Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor.

Hypoxia-inducible factor prolyl hydroxylase (PHD) inhibitors have been approved for treating renal anemia yet have failed clinical testing for inflammatory bowel disease because of a lack of efficacy. Here we used a multimodel multimodal generative artificial intelligence platform to design an orally gut-restricted selective PHD1 and PHD2 inhibitor that exhibits favorable safety and pharmacokinetic profiles in preclinical studies. ISM012-042 restores intestinal barrier function and alleviates gut inflammation in multiple experimental colitis models.

Roles of hypoxia-inducible factor-prolyl hydroxylases in aging and disease.

The prolyl hydroxylase domain-containing (PHD or EGL9-homologs) enzyme family is mainly known for its role in the cellular response to hypoxia. HIF-PH inhibitors can stabilize hypoxia-inducible factors (HIFs), activating transcriptional programs that promote processes such as angiogenesis and erythropoiesis to adapt to changes in oxygen levels. HIF-PH inhibitors have been clinically approved for treating several types of anaemia.

Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis.

Traf2- and Nck-interacting kinase (TNIK) has been identified as a promising therapeutic target for the treatment of fibrosis-driven diseases. Utilizing a structure-based drug design workflow, we developed a series of potent TNIK inhibitors that modulate the conformation of the gatekeeper Met105 side chain and access the TNIK back pocket. The lead optimization efforts culminated in the discovery of the recently reported compound (INS018_055), a novel TNIK inhibitor.

Sampling clustering based on multi-view attribute structural relations.

In light of the exponential growth in information volume, the significance of graph data has intensified. Graph clustering plays a pivotal role in graph data processing by jointly modeling the graph structure and node attributes. Notably, the practical significance of multi-view graph clustering is heightened due to the presence of diverse relationships within real-world graph data.

A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models.

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as an anti-fibrotic target using a predictive artificial intelligence (AI) approach.

A novel approach to attention mechanism using kernel functions: Kerformer.

Artificial Intelligence (AI) is driving advancements across various fields by simulating and enhancing human intelligence. In Natural Language Processing (NLP), transformer models like the Kerformer, a linear transformer based on a kernel approach, have garnered success. However, traditional attention mechanisms in these models have quadratic calculation costs linked to input sequence lengths, hampering efficiency in tasks with extended orders.

Titanium dioxide nanoparticles induced the apoptosis of RAW264.7 macrophages through miR-29b-3p/NFAT5 pathway.

Titanium dioxide nanoparticles (TiO NPs) are widely found in consumer and industrial products, contributing to their prevalent presence in our surroundings. In this study, several miRNAs in the immuno-related pathways were found to be dysregulated in RAW264.7 cells after 24-h exposure to TiO NPs, including miR-29b-3p, which had not been previously found to be associated with the dysregulation of immunity after exposure to TiO NPs.

Seipin Knockout Mice Develop Heart Failure With Preserved Ejection Fraction.

The lean diabetic patients with heart failure with preserved ejection fraction (HFpEF) in Asia suffer from adverse clinical outcomes and poor life quality. The suitable animal models are urgently needed for mechanistic study and therapeutic innovations. Our study reports that lipodystrophic mice with seipin depletion are lean, diabetic, and recapitulate major manifestations of clinical HFpEF, thereby clarifying that lean diabetes per se may produce HFpEF characteristics.

Indian Hedgehog links obesity to development of hepatocellular carcinoma.

Obesity increases the risk of hepatocellular carcinoma (HCC), but precise identification and characterization of druggable oncogenic pathways that contribute to the progression of NAFLD to HCC, and hence to the increased incidence and aggressiveness of HCC in obese individuals is lacking. In this regard, we demonstrate that the Indian Hedgehog (Ihh) signaling pathway is upregulated in the fatty livers of mice consuming a high fat diet, and furthermore sustained in HCC tumors specifically within the context of a NAFLD microenvironment. Using a diet-induced mouse model of HCC wherein only obese mice develop HCC, targeted ablation of hepatocyte-secreted Ihh results in a decreased tumor burden and lower grade tumors.

Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease.

Objective: Mutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans.

Molecular mechanism for miR-350 in regulating of titanium dioxide nanoparticles in macrophage RAW264.7 cells.

This study investigated the role of microRNA(miRNA) in regulating the cytotoxicity of TiO nanoparticles (nano-TiO) to RAW264.7 cells. RAW264.

miRNA-32 Drives Brown Fat Thermogenesis and Trans-activates Subcutaneous White Fat Browning in Mice.

Brown adipose tissue (BAT) activation and subcutaneous white fat browning are essential components of the thermogenic response to cold stimulus in mammals. microRNAs have been shown to regulate both processes in cis. Here, we identify miR-32 as a BAT-specific super-enhancer-associated miRNA in mice that is selectively expressed in BAT and further upregulated during cold exposure.

A Critical Role for β-Catenin in Modulating Levels of Insulin Secretion from β-Cells by Regulating Actin Cytoskeleton and Insulin Vesicle Localization.

The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic β-cells are only partly understood. Here we investigate the involvement of β-catenin in these processes. Reducing β-catenin levels using siRNA knockdown attenuated GSIS in a range of β-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this.

2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice.

Aim: Sterol-regulatory element binding proteins (SREBPs) are major transcription factors that regulate liver lipid biosynthesis. In this article we reported a novel synthetic compound 2-(3-benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (ZJ001) that inhibited the SREBP-1c pathway, and effectively reduced hepatic lipid accumulation in diet-induced obesity (DIO) mice.

Methods: A luciferase reporter driven by an SRE-containing promoter transfected into HepG2 cells was used to discover the compound.

MicroRNA-125b may function as an oncogene in lung cancer cells.

The present study aimed to investigate the biofunctions of microRNA (miR)‑125b on lung cancer cells. A miR genechip array was used to examine the differential expression of miRs between 95D lung cancer cells and 16 human bronchial epithelial (HBE) cells. Overexpression of miR‑125b was observed in the cell lines and in the lung carcinoma tissues compared with the adjacent tissues, confirmed using reverse transcription quantitative polymerase chain reaction.

Systemic immune effects of titanium dioxide nanoparticles after repeated intratracheal instillation in rat.

The potential immune effects of titanium dioxide nanoparticles (nano-TiO₂) are raising concern. Our previous study verified that nano-TiO₂ induce local immune response in lung tissue followed by intratracheal instillation administration. In this study, we aim to evaluate the systemic immune effects of nano-TiO₂.

Azoxystrobin, a mitochondrial complex III Qo site inhibitor, exerts beneficial metabolic effects in vivo and in vitro.

Background: Several anti-diabetes drugs exert beneficial effects against metabolic syndrome by inhibiting mitochondrial function. Although much progress has been made toward understanding the role of mitochondrial function inhibitors in treating metabolic diseases, the potential effects of these inhibitors on mitochondrial respiratory chain complex III remain unclear.

Methods: We investigated the metabolic effects of azoxystrobin (AZOX), a Qo inhibitor of complex III, in a high-fat diet-fed mouse model with insulin resistance in order to elucidate the mechanism by which AZOX improves glucose and lipid metabolism at the metabolic cellular level.

Effects of Th1 and Th2 cells balance in pulmonary injury induced by nano titanium dioxide.

To explore the potential immunoregulatory mechanisms linking nano TiO₂ and pulmonary injury, Sprague Dawley rats were exposed by intra-tracheal instillation to nano TiO₂ with the individual doses of 0.5, 4.0 and 32 mg/kgb.

Novel small-molecule PGC-1α transcriptional regulator with beneficial effects on diabetic db/db mice.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1α expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1α promoter to drive expression of luciferase.