IKK x NF-κB x NOX4

Curcuminoids are the active compounds richest in turmeric rhizomes (Curcuma longa L.), comprising curcumin I, demethoxycurcumin (curcumin II), and bisdemethoxycurcumin (curcumin III). This study hypothesized that particular curcumin derivatives could mitigate oxidative stress and inflammation response by targeting specific inflammatory mediators. Therefore, this study aimed to quantify the concentrations of these curcuminoid forms in local turmeric extracts from Thailand. Subsequently, the study analyzed their in vitro antioxidant properties, alongside molecular docking and dynamics simulations targeting key oxidative stress- and inflammation-related proteins. Samples were collected from three representative cultivated areas in Thailand: the eastern, southern, and northern regions. The ethanolic extracts from all samples exhibited relatively high total curcuminoid content (eastern: 15.1 %, southern: 25.9 %, and northern: 31.6 % w/w in extract), as determined by high-performance liquid chromatography. Curcumin I emerged as the predominant variant, followed closely by curcumin II and III. The ethanolic extracts from the three cultural areas demonstrated significant antioxidant activity, as assessed by ORAC, FRAP, and DPPH assays. Among the three curcuminoids, curcumin III exhibited the strongest predicted binding affinities in molecular docking studies toward antioxidant and anti-inflammatory targets, including 5-LOX, NRF2, IKK1, NF-κB, and NOX4. Molecular dynamics simulations corroborated these findings, revealing that curcumin III formed the most stable complexes, particularly with IKK1, as indicated by low RMSD values (2-3 Å), and high hydrogen bond occupancy. Thus, curcumin III exhibits potential in silico inhibition of inflammatory mediators, supporting its promise as a natural compound for antioxidant and anti-inflammatory nutraceutical development.

C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the accumulation of toxic dipeptide repeat proteins (DPRs) generated from G₄C₂ hexanucleotide repeat expansions. Among these, the arginine-rich poly-PR (proline-arginine) species is the most neurotoxic, eliciting glial activation and neuroinflammation via non-cell-autonomous mechanisms. Although growing evidence implicates glial cells, particularly astrocytes, in disease progression, the molecular pathways linking neuron-derived poly-PR to astrocyte-mediated oxidative stress remain poorly understood. We demonstrate that exogenous poly-PR induces robust NOX4 expression and hydrogen peroxide (H₂O₂) production in astrocytes through activation of the IKK/IκB/NF-κB p65 signaling pathway. Mechanistically, poly-PR promotes nuclear translocation of p65 and enhances its binding to the NOX4 promoter, thereby amplifying astrocytic oxidative stress. Overexpression of the Sigma-1 receptor (Sigma-1R), an endoplasmic reticulum-resident chaperone, significantly attenuates poly-PR-induced NOX4 transcription and reactive oxygen species (ROS) production by interacting with p65 and blocking its nuclear translocation, independently of upstream p65 phosphorylation. Notably, clemastine, a clinically approved Sigma-1R agonist, suppresses astrocytic NOX4 expression by disrupting p65 binding to the NOX4 promoter. In a mouse model of C9orf72 ALS, Sigma-1R deficiency exacerbates poly-PR-induced neurodegeneration, astrogliosis, and NOX4 upregulation, whereas Sigma-1R sufficiency confers neuroprotection and anti-inflammatory effects. This study identifies Sigma-1R as a critical modulator of non-cell-autonomous poly-PR toxicity and establishes its activation as a potent suppressor of astrocyte-derived oxidative stress. Our findings uncover a previously unrecognized glial mechanism driving C9orf72 ALS pathogenesis and support Sigma-1R activation, via clemastine, as a promising therapeutic strategy to mitigate neuroinflammation and disease progression.

Pyroptosis is a recently identified form of programmed cell death that plays a crucial role in the pathogenesis and progression of diabetes and associated chronic complications, while the occurrence mechanism remains unclear. Ginseng (Panax Ginseng C. A. Mey.) is a valuable traditional medicinal material with proved therapeutic effects on prevention and treatment of diabetes and diabetic complications. Targeting pyroptosis pathway has become a focus of study for ginseng in improvement of diabetes and related chronic complications.

The review aims to elucidate the happening mechanism of pyroptosis in diabetes and diabetic chronic complications, evaluate the effects of ginseng and its active components on diabetes and its chronic complications via pyroptosis-related pathways, and provide a new perspective for the management of diabetes.

We conducted the literature retrieval with PubMed, Web of Science, and ScienceDirect databases in a systematic manner (up to August 2024). The keywords included pyroptosis, diabetes, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, diabetic neuropathy, ginseng, ginseng extract, and ginsenoside. The obtained literatures were comprehensively sorted out.

Oxidative stress, endoplasmic reticulum stress (ERS), and inflammatory responses were primary contributors to pyroptosis in diabetes and associated chronic complications. In addition, some RNA molecules (miRNAs, circRNAs, and lncRNAs) also contributed to pyroptosis under hyperglycemia. The signaling pathways mainly included Nrf2/HO-1, IκB/NF-κB/NLRP3, NOX1/NOX4/TXNIP, and P2X7R/TXNIP/NLRP3. Ginseng extracts, some ginsenosides and flavonoid (Quercetin) could exert anti-diabetic effect by regulating pyroptosis-related pathways. We also discussed the toxicity, side effects and clinical applications of ginseng.

In summary, this review elucidates the happening mechanisms of pyroptosis in diabetes and associated chronic complications, and summarizes published studies about ginseng and its active ingredients in improving diabetes by regulating pyroptosis-related pathways. However, almost all researches are limited to animal and cell experiments, and more clinical trials are required to prove the therapeutic effect of ginseng on diabetes by targeting pyroptosis.