Using data mining and network pharmacology to explore the rule and mechanism of traditional Chinese medicine for diabetes cognitive impairment
Diabetes is a group of metabolic diseases characterized by chronic hyperglycemia. Epidemiological investigations have found that nearly one-third of DM patients have varying degrees of cognitive impairment, often showing symptoms such as forgetfulness, decreased learning and memory abilities, and cognitive loss. In severe cases, the condition can progress to irreversible diarrhea. Traditional Chinese medicine classifies diabetes cognitive dysfunction (DCD) into the category of “diabetes” and “stupidity”. It is believed that the disease is mainly caused by the combined effects of internal and external causes such as aging, kidney deficiency, emotional injury, eating disorders, and chronic illness. In recent years, research on the use of traditional Chinese medicine to treat DCD has gradually increased, accumulating a large amount of clinical data. Standardizing and summarizing it is the general direction of modern medical research. By exploring traditional Chinese medicine prescriptions for treating DCD, potential combinations of compatible drugs are explored and medication patterns are extracted, providing reference for future clinical prescription and medication selection. This study is based on searching literature databases, using data mining techniques for association, clustering, and factor analysis to investigate its medication patterns. Through network pharmacology, the effective active ingredients and potential targets of the core formula for treating DCD are preliminarily predicted, and relevant biological functional pathways are screened. The complex mechanism of action of the core formula for treating DCD is preliminarily explored, providing new ideas and reliable basis for scientific research and clinical practice.

DCD is one of the common chronic complications of diabetes, which has a negative impact on the prognosis and quality of life of patients. There is no specific disease name for DCD in traditional Chinese medicine, and it is mostly classified as “quenching thirst”, “dementia”, and “dementia”. Nowadays, it is widely believed that its pathogenesis is based on deficiency of the root and excess of the target, with the disease located in the brain and involving multiple organs such as the spleen and kidneys. The spleen loses its healthy function, unable to swim and overflow essence, accumulates in the middle burner, causing damage to its transport and transformation functions, making it difficult to let go, and affecting the mind and spirit; Over time, DCD can occur and develop due to the accumulation of phlegm, blood stasis, obstruction of blood vessels, or the combination of phlegm, blood stasis, and toxins, leading to the loss of brain nourishment. Patients often exhibit forgetfulness, mental confusion, and cognitive decline. Over time, pathological products such as phlegm dampness, blood stasis, and turbid toxins interact and consume yin and yang, ultimately leading to insufficient kidney essence and empty marrow.

There is currently no clear and comprehensive Western medicine treatment plan for DCD, while traditional Chinese medicine has outstanding advantages in treating DCD, achieving good clinical efficacy in reducing blood sugar and blood lipids, delaying memory loss, reducing toxic side effects, and improving quality of life. This study is based on data mining and analysis of clinical prescriptions in traditional Chinese medicine. Through frequency statistics, it was found that DCD drugs mainly include Chuanxiong, Taoren, Danshen, Honghua, Danggui, Huangqi, and Rehmannia glutinosa, which have the taste of promoting blood circulation, removing blood stasis, replenishing qi and blood, as well as Pinellia ternata, Acorus tatarinowii, Yuanzhi and other products that can regulate qi, dampness, awaken the mind and improve intelligence. The drugs for promoting blood circulation and removing blood stasis, as well as tonifying deficiency, have a sweet and warm taste. When used in combination, they can dissolve cerebral blood stasis, regulate qi and blood flow, and nourish deficiency of vital energy. The liver is the key to the generation of blood stasis, and it is important to use liver meridian drugs to stimulate the meridians and promote blood circulation, promote circulation, and remove blood stasis. Qi regulating and opening up herbs are used together with calming herbs to treat both sweetness and bitterness, as well as to treat the lungs and spleen. When the qi flows, it becomes moist, and when the qi flows smoothly, it eliminates phlegm and opens up the orifices, awakening the brain and unblocking the meridians. The correlation analysis results indicate that peach kernel safflower, Chuanxiong safflower, Angelica sinensis safflower, and goji berry dodder have high frequency and strong correlation. Cluster analysis and factor analysis found that the common factors F1 and F8 (including peach kernels, safflower, Chuanxiong, Angelica sinensis, and Danshen) mainly promote blood circulation, remove blood stasis, and unblock collaterals, which is the basis of the “Zhuyu Tang”. It can regulate qi and blood, nourish and apply simultaneously, which can not only eliminate the cause of the disease and promote the circulation of the brain and collaterals, but also tonify the righteous qi and treat the syndrome caused by blood stasis; The common factors F2 and F4 (including prepared rehmannia, Chinese yam, cornus officinalis, wolfberry, dodder, etc.) are mainly used to tonify the deficiency. Among them, prepared rehmannia, Chinese yam, cornus officinalis are three yin tonics, tonifying the kidney and essence, nourishing the liver and spleen, which are an important part of “Dihuang Pill”, which is mainly used to treat the syndrome of liver and kidney deficiency; The common factors F2, F3, T5, F6, F7 (including Pinellia ternata, Poria cocos, Atractylodes macrocephala, Glycyrrhiza uralensis, Acorus tatarinowii, etc.) are mainly used for regulating qi, dispelling dampness, and awakening the brain. The combination of Pinellia ternata and Poria cocos is the basis of the “Er Chen Tang”, which has the effects of drying dampness, dispersing knots, and promoting diuresis and dampness. It is mainly used to treat the syndrome caused by phlegm turbidity. The results of cluster analysis and factor analysis are similar, objectively proving that there are rules and regulations for the compatibility of traditional Chinese medicine in the treatment of DCD.

According to the results of data mining and analysis, the core formula consisting of nine herbs including Angelica sinensis, peach kernel, safflower, Chuanxiong, Rehmannia glutinosa, goji berry, dodder, Acorus tatarinowii, and Paeonia lactiflora can reflect the basic principles of traditional Chinese medicine in treating DCD from multiple perspectives, dimensions, and levels, including promoting blood circulation and removing blood stasis, tonifying the kidney and filling the marrow, and awakening the mind. From a microscopic perspective, compounds such as quercetin, kaempferol, and β – sitosterol play important roles in the core formula. Quercetin can not only reduce insulin resistance and fasting blood glucose levels, but also regulate the expression of SIRT1 active protein and NLRP3 inflammasome in the hippocampus. It can not only alleviate endoplasmic reticulum stress (ERS), but also inhibit abnormal inflammatory reactions in the hippocampus and protect neuronal degeneration. Shannai phenol is a natural flavonoid compound that not only provides antioxidant protection to cells by inhibiting NO degradation, but also reduces the expression of inflammatory factors and inhibits endoplasmic reticulum stress by regulating the MAPK and PI3K Akt pathways. β – sitosterol can activate downstream signaling molecules of insulin to reduce IRS-1 phosphorylation, upregulate the expression of IR-1 and AKT proteins, inhibit PKCq and NF – κ B pathway transduction, and weaken hippocampal inflammatory response. PPI network and topology analysis indicate that the core formula has a high possibility of treating DCD through core targets such as TP53, FOS, IL6, MAPK14, CASP3, ERS1, IL1B, involving biological processes such as glucose and lipid metabolism, angiogenesis, inflammatory response, cell aging, and apoptosis.

Through genes such as FOS, IL6, IL1B, MAPK14, CASP3, downstream transcription factors can be induced to activate the TNF signaling pathway, MAPK signaling pathway, Toll like pathway, and FoxO signaling pathway, leading to phosphorylation of inflammatory factors to regulate cellular inflammatory response. These signaling pathways are closely related not only to cell apoptosis and inflammatory response, but also to ERS and autophagy. When the body’s energy supply is insufficient and the endoplasmic reticulum balance is disrupted, cellular autophagy is regulated through multiple pathways of MAPK and FoxO signaling, clearing abnormal proteins in the cytoplasm, regulating autophagy flux, inhibiting ERS, and reducing abnormal deposition of amyloid proteins in the hippocampus to protect neurons. The estrogen signaling pathway mediates the inhibition of endoplasmic reticulum (ER) in hippocampal neurons by various estrogen nuclear receptors, maintains endoplasmic reticulum stability, blocks Caspase cascade reactions, regulates CASP3 gene to protect cell survival, and has a certain degree of benign regulation on cognitive dysfunction. Toll like receptors (TLRs) have been shown to activate downstream signaling molecules of insulin through the insulin signaling pathway and Toll like pathway, upregulate the activity of pancreatic beta cell peripheral proteins, regulate systemic insulin sensitivity and lipid distribution.

Through data mining, it was found that the current traditional Chinese medicine formula for treating DCD mainly focuses on promoting qi circulation, activating blood circulation, resolving phlegm, awakening the brain, and nourishing yin, filling essence, and strengthening the kidneys. From this, core drug combinations such as Danggui Taoren Chuanxiong, Danggui Honghua Chuanxiong, Chuanxiong Honghua Taoren, and Rehmannia glutinosa Cuscuta chinensis Goji berries were identified, providing valuable treatment experience and reference for future clinical applications; Based on network pharmacology, a preliminary analysis is conducted on the potential mechanism of action of the core components in the traditional Chinese medicine treatment of DCD, providing a scientific explanation for the drugs used by Chinese medicine practitioners in the process of treating diseases. At the same time, this study still has certain shortcomings and deficiencies, including limited inclusion of traditional Chinese medicine clinical prescriptions, uneven literature quality, etc. Data mining and network pharmacology are still at the theoretical level, and further basic experiments are needed to verify the specific mechanism of action of the active ingredients of core drugs on DCD.