Evodiae fructus (EF) has been used in China for thousands of years as an analgesic, antiemetic, anti-inflammatory and antidiarrheal drug. EF is a toxic drug and causes hepatotoxicity in humans. Although recent chronic toxicity studies performed on aqueous extract of EF has revealed that it can produce obvious cumulative hepatotoxicity, the mechanism behind this toxicity is still uncertain. In the present study, we investigated the influence of EF on oxidative stress, mitochondrial permeability transition, adenosine triphosphate (ATP), and cytochrome C release of hepatic mitochondria. Rats were divided into four groups and fed distilled water, 6, 12, 24 g/kg of aqueous extract of EF daily for 15 days. Evodiamine, rutaecarpine and evodine were quantified in the aqueous extract by high performance liquid chromatography with ultraviolet detection (HPLC/UV). The results showed that aqueous extract of EF could significantly (p < 0.05) decrease MnSOD levels to 56.50%, 46.77% and 19.67% of control group, GSH level was decreased to 74.24%, 53.97% and 47.91% of control group and MDA level was increased to 131.55%, 134.34% and 150.81% of control group in the 6, 12 and 24 g/kg groups, respectively; extract also induced mitochondria swelling, vacuolation, MPT pore opening and a significant decrease (p < 0.05) in mitochondrial potential, while ATP levels were significant decreased (p < 0.05) to 65.24%, 38.08% and 34.59% of control group in the 6, 12 and 24 g/kg groups, respectively, resulting in ATP depletion and CytC release, finally trigger cell death signaling, which are the partial hepatotoxicity mechanisms of EF.

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer’s disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment.

Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer’s disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Atractylodes macrocephala Koidz., exhibits multimodal bioactivities with demonstrated anti-inflammatory and neuroprotective properties. To explore its therapeutic potential against AD pathology, we use high-fat diet (HFD)-fed ApoE knockout (ApoE^−/−) mice treated with or without AI for 12 weeks. Integrated bioinformatics analyses and experimental validation reveal that AI treatment markedly attenuates systemic lipid dyshomeostasis, particularly cerebral lipid deposition, suppresses neuroinflammation via downregulation of M1 macrophage polarization markers, and restores cognitive function through neuronal preservation in hippocampal regions. Mechanistically, AI orchestrates cholesterol efflux by upregulating ATP-binding cassette transporter A1 (ABCA1) and liver X receptor (LXR) expression, while concurrently modulating the abundance of arginine biosynthesis metabolites (urea, malic acid, creatinine) to rebalance neurovascular homeostasis. Notably, Western blot and RT-qPCR analyses reveal that AI differentially regulates key enzymes including arginase 1 (ARG1) and simultaneously upregulates the expression of neuronal nitric oxide synthase (nNOS). Further molecular docking and surface plasmon resonance (SPR) analyses confirm the direct binding of AI to ARG1, indicating a novel neuroprotective mechanism involving the modulation of arginine metabolism. These findings delineate the pleiotropic effects of AI against AD pathology and establish a preclinical foundation for the development of AI-based therapeutics targeting neurodegenerative-cardiovascular comorbidities.