Periodontitis and Type 2 Diabetes Mellitus (T2DM) are chronic conditions with dysregulated immune responses. Periodontitis involves immune dysfunction and dysbiotic biofilms, leading to tissue destruction. T2DM is marked by insulin resistance and systemic inflammation, driving metabolic and tissue damage. Both conditions share activation of key pathways, including Nuclear Factor Kappa B (NF-κB), Activator Protein-1 (AP-1), and Signal Transducer and Activator of Transcription (STAT) proteins, reinforcing an inflammatory feedback loop. This review highlights the role of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ), a transcription factor central to lipid and glucose metabolism, adipogenesis, and immune regulation. PPAR-γ activation has been shown to suppress inflammatory mediators such as Tumor Necrosis Factor Alpha (TNF-α) and Interleukin 6 (IL-6) through the inhibition of NF-κB, AP-1, and STAT pathways, thereby potentially disrupting the inflammatory-metabolic cycle that drives both diseases. PPAR-γ agonists, including thiazolidinediones (TZDs) and endogenous ligands such as 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), show promise in reducing inflammation and improving insulin sensitivity but are limited by adverse effects. Emerging therapies, including Selective Peroxisome Proliferator-Activated Receptor Modulators (SPPARMs), have been developed to offer a more targeted approach, allowing for selective modulation of PPAR-γ activity to retain its anti-inflammatory benefits while minimizing side effects. By integrating insights into PPAR-γ's molecular mechanisms, this review underscores its therapeutic potential in mitigating inflammation and enhancing metabolic control.

Metabolic dysfunction associated steatotic liver disease (MASLD) is a widespread liver disease that progresses from simple steatosis to severe steatohepatitis stage. Despite the recognized importance of carboxylesterase 2 (CES2) in hepatic lipid metabolism, the role of CES2 in hepatic inflammation remains unclear. The rat genome encodes six Ces2 genes and Ces2a shows high expression in the liver and intestine. Lipid metabolism, inflammation, fibrosis, and endoplasmic reticulum (ER) stress were investigated in Ces2a knockout (KO) rats. KO rats showed spontaneous liver lipid accumulation due to increased lipogenesis and reduced fatty acid oxidation. Non-targeted lipidomic analysis revealed enhanced lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) in KO rats and increased concentrations of ligands, thus activating the expression of PPARγ. Although there was simple lipid accumulation in the liver of KO rats, Ces2a deficiency showed a significant protective effect against LPS and diet-induced hepatic steatohepatitis by inhibiting ER stress regulated by PPARγ activation. In line with this, treatment with tanshinone IIA, a CES2 inhibitor, significantly alleviated the progression of steatohepatitis induced by the MCD diet. In conclusion, the increased PPARγ expression in Ces2a deficiency may counteract liver inflammation and ER stress despite the presence of simple steatosis. Therefore, CES2 inhibition represents a potential therapeutic approach for steatohepatitis.

The antioxidant 6PPD and its oxidized product 6PPD-Quinone (6PPDQ) have attracted considerable attention due to their various acute toxicities to aquatic organisms. However, the chronic toxicity of two compounds in aquatic animals is still unknown. Here, adult zebrafish were exposed to 6PPD and 6PPDQ at environmentally relevant concentrations (20 μg/L) for 28 days, and histological analysis showed that 6PPD caused more severe hepatic vacuolization than 6PPDQ. Meanwhile, 6PPD induced more serious lipid accumulation and a higher increase in triglyceride and total cholesterol levels than 6PPDQ, suggesting higher hepatotoxicity of 6PPD. Furthermore, transcriptomic analysis revealed that both compounds disturbed glucolipid metabolism to different degrees by altering the expression of different peroxisome proliferator-activated receptors (PPARs), in which 6PPD inhibited gene expressions in glucolipid metabolism possibly by PPARα, PPARβ and RXR, while 6PPDQ disrupted the expressions of partial genes in similar pathways probably via PPARγ. Additionally, 6PPD but not 6PPDQ increased Fe2+ content, decreased the protein levels of ferroportin 1, ferritin and glutathione peroxidase 4, accompanied with the increase of malondialdehyde level and the decrease of glutathione content, suggesting ferroptotic response by 6PPD. Overall, our data deepened the understanding of 6PPD- and 6PPDQ-induced hepatotoxicity association with glucolipid metabolism disorders and ferroptotic responses.

Obesity is a prevalent global disease associated with various metabolic disorders. The expansion of white adipose tissue plays a pivotal role in regulating obesity-related metabolic dysfunctions. This study identified serum-defined colon cancer antigen 3 (SDCCAG3) as a novel key modulator of adipocyte metabolism. In adipose-specific SDCCAG3 knockout mice fed a high-fat diet, pathological expansion of adipose tissue, impaired glucose tolerance, insulin resistance, increased inflammatory markers, and augmented hepatic lipid accumulation were observed. Conversely, obesity models by specific overexpression of SDCCAG3 in adipose tissue confirmed that SDCCAG3 alleviated pathological expansion of adipose tissue, improved obesity-related metabolic disorders, with no observed changes in adipose tissue development under normal dietary conditions. Mechanistically, SDCCAG3 enhanced the stability of peroxisome proliferator-activated receptor gamma (PPARγ) by preventing its degradation via the ubiquitin-proteasome system through the SMAD specific E3 ubiquitin protein ligase 1 (SMURF1). Additionally, SDCCAG3 was subjected to negative transcriptional regulation by PPARγ, forming a SDCCAG3-PPARγ-SDCCAG3 loop that enhanced adipocyte lipid metabolism. Collectively, these findings demonstrated that SDCCAG3 functioned as a beneficial positive regulator of adipose tissue expansion and metabolic homeostasis, indicating its potential as a therapeutic target for metabolic diseases associated with nutrient excess.

Ovarian Cancer (OC) is the most lethal gynecological malignancy, characterized by peritoneal metastasis, directly linked to most OC-related deaths. Here, by interrogating CRISPR-Cas9 loss-of-function genetic screen data, we identified a list of genes essential for metastatic OC, including several well-known oncogenes (PAX8, CCNE1, WWTR1, WT1, KAT6A, MECOM, and SOX17) and others whose roles in OC have not yet been explored. Protein-protein interaction analysis of the selected genes revealed the presence of a protein network participating in the epigenetic regulation of gene expression. For one of the network components, BRPF1, we found that its increased expression correlates with OC progression and a poor prognosis for OC patients. Functional assays demonstrated that BRPF1 inhibition significantly reduces cellular migration and invasion, supporting its role in metastatic progression. Pharmacological blockade of BRPF1 using small molecule inhibitors resulted in reduced proliferation of high-grade serous OC cells through mechanisms involving the activation of programmed cell death, cell cycle deregulation, and enhanced DNA damage. Furthermore, analysis of transcriptional changes induced by BRPF1 targeting showed that the growth inhibitory effects may be mediated by the deregulation of PPARα signaling. The obtained results indicate that BRPF1 represents a novel potential therapeutic target for metastatic OC treatment.

The year 2024 witnessed the accelerated approvals of two peroxisome proliferator-activated receptor (PPAR) agonists for the treatment of primary biliary cholangitis (PBC). PPARs, including three isoforms (PPARα, PPARγ, and PPARδ), are therapeutic targets generating considerable debate yet also seeing significant advances in their successful targeting. Currently, selective PPAR agonists are used to manage hyperlipidemia, type 2 diabetes mellitus (T2DM), and PBC, and dual/pan-PPAR agonists have been developed to address various disorders. In this review, we summarize the PPAR agonists approved globally, and their pros and cons as therapeutic agents for various diseases, with a particular focus on those agonists marketed since 2010.

Skin is the largest organ in the human body, and it is also the most important natural barrier. However, some accidents can cause skin damage. Bacterial infections and inflammatory reactions can hinder wound healing. Therefore, eliminating bacterial infections and regulating oxidative stress are essential. The use of antibiotics is no longer sufficient because of bacterial resistance. The development of new nanomaterials provides another way of thinking about bacterial drug resistance. In this study, bismuth selenide is modified with polyethylpyrrolidone to obtain a 2D nanomaterial with negligible toxicity and then added to a sodium polyacrylate hydrogel, which is nontoxic and has strong tissue adhesion and a weak antibacterial effect. To further enhance antibacterial performance, photothermal therapy is a good strategy. Under near-infrared light, Bi2Se3/PAAS shows a strong bactericidal effect. Bi2Se3/PAAS hydrogels also have certain antioxidant effects and are used to remove excess free radicals from wound infections. The effective therapeutic effect of Bi2Se3/PAAS/NIR on methicillin-resistant Staphylococcus aureus (MRSA) infection is further verified in animal models. Transcriptome analysis reveals that the Bi2Se3/PAAS hydrogel improves the function of vascular endothelial cells, regulates glucose and lipid metabolism, and promotes the healing of infected wounds.

As people live longer, maintaining brain health becomes essential for extending health span and preserving independence. Brain degeneration and cognitive decline are major contributors to disability. In this study, we investigated how metabolic health influences the brain age gap estimate (brainAGE), which measures the difference between neuroimaging-predicted brain age and chronological age.

K-means clustering was applied to fasting metabolic markers including insulin, glucose, leptin, cortisol, triglycerides, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol, steady-state plasma glucose, and body mass index of 114 physically and cognitively healthy adults. The homeostatic model assessment for insulin resistance served as a reference. T1-weighted brain magnetic resonance imaging was used to calculate voxel-level and global brainAGE. Longitudinal data were available for 53 participants over a 3-year interval.

K-means clustering divided the sample into 2 groups, those with favorable (n = 58) and those with suboptimal (n = 56) metabolic health. The suboptimal group showed signs of insulin resistance and dyslipidemia (false discovery rate-corrected p < .05) and had older global brainAGE and local brainAGE, with deviations most prominent in cerebellar, ventromedial prefrontal, and medial temporal regions (familywise error-corrected p < .05). Longitudinal analysis revealed group differences but no significant time or interaction effects on brainAGE measures.

Suboptimal metabolic status is linked to accelerated brain aging, particularly in brain regions rich in insulin receptors. These findings highlight the importance of metabolic health in maintaining brain function and suggest that promoting metabolic well-being may help extend health span.

Neurodegenerative disorders are characterized by a continuous neurons loss resulting in a wide range of pathogenesis affecting the motor impairment. Several strategies are outlined for therapeutics of synthetic and natural PPARs agonists in some neurological disorders; Parkinson's disease (PD), Alzheimer's disease (AD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The aim of this review is to provide a recent update of the previously reported studies, and reviews dealing with the medicinal chemistry of PPARs and their agonists, and to highlight the outstanding advances in the development of both synthetic compounds including; PPARα agonists (fibrates), PPARγ agonists (thiazolidindiones), and PPARβ/δ agonists either as sole or dual acting PPAR full or pan agonists, in addition to the natural phytochemicals; acids, cannabinoids, and flavonoids for their different neuroprotection effects in the previously mentioned neurodegenerative disorders (PD, AD, MS, ALS, and HD). Moreover, this review reports the diverse pre-clinical and clinical studies of PPARs agonists in the neurodegenerative diseases via cellular, and animal models and human.

Peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in liver physiological and pathological processes. Yes-associated protein (YAP) is a key effector in regulating cell growth and organ size. Ubiquitination is known to modulate YAP protein expression, stability, and nuclear localization. Our previous study demonstrated that PPARα activation promotes hepatomegaly and liver regeneration via YAP activation. However, the underlying molecular mechanisms by which PPARα regulates YAP are unclear. In this study, PPARα was activated by the classical agonist WY-14643, and its effects on YAP ubiquitination were examined using plasmid transfection and immunoprecipitation. The ubiquitination of YAP was further investigated through mutant YAP plasmids, gene knockdown, and immunofluorescence staining. YAP mRNA and protein expression were measured via qRT-PCR and western blotting.

The results demonstrated that PPARα activation upregulated YAP protein levels and enhanced its activity, while reducing overall YAP ubiquitination. Specifically, PPARα activation inhibited K48-linked ubiquitination while promoting K63-linked ubiquitination of YAP. Mutations at the K252, K321, and K497 residues of YAP markedly reduced the capacity of PPARα activation to facilitate YAP nuclear translocation. Furthermore, knockdown of the E3 ligase TRAF6 abolished the PPARα-induced K63-linked ubiquitination of YAP and the upregulation of its downstream target genes.

These findings highlight the pivotal role of ubiquitination in regulating YAP through PPARα activation, providing novel insights for future studies on the post-translational regulation of YAP by PPARα activation.

Colorectal cancer (CRC) is the third most common malignancy globally and the second leading cause of cancer-related mortality. Its development is a multifactorial and multistage process influenced by a dynamic interplay between gut microbiota, environmental factors, and fatty acid metabolism. Dysbiosis of intestinal microbiota and abnormalities in microbiota-associated metabolites have been implicated in colorectal carcinogenesis, highlighting the pivotal role of microbial and metabolic interactions. Fatty acid metabolism serves as a critical nexus linking dietary patterns with gut microbial activity, significantly impacting intestinal health. In CRC patients, reduced levels of short-chain fatty acids (SCFAs) and SCFA-producing bacteria have been consistently observed. Supplementation with SCFA-producing probiotics has demonstrated tumor-suppressive effects, while therapeutic strategies aimed at modulating SCFA levels have shown potential in enhancing the efficacy of radiation therapy and immunotherapy in both preclinical and clinical settings. This review explores the intricate relationship between gut microbiota, fatty acid metabolism, and CRC, offering insights into the underlying mechanisms and their potential translational applications. Understanding this interplay could pave the way for novel diagnostic, therapeutic, and preventive strategies in the management of CRC.

The adverse effects of goose astrovirus (GoAstV) on avian growth and health have been widely reported previously, while the stress reactions and corresponding mechanism of gosling liver responding to GoAstV infection remain not entirely clear.

One-day-old goslings inoculated subcutaneously with 2 × 10-6 TCID50 of GoAstV were employed as an experimental model, and the potential effects and pathways of GoAstV infection on gosling liver functions were investigated by combining the morphological, biochemical and RNA sequencing (RNA-seq) techniques.

Structural and functional impairments were found in gosling livers post the virus infection, as characterized by the histological alterations in liver index and morphology of hepatic cord and sinuses, as well as the abnormal expression patterns of the cellular antioxidant, inflammation and apoptosis-related genes. RNA sequencing analysis were performed to investigate the underlying mechanism. Results showed that the analysis of screened 1949 differentially expressed genes (DEGs) were mainly enriched in GO terms related to organic immune defense and substance metabolism, and their corresponding KEGG pathways represented by PPAR signaling pathway, intestinal immune network for IgA production, and fatty acid metabolism and degradation, suggesting that the functions of avian immunity and lipid metabolism were greatly changed after the GoAstV infection. Finally, the lipid deposition in gosling hepatocytes were further demonstrated by the subsequent Oil red O staining, biochemical detection of serum TG and HDL-C, and the gene expression analysis including PPARα, PPARγ, ACSBG2, ACSL5, CPT1A and PCK1.

Though limitations exist, the findings of this study are helpful to expand our understanding about the negative effects of GoAstV on goslings, and provide us with new clues for the salvaging of GoAstV-induced liver dysfunctions in poultry industry.

Abnormal accumulation of hepatocyte lipids is a hallmark feature of NAFLD. Ferulic acid (FA), an ingredient with antioxidant activity in Chinese herbs, can be used to treat NAFLD by activating AMPK phosphorylation. In this study, we synthesized ten acrylic acid derivatives A1-A10. The inhibition of lipid accumulation showed that most target compounds could inhibit lipid accumulation at 400 μM; compound A3 showed a better inhibitory effect than other compounds. Molecular docking results proved that A3 could bind to PPARγ, and multiple binding sites existed in both the ferulic acid cohort and the substituted benzene cohort.

Peroxisome proliferator-activated receptor gamma (PPARγ), a critical nuclear receptor, plays a pivotal role in regulating metabolic and inflammatory processes. However, various environmental contaminants can disrupt PPARγ function, leading to adverse health effects. This study introduces a novel approach to predict the inhibitory activity (IC50 values) of 140 chemical compounds across 13 categories, including pesticides, organochlorines, dioxins, detergents, flame retardants, and preservatives, on PPARγ. The predictive model, based on the light-gradient boosting machine (LightGBM) algorithm, was trained on a dataset of 1804 molecules showed r2 values of 0.82 and 0.59, Mean Absolute Error (MAE) of 0.38 and 0.58, and Root Mean Square Error (RMSE) of 0.54 and 0.76 for the training and test sets, respectively. This study provides novel insights into the interactions between emerging contaminants and PPARγ, highlighting the potential hazards and risks these chemicals may pose to public health and the environment. The ability to predict PPARγ inhibition by these hazardous contaminants demonstrates the value of this approach in guiding enhanced environmental toxicology research and risk assessment.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in transcriptional regulation and play an important role in many physiological and metabolic processes. Unlike PPAR-alpha and PPAR-gamma, PPAR-delta is ubiquitously expressed, and its activity is key to maintaining proper metabolic homeostasis within the liver. PPAR-delta not only regulates physiologic processes of lipid, glucose, and bile acid metabolism but also attenuates pathologic responses to alcohol metabolism, inflammation, fibrosis, and carcinogenesis, and is considered an important therapeutic target in liver diseases. Promising results have been reported in clinical trials for PPAR-delta agonists in liver disease, and the selective agonist seladelpar was recently conditionally approved in the United States as a new treatment option for primary biliary cholangitis. This review provides an overview of PPAR-delta's function and biology in the liver, examines its kinetics and therapeutic potential across different liver diseases, and discusses the current status of clinical trials involving its agonists.

The inevitable attrition of skin due to ultraviolet radiation, termed photoaging, can be partially restored by treatment with retinoid compounds. Photoaged skin in lightly pigmented individuals, clinically presents with the appearance of wrinkles, increased laxity, and hyper- and hypopigmentation. Underlying these visible signs of ageing are histological features such as epidermal thinning, dermal-epidermal junction flattening, solar elastosis and loss of the dermal fibrillin microfibrillar network, fibrillar collagen and glycosaminoglycans. Retinoid compounds are comprised of three main generations with the first generation (all-trans retinoic acid, retinol, retinaldehyde and retinyl esters) primarily used for the clinical and cosmetic treatment of photoaging, with varying degrees of efficacy, tolerance and stability. All-trans retinoic acid is considered the 'gold standard' for skin rejuvenation; however, it is a prescription-only product largely confined to clinical use. Therefore, retinoid derivatives are readily incorporated into cosmeceutical formulations. The literature reported in this review suggests that retinol, retinyl esters and retinaldehyde that are used in many cosmeceutical products, are efficacious, safe and well-tolerated. Once in the skin, retinoids utilize a complex signalling pathway that promotes remodelling of photoaged epidermis and dermis and leads to the improvement of the cutaneous signs of photoaging.

Cinnamic acid (CA) is a bioactive compound isolated from cinnamon. It has been demonstrated to ameliorate inflammation and metabolic diseases, which are associated with endothelial dysfunction. This study was aimed to study the potential protective effects of CA against diabetes-associated endothelial dysfunction and its underlying mechanisms.

High-fat diet (HFD) with 60 kcal% fat was used to induce obesity/diabetes in C57BL/6 mice for 12 weeks. These diet-induced obese (DIO) mice were orally administered with CA at 20 or 40 mg/kg/day, pioglitazone (PIO) at 20 mg/kg/day or same volume of vehicle during the last 4 weeks. Isolated mouse aortic segments and primary culture rat aortic endothelial cells (RAECs) were induced with high glucose (HG) to mimic hyperglycemia and co-treated with different concentrations of CA.

In DIO mice, four-week administration of CA, particularly at 40 mg/kg/day, diminished the body weights, blood pressure, fasting blood glucose and plasma lipid levels, and ameliorated endothelium-dependent relaxations (EDRs) and oxidative stress in aortas. The beneficial effects of CA were comparable to the positive control group, PIO. Western blotting results indicated that CA treatment upregulated the expression of peroxisome proliferator-activated receptor delta (PPARδ), and activated nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) and AMP-activated protein kinase (AMPK)/ protein kinase B (Akt)/ endothelial nitric oxide synthase (eNOS) signaling pathways in mouse aortas in vivo and ex vivo. HG stimulation impaired EDRs in mouse aortas and inhibited nitric oxide (NO) production but elevated reactive oxygen species (ROS) levels in RAECs. CA reversed these impairments. Importantly, PPARδ antagonist GSK0660 abolished the vasoprotective effects of CA. Molecular docking analysis suggested a high likelihood of mutual binding between CA and PPARδ.

CA protects against endothelial dysfunction and oxidative stress in diabetes and obesity by targeting PPARδ through Nrf2/HO-1 and Akt/eNOS signaling pathways.

As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.

Mitochondrial biogenesis requires the expression of genes encoded by both the nuclear and mitochondrial genomes. However, aside from a handful transcription factors regulating specific subsets of mitochondrial genes, the overall architecture of the transcriptional control of mitochondrial biogenesis remains to be elucidated. The mechanisms coordinating these two genomes are largely unknown. We performed a targeted RNAi screen in developing eyes with reduced mitochondrial DNA content, anticipating a synergistic disruption of tissue development due to impaired mitochondrial biogenesis and mitochondrial DNA (mtDNA) deficiency. Among 638 transcription factors annotated in the Drosophila genome, 77 were identified as potential regulators of mitochondrial biogenesis. Utilizing published ChIP-seq data of positive hits, we constructed a regulatory network revealing the logic of the transcription regulation of mitochondrial biogenesis. Multiple transcription factors in core layers had extensive connections, collectively governing the expression of nearly all mitochondrial genes, whereas factors sitting on the top layer may respond to cellular cues to modulate mitochondrial biogenesis through the underlying network. CG1603, a core component of the network, was found to be indispensable for the expression of most nuclear mitochondrial genes, including those required for mtDNA maintenance and gene expression, thus coordinating nuclear genome and mtDNA activities in mitochondrial biogenesis. Additional genetic analyses validated YL-1, a transcription factor upstream of CG1603 in the network, as a regulator controlling CG1603 expression and mitochondrial biogenesis.

Crohn's disease (CD) is a chronic, complex inflammatory disorder of the gastrointestinal tract that presents significant therapeutic challenges. Despite the availability of a wide range of treatments, many patients experience primary non-response, secondary loss of response, or adverse events, limiting the overall effectiveness of current therapies. Clinical trials often report response rates below 60%, partly due to stringent inclusion criteria. Emerging therapies that target novel pathways offer promise in overcoming these limitations. This review explores the latest investigational drugs in phases I, II, and III clinical trials for treating both luminal and perianal CD. We highlight promising therapies that target known mechanisms, including selective Janus kinase inhibitors, anti-adhesion molecules, tumor necrosis factor inhibitors, and IL-23 selective inhibitors. In addition, we delve into novel therapeutic strategies such as sphingosine-1-phosphate receptor modulators, miR-124 upregulators, anti-fractalkine (CX3CL1), anti-TL1A, peroxisome proliferator-activated receptor gamma agonists, TGFBRI/ALK5 inhibitors, anti-CCR9 agents, and other innovative small molecules, as well as combination therapies. These emerging approaches, by addressing new pathways and mechanisms of action, have the potential to surpass the limitations of existing treatments and significantly improve CD management. However, the path to developing new therapies for inflammatory bowel disease (IBD) is fraught with challenges, including complex trial designs, ethical concerns regarding placebo use, recruitment difficulties, and escalating costs. The landscape of IBD clinical trials is shifting toward greater inclusivity, improved patient diversity, and innovative trial designs, such as adaptive and Bayesian approaches, to address these challenges. By overcoming these obstacles, the drug development pipeline can advance more effective, accessible, and timely treatments for CD.

The endothelium is a well known regulator of vascular homeostasis. Several factors can influence the balance of the bioavailability of active substances. This imbalance can lead to inflammation and, consequently, endothelial dysfunction, which is an underlying pathology in cardiovascular disease that commonly coexists with metabolic and chronic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). In MASLD, a reduction in nitric oxide availability is observed, and as a result, hepatic stellate cells and liver sinusoidal endothelial cells are activated. Considering the extensive research dedicated to finding several targets with diagnostic and therapeutic effects, nuclear hormone receptors such as peroxisome proliferator-activated receptors have been highlighted as being highly influential in the gut-liver-adipose axis and are considered potential regulators of metabolism and inflammation in several pathologies. Currently, PPAR agonists are widely explored in clinical trials and experimental studies. Agents such as lanifibranor, elafibranor, daidzein, and Icariin have shown promise in improving the metabolic, hepatic, and cardiovascular health of patients with MASLD. This review aims to provide a comprehensive overview of the role of peroxisome proliferator-activated receptors in endothelial dysfunction and MASLD, exploring their mechanisms in disease progression and potential pharmacological targeting.

As a defense mechanism against deleterious stimuli, inflammation plays a vital role in the development of many disorders, including atherosclerosis, inflammatory bowel disease, experimental autoimmune encephalomyelitis, septic and non-septic shock, and non-alcoholic fatty liver disease (NAFLD). Despite the serious adverse effects of extended usage, traditional anti-inflammatory medications, such as steroidal and non-steroidal anti-inflammatory medicines (NSAIDs), are commonly used for alleviating symptoms of inflammation. The PPARδ subtype of peroxisome proliferator-activated receptors (PPARs) has attracted interest because of its potential for reducing inflammation and related disorders. In this study, a series of 1,3,4-thiadiazole derivatives were designed, synthesized, and evaluated. Compound 11 exhibited potent PPARδ agonistic activity with EC50 values 20 nM and strong selectivity over PPARα and PPARγ. Furthermore, compound 11 demonstrated favorable in vitro and in vivo pharmacokinetic properties. In vivo experiments using labeled macrophages and paw thickness measurements confirmed compound 11's potential to reduce macrophage infiltration and alleviate inflammation. These findings highlight compound 11 as a potent and promising therapeutic candidate for the treatment of acute inflammatory diseases and warrant further investigation to explore various biological roles.

Elevated uric acid levels are associated with lipid metabolism disorders. The effects of Imperata cylindrica polysaccharide (ICPC-a) were explored using a hyperuricemia mouse model and a uric acid-induced HepG2 hepatocyte model. ICPC-a significantly improved total cholesterol, triglycerides, low-density lipoprotein levels, and hepatic lipid deposition in hyperuricemia mice. The liver/body weight ratio decreased, and markers of liver damage, inflammation, and dyslipidemia improved. Metabolomics analysis suggested that ICPC-a modulates lipid metabolism by influencing the glycerophospholipid pathway and the enzyme LPCAT3. Stable HepG2 cell lines with knocked-down LPCAT3 were constructed, and western blot and RT-PCR were used to assess the impact of its knockdown on lipid metabolism under uric acid stimulation. In cells with reduced LPCAT3 expression, ICPC-a was still able to alleviate uric acid-induced lipid accumulation, though the effect was less pronounced compared to cells with normal LPCAT3 levels. However, the effectiveness was diminished compared to cells where LPCAT3 was not knocked down. These findings indicated that LPCAT3 was an important target through which ICPC-a regulated lipid metabolism disorders induced by hyperuricemia. These discoveries emphasized that ICPC-a, as a prebiotic, could modulate hepatic lipid accumulation and inflammation, contributing to the maintenance of hepatic lipid homeostasis.

Our objective was to explore the pharmacogenetic impact of three known functional variants in drug target genes and determine whether they can explain the inter-individual variation in therapeutic response.

In a post hoc analysis of data from randomized controlled clinical trials of chiglitazar, we genotyped 481 Chinese patients with T2DM and investigated the association of variants in PPAR genes with the therapeutic outcome separated by dose using linear regression.

rs1800234, a gain-of-function variant of PPARA, had a dose-dependent pharmacogenetic impact on the therapeutic response to chiglitazar. The C allele was significantly associated with reduced therapeutic response in the 48 mg group, while no significant association was observed in the 32 mg group. In addition, in patients without the C allele, patients treated with 48 mg chiglitazar had a better therapeutic response than those treated with 32 mg chiglitazar. To the contrary, in patients with the C allele, patients treated with 48 mg chiglitazar had a worse therapeutic response than those treated with 32 mg of chiglitazar.

The PPARA variant rs1800234 had a dose-dependent pharmacogenetic impact on the therapeutic response to chiglitazar. It could help explain the absence of a dose effect of chiglitazar and serve as a potential biomarker for the chosen dose of chiglitazar in the future. In addition, our study provided important reference for the design and clinical application of multi-target drugs.

The TiaoPi AnChang Decoction (TPACD), a Traditional Chinese Medicine (TCM) prescription based on Xiangsha Liujunzi Decoction, has demonstrated clinical efficacy as an adjuvant therapy for colorectal cancer (CRC) patients. However, its specific ingredients and potential mechanisms of action remain unclear.

To identify the primary active ingredients of TPACD, their molecular targets, and potential mechanisms underlying the efficacy of TPACD in CRC treatment.

This study investigated the clinically validated TCM formula TPACD. In vitro and in vivo experiments were used to demonstrate TPACD's regulatory effects on various malignant phenotypes of tumors, providing basic research support for its anti-cancer activity. To understand its pharmacodynamic basis, we utilized ultra-high performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry/mass spectrometry (UHPLC-Q-TOF-MS/MS) to analyze TPACD constituents present in the bloodstream. Network pharmacology and bioinformatics analyses were used to identify potential active components and their molecular targets for TPACD's therapeutic effects in CRC. Subsequent experiments further elucidated its pharmacological mechanism.

TPACD inhibits various malignant cellular processes, such as cell proliferation, apoptosis, migration, and invasion, and has shown potential anti-CRC activities both in vitro and in vivo. Following the identification of 109 constituents absorbed into the blood from TPACD, network pharmacology analysis predicted 42 potential anti-CRC targets. Clinical analyses highlighted three genes as prognostic key genes of TPACD's therapeutic action: C-X-C motif chemokine ligand 8 (CXCL8), fatty acid binding protein 4 (FABP4), and matrix metallopeptidase 3 (MMP3). Drug sensitivity analyses, molecular docking simulations and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) identified MMP3 as the most promising target for TPACD's anti-CRC action. Enzyme activity assays confirmed that TPACD inhibits MMP3 enzyme activity. Surface plasmon resonance (SPR) characterized the binding affinity between MMP3 and effective active components of TPACD, including luteolin, quercetin, kaempferol, and liensinine.

TPACD exhibits anti-CRC activity in vitro and in vivo, with MMP3 identified as a critical target. The active compounds, including luteolin, quercetin, kaempferol, and liensinine, absorbed into the bloodstream, contribute to TPACD's efficacy by targeting MMP3.

Chronic kidney disease (CKD) is a major risk factor for death in adults. Inflammation plays a role in the pathogenesis of CKD, but the mechanisms are poorly understood. Peroxisome proliferator-activated receptor alpha (PPAR-α) is a nuclear receptor and one of the three members (PPARα, PPARβ/δ, and PPARγ) of the PPARs that plays an important role in ameliorating pathological processes that accelerate acute and chronic kidney disease. Although other PPARs members are well studied, the role of PPAR-α is not well described and its role in inflammation-mediated chronic disease is not clear. Herein, we review the role of PPAR-α in chronic kidney disease with implications for the immune system.

Methotrexate (MTX) is a folic acid reductase inhibitor that manages various malignancies as well as immune-mediated inflammatory chronic diseases. Despite being frequently prescribed, MTX's severe multiple toxicities can occasionally limit its therapeutic potential. Intestinal toxicity is a severe adverse effect associated with the administration of MTX, and patients are significantly burdened by MTX-provoked intestinal mucositis. However, the mechanism of such intestinal toxicity is not entirely understood, mechanistic studies demonstrated oxidative stress and inflammatory reactions as key factors that lead to the development of MTX-induced intestinal injury. Besides, MTX causes intestinal cells to express pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which activate nuclear factor-kappa B (NF-κB). This is followed by the activation of the Janus kinase/signal transducer and activator of the transcription3 (JAK/STAT3) signaling pathway. Moreover, because of its dual anti-inflammatory and antioxidative properties, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) has been considered a critical signaling pathway that counteracts oxidative stress in MTX-induced intestinal injury. Several agents have potential protective effects in counteracting MTX-provoked intestinal injury such as omega-3 polyunsaturated fatty acids, taurine, umbelliferone, vinpocetine, perindopril, rutin, hesperidin, lycopene, quercetin, apocynin, lactobacillus, berberine, zinc, and nifuroxazide. This review aims to summarize the potential redox molecular mechanisms of MTX-induced intestinal injury and how they can be alleviated. In conclusion, studying these molecular pathways might open the way for early alleviation of the intestinal damage and the development of various agent plans to attenuate MTX-mediated intestinal injury.

Autophagy is a molecular process essential for maintaining cellular homeostasis, with its impairment or dysregulation linked to the progression of various diseases in mammals. Specific lipids, including phosphoinositides, sphingolipids, and oxysterols, play pivotal roles in inducing and regulating autophagy, highlighting their significance in this intricate process. This review focuses on the critical involvement of these lipids in autophagy and lipophagy, providing a comprehensive overview of the current understanding of their functions. Moreover, we delve into how abnormalities in autophagy, influenced by these lipids, contribute to the pathogenesis of various diseases. These include age-related conditions such as cardiovascular diseases, neurodegenerative disorders, type 2 diabetes, and certain cancers, as well as inflammatory and liver diseases, skeletal muscle pathologies and age-related macular degeneration (AMD). This review aims to highlight function of lipids and their potential as therapeutic targets in treating diverse human pathologies by elucidating the specific roles of phosphoinositides, sphingolipids, and oxysterols in autophagy.

Meibomian gland dysfunction (MGD), complicated by type 2 diabetes, is associated with a high incidence of ocular surface disease, and no effective drug treatment exists. Diabetes mellitus (DM) MGD shows a notable disturbance in lipid metabolism. Er-Dong-Xiao-Ke decoction (EDXKD) has important functions in nourishing yin, clearing heat, and removing blood stasis, which are effective in the treatment of DM MGD.

To observe the therapeutic effect of EDXKD on DM MGD and its underlying molecular mechanism.

After establishing a type 2 DM (T2DM)-induced MGD rat model, different doses of EDXKD and T0070907 were administered. The chemical constituents of EDXKD were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the molecular mechanism of EDXKD in treating DM MGD was predicted using network pharmacology. Lipid metabolism in DM meibomian glands (MGs) was analyzed using LC-MS/MS, and lipid biomarkers were screened and identified. Histological changes and lipid accumulation in MGs were detected by staining, and Peroxisome proliferator-activated receptor gamma (PPARG) expression in MG acinar cells was detected by immunofluorescence. The expression of lipid metabolism-related factors was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or western blotting.

EDXKD reduced lipid accumulation in the MGs and improved the ocular surface index in DM MGD rats. The main active components of EDXKD had advantages in lipid regulation. Additionally, the PPARG signaling pathway was the key pathway of EDXKD in the treatment of DM MGD. Twelve lipid metabolites were biomarkers of EDXKD in the treatment of DM MGD, and glycerophospholipid metabolism was the main pathway of lipid regulation. Moreover, EDXKD improved lipid deposition in the acini and upregulated the expression of PPARG. Further, EDXKD regulated the PPARG-mediated UCP2/AMPK signaling network, inhibited lipid production, and promoted lipid transport.

EDXKD is an effective treatment for MGD in patients with T2DM. EDXKD can regulate lipids by regulating the PPARG-mediated UCP2/AMPK signaling network, as it reduced lipid accumulation in the MGs of DM MGD rats, promoted lipid metabolism, and improved MG function and ocular surface indices.

Pressure ulcer is common in the bedridden elderly with high mortality and lack of effective treatment. In this study, human-adipose-derived-stem-cells-hyaluronic acid gel (hADSCs-HA gel) was developed and applied topically to treat pressure ulcers, of which efficacy and paracrine mechanisms were investigated through in vivo and in vitro experiments.

Pressure ulcers were established on the backs of C57BL/6 mice and treated topically with hADSCs-HA gel, hADSCs, hyaluronic acid, and normal saline respectively. The rate of wound closure was observed continuously during the following 14 days and the wound samples were obtained for Western blot, histopathology, immunohistochemistry, and proteomic analysis. Human dermal fibroblasts (HDFs) and human venous endothelial cells (HUVECs) under normal or hypoxic conditions were treated with conditioned medium of human ADSCs (ADSC-CM), then CCK-8, scratch test, tube formation, and Western blot were conducted to evaluate the paracrine effects of hADSCs and to explore the underlying mechanism.

The in vivo data demonstrated that hADSCs-HA gel significantly accelerated the healing of pressure ulcers by enhancing collagen expression, angiogenesis, and skin proliferation. The in vitro data revealed that hADSCs strengthened the proliferation and wound healing capabilities of HDFs and HUVECs, meanwhile promoted collagen secretion and tube formation through paracrine mode. ADSC-CM was also proved to exert protective effects on hypoxic HDFs and HUVECs. Besides, the results of proteomic analysis and Western blot elucidated that lipid metabolism and PPARβ/δ pathway mediated the healing effect of hADSCs-HA gel on pressure ulcers.

Our research showed that topical application of hADSCs-HA gel played an important role in dermal regeneration and angiogenesis. Therefore, hADSCs-HA gel exhibited the potential as a novel stem-cell-based therapeutic strategy of treating pressure ulcers in clinical practices.

This study demonstrated the correlation of molecular structures of Peroxisome proliferator-activated receptor gamma (PPARγ) modulators and their biological activities. Bayesian classification, and recursive partitioning (RP) studies have been applied to a dataset of 323 PPARγ modulators with diverse scaffolds. The results provide a deep insight into the important sub-structural features modulating PPARγ. The molecular docking analysis again confirmed the significance of the identified sub-structural features in the modulation of PPARγ activity. Molecular dynamics simulations further underscored the stability of the complexes formed by investigated modulators with PPARγ. Overall, the integration of many computational approaches unveiled key structural motifs essential for PPARγ modulatory activity that will shed light on the development of effective modulators in the future.

Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.

Mitochondrial biogenesis requires the expression of genes encoded by both the nuclear and mitochondrial genomes. However, aside from a handful transcriptional factors regulating specific subsets of mitochondrial genes, the overall architecture of the transcriptional control of mitochondrial biogenesis remains to be elucidated. The mechanisms coordinating these two genomes are largely unknown. We performed a targeted RNAi screen in developing eyes with reduced mitochondrial DNA content, anticipating a synergistic disruption of tissue development due to impaired mitochondrial biogenesis and mtDNA deficiency. Among 638 transcription factors annotated in Drosophila genome, 77 were identified as potential regulators of mitochondrial biogenesis. Utilizing published ChIP-seq data of positive hits, we constructed a regulatory network revealing the logic of the transcription regulation of mitochondrial biogenesis. Multiple transcription factors in core layers had extensive connections, collectively governing the expression of nearly all mitochondrial genes, whereas factors sitting on the top layer may respond to cellular cues to modulate mitochondrial biogenesis through the underlying network. CG1603, a core component of the network, was found to be indispensable for the expression of most nuclear mitochondrial genes, including those required for mtDNA maintenance and gene expression, thus coordinating nuclear genome and mtDNA activities in mitochondrial biogenies. Additional genetics analyses validated YL-1, a transcription factor upstream of CG1603 in the network, as a regulator controlling CG1603 expression and mitochondrial biogenesis.

Metabolic syndrome (MetS) is an ever-evolving set of diseases that poses a serious health risk in many countries worldwide. Existing evidence illustrates that individuals with MetS have a 30%-40% higher chance of acquiring type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), or both. This study was undertaken to uncover the regulatory role of natural organosulfur compounds (OSCs), S-allyl-L-cysteine (SAC), and S-ethyl-L-cysteine (SEC), in targeting high carbohydrate high fat (HCHF)-diet-induced MetS-associated risk management. Our findings suggested that SAC and SEC ameliorated HCHF-diet-induced diabetic profiles, plasma lipid and lipoprotein level, liver function, oxidative-stress, inflammatory cytokines, and chemokines including monocyte chemoattractant protein-1 (MCP-1), lipid peroxidation, plasma proprotein convertase subtilisin/kexin type-9 (PCSK-9), and high-sensitivity C-reactive protein (hs-CRP). Moreover, the assessment of the hepatic mRNA expression of the key genes involved in cholesterol homeostasis depicted that SAC and SEC downregulated the PCSK-9 mRNA expression via targeting the expression of HNF-1α, a transcriptional activator of PCSK-9. On the other hand, the LDL-receptor (LDL-R) expression was upregulated through the activation of its transcriptional regulator sterol regulatory element binding protein-2 (SREBP-2). In addition, the activity and the mRNA expression of 3-hydroxy-3-methylglutaryl coenzyme-A reductases (HMG-R) and peroxisome proliferator-activated receptors (PPARs) were also improved by the treatment of SAC and SEC. We concluded that SAC and SEC can protect against MetS via improving the lipid and lipoprotein content, glycemic indices, hepatic function, targeting the inflammatory cascades, and oxidative imbalance, regulation of the mRNA expression of PCSK-9, LDL-R, SREBP-2, HNF-1α, PPARs, and inflammatory biomarkers.

Pathogenic ACAD9 variants cause complex I deficiency. Patients presenting in infancy unresponsive to riboflavin have high mortality. A six-month-old infant presented with riboflavin unresponsive lactic acidosis and life-threatening cardiomyopathy. Treatment with high dose bezafibrate and nicotinamide riboside resulted in marked clinical improvement including reduced lactate and NT-pro-brain type natriuretic peptide levels, with stabilized echocardiographic measures. After a long stable period, the child succumbed from cardiac failure with infection at 10.5 months. Therapy was well tolerated. Peak bezafibrate levels exceeded its EC50. The clinical improvement with this treatment illustrates its potential, but weak PPAR agonist activity of bezafibrate limited its efficacy.

Alzheimer's disease (AD) is a leading cause of cognitive impairment worldwide. Overweight and obesity are strongly associated with comorbidities, such as hypertension, diabetes, and insulin resistance (IR), which contribute substantially to the development of AD and subsequent morbidity and mortality. Adipose tissue (AT) is a highly dynamic organ composed of a diverse array of cell types, which can be classified based on their anatomic localization or cellular composition. The expansion and remodeling of AT in the context of obesity involves immunometabolic and functional shifts steered by the intertwined actions of multiple immune cells and cytokine signaling within AT, which contribute to the development of metabolic disorders, IR, and systemic markers of chronic low-grade inflammation. Chronic low-grade inflammation, a prolonged, low-dose stimulation by specific immunogens that can progress from localized sites and affect multiple organs throughout the body, leads to neurodystrophy, increased apoptosis, and disruption of homeostasis, manifesting as brain atrophy and AD-related pathology. In this review, we sought to elucidate the mechanisms by which AT contributes to the onset and progression of AD in obesity through the mediation of chronic low-grade inflammation, particularly focusing on the roles of adipokines and AT-resident immune cells.

Uterine fibroids, the most common nonmalignant tumors affecting the female genital tract, are a significant medical challenge. This article focuses on the most recent studies that attempted to identify novel non-hormonal therapeutic targets and strategies in UF therapy.

This review covers the analysis of the pharmacological and biological mechanisms of the action of natural substances and the role of the microbiome in reference to UFs. This study aimed to determine the potential role of these compounds in UF prevention and therapy.

While there are numerous approaches for treating UFs, available drug therapies for disease control have not been optimized yet. This review highlights the biological potential of vitamin D, EGCG and other natural compounds, as well as the microbiome, as promising alternatives in UF management and prevention. Although these substances have been quite well analyzed in this area, we still recommend conducting further studies, particularly randomized ones, in the field of therapy with these compounds or probiotics. Alternatively, as the quality of data continues to improve, we propose the consideration of their integration into clinical practice, in alignment with the patient's preferences and consent.

Seladelpar (MBX-8025) is a once-daily administered highly specific PPAR-δ agonist in Phase 3 and extension trials for use in patients with primary biliary cholangitis (PBC).

This review provides background on current treatment options for PBC, and summarizes clinical trial data regarding the safety and effectiveness of seladelpar within the context of these treatments.

Clinical trials results demonstrate the safety and tolerability of seladelpar use for PBC, including in patients with cirrhosis. The primary composite endpoint (ALP <1.67 times ULN, decrease ≥ 15% from baseline, and TB ≤ULN) was met in 61.7% of the patients treated with seladelpar and in 20% receiving placebo (p < 0.001). Moreover, pruritus - a cardinal and often intractable symptom of PBC - was improved with seladelpar treatment, as were overall quality of life measurements. Improvements in markers of inflammation were likewise observed. These biochemical and clinical findings therefore represent landmark developments in PBC treatment and offer a therapeutic option for PBC.