl–coenzyme A:cholesterol acyltransferase (ACAT), which esterifies cholesterol in a variety . . .

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment 1 , 2 . Less than half of all patients respond to the primary treatment for PDAC, chemotherapy 3 , 4 , and genetic alterations alone cannot explain this 5 . Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer. Indole-3-acetic acid (3-IAA), a tryptophan metabolite derived from the gut microbiota, is associated with a better response to chemotherapy in pancreatic ductal adenocarcinoma (PDAC), and dietary interventions could have a role in the treatment of PDAC.

Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.

Background Gut microbiota has emerged as a promising therapeutic target for neurodegenerative disorders through regulation of neuroinflammatory responses, while its role in optic nerve degeneration remains incompletely characterized. This study elucidates the neuroprotective role of gut microbiota derived tryptophan metabolites in glaucoma through gut-eye communication and inhibition of microglia-mediated neuroinflammation. Methods Gut microbiota profiling (16 S rRNA sequencing) and serum indoleacetic acid (IAA) quantification were performed in glaucoma patients versus controls. Microbiota–metabolite relationships were further validated through fecal microbiota transplantation (FMT). The neuroprotective and anti-neuroinflammatory effect of Bacteroides fragilis ( B. fragilis ) and IAA was assessed in both microbead-induced ocular hypertension mice model and in vitro BV-2 microglial cell inflammation model via immunofluorescence, qPCR, Western blot and mice behavioral assays. To explore the underlying mechanisms, retinal transcriptomics and microglia-neuron co-cultures were also employed. Result Glaucoma patients exhibited gut dysbiosis characterized by depleted tryptophan-metabolizing bacteria ( B. fragilis , Bacteroides thetaiotaomicron , Anaerostipes hadrus ) and reduced serum IAA levels. Mice receiving FMT from glaucoma patients exhibited lower systemic IAA levels. In in vivo and in vitro models, B. fragilis or IAA restored AhR activation, suppressed inflammation by inhibiting microglial activation and the release of pro-inflammatory mediators throughout the retina, reduced retinal ganglion cells (RGCs) loss and preserved visual function. Mechanistically, IAA attenuated RAGE/NF-κB pathway activation via AhR-dependent signaling, conferring neuroprotection. Conclusion Our study proposes a novel AhR-mediated gut microbiota-eye axis in glaucoma pathogenesis and demonstrates that IAA serves as an effective neuroprotective strategy with clinical potential for managing RGCs neurodegeneration.

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

The exact mechanism of calcium oxalate stone (CaOx) formation is not fully understood. Evidence suggests that disruptions in the gut microbiota and its metabolites influence kidney stone formation. We conducted microbiome-metabolome analysis to pinpoint microbial metabolites linked to kidney stones in both patient and healthy control groups. We explored the impact of these kidney stone-related microbial metabolites on CaOx-induced stones, along with their underlying mechanisms of action. We exposed NRK-52E cells to CaOx crystals that had been pretreated with indole-3-acetic acid. Rats, induced to develop CaOx stones via ethylene glycol and ammonium chloride administration, were also treated with IAA. Our investigations encompassed assessments of Ca 2+ levels, reactive oxygen species levels, markers of oxidative stress, apoptosis levels, inflammation levels, and gene expression within AHR/NF‑κB pathway, both in cellular and tissue samples.Indole-3-acetic acid showed significantly reduction in patients with renal stones. The administration of IAA has been found to alleviate the deposition and adhesion of calcium oxide stones in the kidneys. Furthermore, IAA demonstrates beneficial effects on kidney damage and inflammation. IAA efficiently reduces intracellular levels of ROS, osteopontin, and CD44 in NRK-52E cells exposed to CaOx as well as in a rat model of stone formation. Mechanistically, IAA inhibits the activation of the NF-κB signaling pathway through the elevation of AHR in kidney stones. Our research has uncovered a novel connection between gut microbiota-derived tryptophan metabolites and kidney stones. The microbial metabolite IAA/AHR/NF-κB pathway may be a promising target for kidney stone treatment.

Inhibiting the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) has beneficial effects on foam cell formation and therefore has the potential to favorably influence the progression of coronary atherosclerosis. The aim of this study is to determine whether ACAT inhibition, when added to usual medical care, reduces atheroma progression in subjects with coronary artery disease. Five hundred thirty-four subjects with established coronary artery disease on angiography were randomized to receive the experimental ACAT inhibitor, pactimibe, 100 mg daily or matching placebo for 18 months. The primary efficacy parameter will be the nominal change in percent atheroma volume determined by analysis of pullback intravascular ultrasound (IVUS) images of matched coronary artery segments acquired at baseline and 18-month follow-up. In addition, the effect of pactimibe on plasma lipids and inflammatory markers and the incidence of clinical cardiovascular events will also be assessed. Serial IVUS has emerged as a sensitive imaging modality to assess the impact that novel antiatherosclerotic strategies have on the arterial wall. In this study, IVUS will be used to assess whether ACAT inhibition modifies progression of atherosclerotic plaque.

Hyperglycemia is considered a key risk factor for development of diabetic complications including neuropathy. There is strong scientific evidence showing a primary role of aldose reductase, the first enzyme of the polyol pathway, in the cascade of metabolic imbalances responsible for the detrimental effects of hyperglycemia. Aldose reductase is thus considered a significant drug target. We investigated the effects of cemtirestat, a novel aldose reductase inhibitor, in the streptozotocin-induced rat model of uncontrolled type 1 diabetes in a 4-month experiment. Markedly increased sorbitol levels were recorded in the erythrocytes and the sciatic nerve of diabetic animals. Osmotic fragility of red blood cells was increased in diabetic animals. Indices of thermal hypoalgesia were significantly increased in diabetic rats. Tactile allodynia, recorded in diabetic animals in the early stages, turned to mechanical hypoalgesia by the end of the experiment. Treatment of diabetic animals with cemtirestat (i) reduced plasma triglycerides and TBAR levels; (ii) did not affect the values of HbA1c and body weights; (iii) reversed erythrocyte sorbitol accumulation to near control values, while sorbitol in the sciatic nerve was not affected; (iv) ameliorated indices of the erythrocyte osmotic fragility; and (v) attenuated the symptoms of peripheral neuropathy more significantly in the middle of the experiment than at the end of the treatment. Taking into account the lipid metabolism as an interesting molecular target for prevention or treatment of diabetic peripheral neuropathy, the triglyceride-lowering effect of cemtirestat should be considered in future studies. The most feasible mechanisms of triglyceride-lowering action of cemtirestat were suggested.

The radical-cations formed on one-electron oxidation of indole-3-acetic acid (IAA) and its ringsubstituted derivatives rapidly fragment, eliminating carbon dioxide from the sidechain and forming a carbon-centred free radical (3-indolylmethyl or skatolyl, or analogues). This radical is reactive towards DNA and possibly other targets in anoxia, but in oxic or hypoxic cells rapidly adds oxygen to form a peroxyl radical. Subsequent products include 3-methylene-2-oxindole or analogues, reactive towards cellular nucleophiles such as thiols and DNA. The one-electron oxidation of indole-3-acetic acids is efficiently achieved by horseradish peroxidase (HRP), not requiring added hydrogen peroxide cofactor. The combination of IAA and HRP is cytotoxic towards mammalian cells, including human tumour cells. Unexpectedly, some halogen-substituted derivatives of IAA are very cytotoxic with HRP even though they are more difficult to oxidize. IAA is tolerated by humans in high doses and HRP is a robust enzyme meeting many of the requirements for targeting to tumours by coupling to antibodies or polymers, or by gene transfection. It is suggested that the indole acetic acids merit further evaluation as potential prodrugs for use in cancer therapy based on targeted delivery of HRP to tumours.

Medical management of atherosclerosis is based on the control of its risk factors (dyslipidemia, hypertension, family history, and smoking) and predisposing conditions (e.g., the metabolic syndrome and diabetes), but no drugs specifically target the arterial plaque. The search is on for therapeutic interventions that can act as antiatherosclerosis agents, selectively targeting one or more of the features of the atheroma, such as endothelial dysfunction, inflammation, or foam-cell formation. Approaches that target arterial plaque through the use of acyl–coenzyme A:cholesterol acyltransferase (ACAT) inhibitors have been investigated experimentally for two decades. ACAT inhibitors interfere with intracellular cholesterol transport within plaque macrophages and . . .