According to the data showed by the International Diabetes Federation (Tang et al., 2023): in 2021, there were 537 million people (aged 20–79 years) with diabetes in the world, and the number is expected to reach 643 million and 783 million by 2030 and 2045, respectively. Among of which, more than 90% of diabetic patients are diagnosed with type 2 diabetes mellitus (T2DM). A growing body of evidence show the linking of T2DM to cognitive impairment, which is usually the prodromal stage of dementia (Biessels et al., 2014; Dove et al., 2021; McMillan et al., 2018; van Sloten et al., 2020). Type 2 diabetes associated cognitive dysfunction (DACD), characterized by dysfunction of learning and memory ability, attention, information processing speed, and executive function, may exacerbate to irreversible dementia. Fortunately, early intervention can effectively prevent its progression, such as Traditional Chinese Medicine prescriptions (Schneider et al., 2011; Meng et al., 2021b). Emerging evidence show that chronic hyperglycemia in T2DM results in oxidative stress, activation of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome (Liu et al., 2020; Wu et al., 2020; Zhai et al., 2018), and increased interleukin-1β (IL-1β) secretion (Chen et al., 2021; Esmaeili et al., 2020; Meng et al., 2021b). Those of which in turn leads to cognitive dysfunction by damaging hippocampal synaptic plasticity (Erion et al., 2014), down-regulating brain-derived neurotrophic factor (BDNF) expression (Barrientos et al., 2004), and promoting tau phosphorylation (Griffin et al., 2006; White et al., 2017). Autophagy is a highly regulated route of cell degradation, which is essential for cell quality control and homeostasis maintenance. Recent studies have shown that it negatively regulates NLRP3 inflammasome activation by clearing the inflammasome complex (Tang et al., 2021), degrading IL-1β precursors (Harris et al., 2011), or clearing damaged mitochondria (Ye et al., 2019). Interestingly, inhibition of NLRP3 inflammasome activity caused by autophagy can improve cognitive dysfunction (Farré-Alins et al., 2020; Liu et al., 2019; Qiu et al., 2022; Ye et al., 2019). Emerging evidence also manifests that the enhanced microglial autophagy has an inhibiting effect on neuroinflammatory injury in Alzheimer's disease (AD), evidenced by reducing the expression of NLRP3 protein, secretion of TNF-α and IL-1β, and activation of Caspase-1 (Qiu et al., 2020; Liu et al., 2015). Autophagy-related 7(Atg7) is an essential autophagy gene for autophagosome formation. Knocking out this gene has been linked to a variety of neurodegenerative diseases, especially DACD (Hara et al., 2006; Komatsu et al., 2006; Wu et al., 2019). Therefore, targeting the Atg7 mediated autophagy/NLRP3 signaling pathway may be an effective strategy to improve IL-1β triggered neuroinflammation in DACD.

Huang-Lian-Jie-Du decoction (HLJDD), composed with Coptis chinensis Franch, Scutellaria baicalensis Georgi, Phellodendron amurense Rupr, and Gardenia jasminoides J.Ellis, is a well-known formula with heat-clearing and detoxifying effects. The plant name has been checked with http://www.theplantlist.org on October 25, 2023. HLJDD was first published in Volume 2 of Ge Hong's book “The Handbook of Prescriptions for Emergencies”, “The thirteenth Prescription for Treating Typhoid Fever with Qi and temperature”, which can make the fire of sanjiao and heat poison clear away (Zhang et al., 2014). HLJDD has been reported to be effective in several diseases, such as diabetes, dementia, stroke, Parkinson's disease (Zheng et al., 2023). Emerging evidence (He et al., 2021) and our previous study (Tian et al., 2022) have confirmed that HLJDD can improve the cognitive dysfunction of DACD rats or mice. Our previous in vivo study confirmed that after 8 weeks of treatment, HLJDD significantly improved the learning and memory level of T2DM rats, with the attenuated synaptic damage of hippocampal neurons, upregulated expression level of BDNF, and the inhibited tau phosphorylation. Notedly, it was found that HLJDD exerted the ability to suppress the NLRP3 inflammasome activation and IL-1β secretion. Meanwhile, HLJDD could also enhance the antioxidant stress ability and promote the level of autophagy in hippocampus (Tian et al., 2022). However, whether the inhibitory effects of HLJDD on NLRP3 inflammasome and IL-1β secretion are related to autophagy promotion remains unclear.

Microglia are macrophages in the brain and vital players in innate immunity of the central nervous system. Adverse stimuli within the brain can activate microglia cells to promote the secretion of a series of inflammatory cytokines especially IL-1β, interleukin-6, and tumor necrosis factor, resulting in neuroinflammation. Long-term chronic neuroinflammation will lead to neuronal damage and further cognitive dysfunction (Bilbo and Stevens, 2017). BV2 cells have been widely used in in vitro studies because of their morphological, phenotypic, and functional characteristics of microglia. In the present study, we established an inflammatory model of BV2 cells by D-glucose and palmitic acid (PA) (Mao et al., 2021; Ward and Ergul, 2016) to observe the effects of the HLJDD drug-containing serum on IL-1β-mediated neuroinflammation, autophagy level, and the activity of NLRP3 inflammasome. Furthermore, by silencing Atg7 with small interfering RNA in BV2 cells, we further clarify the mechanisms involved in HLJDD against DACD by regulating autophagy/NLRP3 signaling (Fig. 1).