Latest ArticlesMetabolic cardiovascular diseases are a category of cardiovascular conditions driven by metabolic risk factors, such as obesity, hypertension, metabolic-associated fatty liver disease (MAFLD), and diabetes, in which metabolism disturbance and inflammatory responses are key contributors. Peroxisome proliferator-activated receptor α (PPARα), a member of the nuclear receptor superfamily, plays a critical role in the maintenance of metabolic homeostasis. Recent studies have indicated that PPARα exerts beneficial effects on metabolic cardiovascular diseases via regulating lipid metabolism, inflammatory responses, and mitigating oxidative stress. This review summarized the molecular structure and biological functions of PPARα, with a focus on the underlying mechanisms in PPARα regulating metabolic cardiovascular diseases and translational significance of PPARα agonists in preclinical-clinical studies, aiming to establish novel therapeutic paradigms for these disorders.
The pregnane X receptor (PXR) is a crucial member of the nuclear receptor superfamily and plays a pivotal role in regulating various biological processes. In recent years, significant progress has been made in the development of PXR antagonists and PXR-targeting proteolysis-targeting chimera (PROTAC). This review systematically summarizes recent advances in the study of PXR antagonists and PXR PROTAC drugs, with the aim of providing valuable insights and references for novel drug development and the exploration of new therapeutic targets in related fields.
With the advancement of industrialization in modern society, exposure to endocrine disrupting chemicals (EDCs) in daily environments is increasingly prevalent. These substances can interfere with physiological functions by activating nuclear receptors. The constitutive androstane receptor (CAR), a crucial member of the nuclear receptor family, serves as a key regulator in detoxifying endogenous substances and sensing exogenous EDCs, participating in the regulation of drug-metabolizing enzyme expression and energy metabolism. This study employed TCPOBOP (TC), a highly specific and potent agonist of CAR, to investigate the impact of exogenous EDC-activated nuclear receptors on mammary gland development and estrogen homeostasis in pubertal female mice. Using 3-week-old female mice as models, TC was administered via intraperitoneal injection at 0.5 mg·kg-1 twice weekly. Mammary gland developmental morphology was observed, and serum estrogen levels were measured (all animal experiments conducted in this study were approved by the Institutional Animal Care and Use Committee of the Animal Experiment Center of Wuhan University, ethics number: WAEF-2023-0077). Results demonstrated that TC exposure significantly inhibited the developmental progression of the mammary ductal system through CAR activation. The underlying mechanism involved downregulating the expression of key estrogen-synthesizing enzymes while promoting estrogen metabolic conversion and inactivation, ultimately leading to reduced systemic estrogen levels. This study reveals the mechanism by which TC-activated nuclear receptor CAR suppresses mammary gland development and disrupts estrogen homeostasis in pubertal female mice. It provides insights for understanding how EDCs affect mammary development and endocrine balance in adolescent females via nuclear receptor pathways, and offers new research clues for exploring CAR's role in mammary development regulation.
Ritonavir (RTV) is widely used as an antiviral drug in clinical practice, but the mechanism underlying its hepatotoxicity remains incompletely understood. This study aimed to investigate the molecular mechanism by which pregnane X receptor (PXR) activation exacerbates RTV-induced hepatotoxicity. This study was approved by the Life Science Ethics Review Committee of Zhengzhou University (approval No.: ZZUIRB2022-142). Pxr gene knockout mice were constructed and treated with a PXR agonist and RTV, followed by evaluation of liver function indicators, hepatic pathological changes, expression of the metabolic enzyme, endoplasmic reticulum (ER) stress- and apoptosis-related genes, as well as the major active metabolites of RTV. Cellular experiments were further conducted for validation. The results demonstrated that PXR activation aggravated RTV-induced liver injury in mice, accompanied by upregulation of the relevant metabolic enzyme, accumulation of active RTV metabolites in the liver, elevated ER stress markers, and increased levels of molecules associated with cell death and tissue damage. In HepG2 cells, knockdown/overexpression of PXR respectively inhibited or enhanced rifampicin (RIF, a human PXR agonist)-induced expression of cytochrome P450 (CYP) 3A4. PXR overexpression combined with RIF increased the hepatotoxicity caused by RTV, which was reversed after CYP3A4 knockdown. Mechanistically, PXR activation accelerates the metabolism of RTV into toxic metabolites via upregulating CYP3A4, and these metabolites trigger ER stress, thereby promoting hepatotoxicity. This study reveals the central role of the PXR-CYP3A4 axis in RTV-induced hepatotoxicity by triggering ER stress, providing a novel strategy for mitigating drug-induced liver injury through targeted modulation of PXR.
This study focused on the medium- and long-chain acylcarnitines (MCACs/LCACs) metabolic axis regulated by peroxisome proliferator-activated receptor alpha (PPARα), aiming to elucidate its potential role in the hepatoprotective effects of herbal medicines. Initially, literature mining and database analysis were conducted to summarize the current research applications of PPARα agonists in liver diseases and the pathological implications of MCACs/LCACs accumulation across different liver disease models. Furthermore, published studies and animal experiments were integrated to validate the potential mechanism by which herbal medicines and herbal ingredients modulate liver disease via the PPARα-MCACs/LCACs pathway. Experimental results showed that co-administration of triptolide and celastrol (TP_Cel) significantly induced liver injury, accompanied by marked accumulation of MCACs/LCACs. In the TP_Cel model, Spearman analysis revealed moderately to strongly inverse correlations between plasma MCACs/LCACs abundances and the expression of hepatic PPARα-target genes, including Cpt1a, Cpt2, and Acox1, with most correlations reaching statistical significance (P < 0.05). In addition, plasma MCACs/LCACs abundances were significantly elevated in Ppara-/- mice compared with wild-type 129 mice (P < 0.05). Based on these findings, a multi-stage screening strategy was established, resulting in the identification of 68 hepatoprotective herbal medicines (HpHMs) and 29 hepatoprotective herbal ingredients (HpHIs), both targeting PPARα with no documented hepatotoxicity. Finally, molecular docking was employed to preliminarily evaluate the binding capacity of HpHIs to PPARα. These findings provide mechanistic insights and potential resources for the development of herbal medicines and herbal ingredients targeting lipid metabolism disorders in liver diseases. All animal experiments were approved by the Animal Ethics Committee of West China Hospital, Sichuan University (approval No. 20220217001).
Rheumatoid arthritis (RA), a chronic autoimmune disease, has a complex interaction with glucose and lipid metabolism in pathological process. Glucose metabolism reprogramming disrupts the metabolic homeostasis of the microenvironment and activates aerobic glycolysis to drive synovial proliferation and inflammation; lipid metabolism dysfunction reshapes the inflammatory regulatory network through lipid-derived mediators. The interplay between glucose and lipid metabolism jointly drives the "metabolism-inflammation" vicious cycle, in which the metabolic hub role of acetyl coenzyme A, the bidirectional regulatory role of lactate, the synergistic regulation of metabolic signals, and the organelle interaction between mitochondria and lipid droplets collectively exacerbate the pathological progression of RA. This review systematically focuses on the abnormal characteristics and interaction mechanisms of the two core pathways of glucose and lipid metabolism in RA, proposes intervention strategies and research directions targeting metabolic homeostasis based on metabolic targets, and provides important scientific references for the in-depth analysis of the pathological mechanism of RA and the development of targeted metabolic intervention therapies.
Depression, a highly disabling psychiatric disorder, involves core disruptions in the epigenetic regulation (DNA methylation, histone modifications, non-coding RNA) of circadian clock genes (e.g., circadian locomotor output cycles kaput, brain and muscle ARNT-like protein 1, period, and cryptochrome). This dysregulation causes abnormal gene expression rhythms, leading to neurotransmitter imbalance, hypothalamic-pituitary-adrenal axis overactivation, and exacerbated neuroinflammation. We propose an "epigenetic-clock-neural circuit" interaction model, wherein suprachiasmatic nucleus master clock dysfunction disrupts synchronization of the hypothalamic-hippocampal-prefrontal circuit, constituting the core mechanism of emotional-cognitive comorbidity. Depression exhibits distinct circadian epigenetic signatures compared to epilepsy or dementia, revealing disease-specific mechanisms. Animal and clinical evidence converge on the pivotal role of circadian epigenetics. Diverse therapeutic strategies target this mechanism, including antidepressants, small-molecule inhibitors, behavioral interventions, gene editing/RNA therapies, and biomarker-guided personalized medicine. Treatment is evolving from generalized to personalized approaches, requiring novel targets and technologies. Despite challenges, this groundbreaking research opens new diagnostic and therapeutic avenues, advancing psychiatry into an era of "circadian medicine".
Due to the unique outer membrane barrier and their complex and diverse multidrug resistance mechanisms, the clinical resistance of Gram-negative bacteria is extremely severe, while the development of related new drugs has progressed slowly. This article systematically reviews representative anti-Gram-negative bacterial drugs that have been marketed in the past decade and those currently in clinical or preclinical research stages. It focuses on introducing drugs with novel targets/mechanisms of action and categorizes them based on intervention strategies targeting key stages of the Gram-negative bacterial life cycle, including: topoisomerase inhibition, protein synthesis disruption, protein transport obstruction, cell wall synthesis inhibition and damage, and bacterial cell division disruption. The content provides a comprehensive review of the structural information, mechanisms of action, antibacterial spectrum, clinical applications, as well as the applicational prospects and challenges of various classes of drugs.
Covalent inhibitors can realize specific binding by forming covalent bonds with the target, which can realize long-lasting inhibition of the target while reducing the dosage, and to a certain extent, they have overcome the traditional targets that are difficult to become drugs, and they have shown unique advantages in drug discovery and development. The binding characteristics of covalent inhibitors to plasma proteins are closely related to the efficacy, in vivo metabolism, and toxic side effects of these drugs, but the current research in this field is still limited, and there is a lack of systematic studies on the binding of covalent inhibitors of different warheads to high abundance proteins in human blood. Meanwhile, mass spectrometry has become an important tool to characterize the binding of covalent inhibitors to plasma proteins, and mass spectrometry-based proteomics can be used to comprehensively investigate the binding rate, binding reversibility, binding influencing factors, binding protein species, and binding sites of covalent inhibitors to plasma proteins. In this paper, the warheads of covalent inhibitors, the binding characteristics of covalent inhibitors to blood proteins and the research progress of mass spectrometry in the binding of covalent inhibitors to plasma proteins in recent years are reviewed to provide a reference for the study of binding of this class of drugs to plasma proteins.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent episodes and unbearable itching, imposing a heavy physical and psychological burden on patients. The pathogenesis of AD is complex, involving multiple factors such as environmental triggers, immune dysregulation, skin olfactory receptors, impaired epidermal barrier, and skin-gut microbiome imbalance. First-line clinical chemical drugs, such as glucocorticoids, can alleviate inflammation and itching to some extent, but relapse after discontinuation and drug resistance remain significant challenges, and effective treatments are still lacking. In recent years, research on essential oils extracted from natural plants for AD treatment has increased, demonstrating notable efficacy, high safety, and no drug resistance. This article explores the pathogenesis of AD, summarizes the therapeutic effects and mechanisms of plant essential oils in AD treatment, and discusses how drug delivery systems can improve the physical properties of essential oils, aiming to provide insights for developing novel AD therapies.
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