Based on Bioinformatics to Explore the Mechanism of "Tangzhiqing" Decoction Alleviating Type 2 Diabetes-associated Cognitive Dysfunction in Mice by Regulating Hippocampal Neuron Apoptosis and Autophagy.

Diabetic cognitive dysfunction (DCD) is emerging as a chronic complication of diabetes that is gaining increasing international recognition. The traditional Chinese medicine (TCM) formulation, Tangzhiqing decoction (TZQ), has shown the capacity to modulate the memory function of mice with DCD by ameliorating insulin resistance. Nevertheless, the precise mechanism underlying the effects of TZQ remains elusive. The chemical constituents of TZQ were screened using TCMSP databases, and DCDassociated disease targets were retrieved from various databases. Subsequently, core targets were identified through network topology analysis. The core targets underwent analysis using Gene Ontology (GO) functional annotations and enrichment in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Models were established through high-fat and high-glucose diet feeding along with intraperitoneal injection of streptozotocin (STZ). TZQ and metformin were administered at varying doses over 8 weeks. The Morris water maze was employed to evaluate the cognitive capabilities of each rat group, while indicators of oxidative stress and insulin were assessed in mice. Neuronal apoptosis in distinct groups of mice's hippocampi was detected using TdT-mediated dUTP Nick-End Labeling (TUNEL), and western blot (WB) analysis was conducted to assess the expression of apoptosis- and autophagy-related proteins, including Bax, Bcl2, Caspase3, Caspase8, Beclin1, ATG7, LC3, p62, and Lamp2, within the hippocampus. TZQ exhibited the capacity to modulate neuronal autophagy, ameliorate endoplasmic reticulum stress, apoptosis, inflammation, and oxidative stress, as well as to regulate synaptic plasticity and conduction. TZQ mitigated cognitive dysfunction in mice, while also regulating hippocampal inflammation and apoptosis. Additionally, it influenced the protein expression of autophagy-related factors such as Bax, Bcl2, Caspase3, Caspase8, Beclin1, ATG7, and LC3. Notably, this modulation significantly reduced neuronal apoptosis in the hippocampus and curbed excessive autophagy. TZQ demonstrated a substantial reduction in neuronal apoptosis within the hippocampus and effectively suppressed excessive autophagy.

Shi Y ，Sheng P ，Zhao Y ，Wang X ，Xu X ，Sun S ... -  《-》

Banxia Xiexin Decoction Prevents HT22 Cells from High Glucose-induced Neurotoxicity via JNK/SIRT1/Foxo3a Signaling Pathway.

Type 2 diabetes-associated cognitive dysfunction (DCD) is a chronic complication of diabetes that has gained international attention. The medicinal compound Banxia Xiexin Decoction (BXXXD) from traditional Chinese medicine (TCM) has shown potential in improving insulin resistance, regulating endoplasmic reticulum stress (ERS), and inhibiting cell apoptosis through various pathways. However, the specific mechanism of action and medical value of BXXXD remain unclear. We utilized TCMSP databases to screen the chemical constituents of BXXXD and identified DCD disease targets through relevant databases. By using Stitch and String databases, we imported the data into Cytoscape 3.8.0 software to construct a protein-protein interaction (PPI) network and subsequently identified core targets through network topology analysis. The core targets were subjected to Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The results were further validated through in vitro experiments. Network pharmacology analysis revealed the screening of 1490 DCD-related targets and 190 agents present in BXXXD. The topological analysis and enrichment analysis conducted using Cytoscape software identified 34 core targets. Additionally, GO and KEGG pathway analyses yielded 104 biological targets and 97 pathways, respectively. BXXXD exhibited its potential in treating DCD by controlling synaptic plasticity and conduction, suppressing apoptosis, reducing inflammation, and acting as an antioxidant. In a high glucose (HG) environment, the expression of JNK, Foxo3a, SIRT1, ATG7, Lamp2, and LC3 was downregulated. BXXXD intervention on HT22 cells potentially involved inhibiting excessive oxidative stress, promoting neuronal autophagy, and increasing the expression levels of JNK, SIRT1, Foxo3a, ATG7, Lamp2, and LC3. Furthermore, the neuroprotective effect of BXXXD was partially blocked by SP600125, while quercetin enhanced the favorable role of BXXXD in the HG environment. BXXXD exerts its effects on DCD through multiple components, targets, levels, and pathways. It modulates the JNK/SIRT1/Foxo3a signaling pathway to mitigate autophagy inhibition and apoptotic damage in HT22 cells induced by HG. These findings provide valuable perspectives and concepts for future clinical trials and fundamental research.

Shi Y ，Sheng P ，Guo M ，Chen K ，Zhao Y ，Wang X ，Wu M ，Li B ... -  《-》

Tangzhiqing decoction attenuates cognitive dysfunction of mice with type 2 diabetes by regulating AMPK/mTOR autophagy signaling pathway.

Yao W ，Zhang Q ，Zhao Y ，Xu X ，Zhang S ，Wang X ... -  《-》

Huang-Lian-Jie-Du decoction attenuates cognitive dysfunction of rats with type 2 diabetes by regulating autophagy and NLRP3 inflammasome activation.

Huang-Lian-Jie-Du decoction (HLJDD) is a traditional Chinese formula that is efficacious in treating diabetes mellitus, Alzheimer's disease, and diabetic encephalopathy; the underlying mechanisms of HLJDD in diabetes-associated cognitive dysfunction remain unclear. This study investigated the neuroprotective effects of HLJDD on cognitive function, and the possible underlying mechanisms in type 2 diabetes mellitus (T2DM) in a rat model of cognitive impairment. Twelve active ingredients in HLJDD were detected using high-performance liquid chromatography analysis. An animal model of cognitive dysfunction in T2DM was induced via a high-sugar and high-fat diet combined with a low dose of streptozotocin. Sprague-Dawley rats were randomly divided into six groups: control, T2DM, metformin (0.34 g/kg/day), and HLJDD groups (3, 1.5, and 0.75 g/kg/day). All treatments were intragastrically administrated for nine continuous weeks after the development of T2DM. Body weight, food and water intake, fasting blood glucose, insulin sensitivity, and blood lipid levels were measured. Spatial learning and memory of the rats were assessed using the Morris water maze test. Hematoxylin and eosin and Nissl staining were performed to evaluate neuronal morphology and vitality. Glutathione, malondialdehyde, and superoxide dismutase levels were measured to determine the level of oxidative stress in the hippocampus. Transmission electron microscopy was performed to observe the synaptic morphology and structure of hippocampal neurons. IL-1β levels in the hippocampus and cerebrospinal fluid were determined. The protein expression of NLRP3, cleaved caspase-1, mature IL-1β, ATG7, P62, LC3, and brain-derived neurotrophic factor (BDNF) was determined using western blotting and immunofluorescence analysis. HLJDD attenuated cognitive dysfunction in rats with T2DM as shown by the decreased escape latency, increased times crossing the platform and time spent in the target quadrant in the Morris water maze test (P < 0.05), improvement in hippocampal histopathological changes, and an elevated level of cell vitality. HLJDD treatment also reduced blood glucose and lipid levels, ameliorated oxidative stress, and downregulated IL-1β expression in the hippocampus and cerebrospinal fluid (P < 0.05). Moreover, HLJDD enhanced BDNF, ATG7, and LC3 protein expression and significantly inhibited the expression of P62, NLRP3, cleaved caspase-1, and mature IL-1β in the hippocampal CA1 region (P < 0.05). Immunofluorescence results further confirmed that the fluorescence intensity of NLRP3 and P62 in the hippocampus decreased after HLJDD intervention (P < 0.05). HLJDD ameliorated cognitive dysfunction in T2DM rats. The neuroprotective effect is exerted via the modulation of glucose and lipid metabolism, upregulation of autophagy, and inhibition of NLRP3 inflammasome signaling pathway.

Tian R ，Liu X ，Jing L ，Yang L ，Xie N ，Hou Y ，Tao H ，Tao Y ，Wu J ，Meng X ... -  《-》

The neuroprotection of liraglutide on diabetic cognitive deficits is associated with improved hippocampal synapses and inhibited neuronal apoptosis.

Diabetes mellitus can cause cognitive impairments, a state between normal aging and dementia. Effective clinical interventions are urgently needed to prevent or treat this complication. Liraglutide as a glucagon-like peptide 1 analog has been shown to exert memory-enhancing and neuroprotective effects on neurodegenerative diseases. This study aims to investigate the neuroprotective effects of liraglutide in streptozotocin (STZ)-induced diabetic mice with cognitive deficits. Male C57BL/6J mice were intraperitoneal injected with STZ (65 mg/kg body weight daily for 5 days) to induce type 1 diabetes model. Then the mice were treated with liraglutide (250 mg/kg/day, for 6 weeks) or saline. Weekly changes of body weight and fasting blood glucose were measured. Cognitive performance was evaluated by Morris water maze test. The ultrastructure of hippocampus was observed by transmission electron microscope. The superoxide dismutase activities and malondialdehyde levels in the hippocampus were detected by biochemistry assay. Apoptosis-related proteins and phosphoinositide 3-kinase (PI3K)/protein kinase-B (Akt) signaling were detected by Western blotting. We found that STZ-induced diabetic mice exhibited impaired learning and memory, ultrastructure damage of hippocampal neurons and synapses, exacerbated oxidative stress and neuronal apoptosis, as compared to the control mice. These effects were attenuated by the treatment with liraglutide. Furthermore, liraglutide reversed diabetes-induced alterations in PI3K/Akt signaling pathway that plays an essential role in modulating neuronal survival, apoptosis and plasticity. These data suggest that the neuroprotective effects of liraglutide on diabetes-induced cognitive impairments are associated with the improvements of hippocampal synapses and inhibition of neuronal apoptosis.

Yan W ，Pang M ，Yu Y ，Gou X ，Si P ，Zhawatibai A ，Zhang Y ，Zhang M ，Guo T ，Yi X ，Chen L ... -  《-》