Both DM and depression are serious chronic diseases, which can lead to a serious decline in the quality of life, increase functional disability and costs of care than many other chronic diseases . The bidirectional link between DM and depression has been confirmed. An epidemiological study has shown that the prevalence rate of depression is more than three times higher in people with type 1 diabetes mellitus (T1DM) and nearly twice as high in people with T2DM than those without . Another research also indicated that the presence of diabetes doubles the odds of comorbid depression . The results of a meta-analysis carried out by Mezuk et al. showed that compared with people without diabetes, people with T2DM had a 15% increased risk of depression, while those with depression had a 60% increased risk of developing T2DM . However, the current treatments for these two diseases are relatively single and there is a lack of the comprehensive treatment needed to improve clinical outcomes .
JTW, one of the most classical Chinese prescription, has been used to treat insomnia for hundreds of years. In recent years, more and more experiments have confirmed that JTW can not only improve the quality of sleep, but also has the dual effects of hypoglycemic and antidepressant [40–42]. In the traditional theories of TCM, different diseases may have similar etiology, pathogenesis, symptoms, and disease location during the occurrence and development, so that different diseases can be cured with the same prescription, which fully reflects the advantages of TCM in syndrome differentiation, holistic treatment and comprehensive treatment . Our study is to explore the targets and mechanisms of the dual effects of JTW through the novel analysis method called network pharmacology.
The results of analysis using Cytoscape software showed that the active compounds with the highest number of targets included quercetin, styrene, cinnamic acid, ethyl-cinnamate, (R)-Canadine, palmatine, berberine and so on. First of all, quercetin, a naturally occurring flavonoid, is one of the active compounds of Huanglian. A number of research results have confirmed that quercetin has multiple pharmacological effects such as antioxidant, anti-tumor, anti-inflammatory, antimicrobial, regulating immune function, and protecting cardiovascular function, etc. [44–47]. The study conducted by Roslan et al. demonstrated that quercetin can ameliorate metabolic derangements in diabetes, including near normal final body weight, fasting blood glucose (FBG) and insulin levels . Jeong et al. also found that quercetin could effectively improve hyperglycemia and dyslipidemia in T2DM and may be useful in the management of DM and prevention of diabetic complications . Not only that, quercetin has also been found to alleviate LPS-induced depression-like behaviors in rats , and can dose-dependently decrease the immobility time of diabetic mice in FST and this effect is comparable to that of fluoxetine, a traditional antidepressant [51, 52].
Berberine, a natural isoquinoline alkaloid, is also an active compound of Huanglian. Berberine has a wide range of pharmacological effects, such as antimicrobial, anti-inflammatory, anti-tumor, antioxidant, neuroprotective, etc. [53, 54], and can be used to treat many gastrointestinal disorders [55, 56]. The results of a clinical trial showed that berberine can significantly reduce FBG and hemoglobin A1c (HbA1c) in patients with diabetes, and its hypoglycemic effect was similar to that of metformin . A randomized controlled trial (RCT) completed by Zhang et al. indicated that the hypoglycemic effect of berberine is mediated by gut microbiome . The therapeutic effect of berberine on depression has also been confirmed by numerous experiments. Studies have found that berberine can exert antidepressant effect by regulating brain biogenic amines such as norepinephrine (NE), serotonin (5-HT) and dopamine (DA), etc. , it can also inhibit neuroinflammation to prevent depression-like behavior . In animal experiments, berberine can greatly shorten the immobility time of mice in FST and TST, which also supports the view that berberine plays an antidepressant effect [61, 62].
Cinnamic acid, one of the effective compounds of Rougui, is a natural aromatic carboxylic acid. Studies have reported that cinnamic acid also has multiple pharmacological effects such as antioxidant, anti-tumor, anti-inflammatory, neuroprotective, and antimicrobial [63–65]. As one of the fundamental herbs in traditional Chinese medicine, cinnamic acid has been widely used to treat many disorders for a long time . Research results show that cinnamic acid can regulate glycogen production and gluconeogenesis , and can also significantly enhance insulin secretion in isolated islets , thereby exerting anti-diabetic activity. In addition, Hemmati et al. found that the administration of cinnamic acid can inhibit the FBG level in diabetic mice . Although there are few researches on the therapeutic effect of cinnamic acid in depression, derivatives of cinnamic acid and other natural products can exert antidepressant effects and have potential applicability as candidates for antidepressant drugs .
In addition, other active compounds of JTW are also considered to have the effect of improving DM and depression. For example, palmatine can protect cells against reactive oxygen species and endoplasmic stress, thus exhibiting antidiabetic properties . The results of behavioral tests such as sucrose preference test (SPT), FST and open-field test (OFT) in rats also confirmed the antidepressant effect of it .
Inflammatory mediators have always been considered to be important factors in promoting the development of insulin resistance (IR), which will lead to the occurrence of T2DM. The results of our PPI network analysis that IL-6 and TNF are the top five targets also confirmed this view, indicating that they may play an important role in the treatment of DM and depression. It was found that the levels of cytokines such as TNF-α and IL-6 were highest in non-treated diabetic rats, and decreased significantly following quercetin or glibenclamide treatments . The systematic review conducted by Esser et al. directly showed that immune system activation and chronic low-grade inflammation are involved in the pathogenesis of IR and diabetes . Inflammation is also thought to have a bidirectional relationship with depression . A meta-analysis demonstrated that there was a significant correlation between depression and C-reactive protein (CRP) and IL-6 in children and adolescents . IL-6 knockout mice exhibit resistance to stress-induced depression-like behavior and showed reduced despair in FST and TST . Vascular endothelial growth factor (VEGF) is a key driver of neovascularization and vascular permeability [76, 77]. Prakash et al. revealed that diabetes-induced cerebral neovascularization is accompanied by increased expression of VEGF-A and activation of VEGF receptor-2 (VEGFR-2) . A case-control study showed that altered VEGF secretion, caused by genetic variation in VEGF-A gene, is involved in T2DM pathogenesis . VEGF is also related to other diabetic complications such as diabetic retinopathy (DR) and diabetic foot ulcer (DFU) [80, 81], and has been considered as a therapeutic target for anti-angiogenesis in DR [82, 83]. In addition, VEGF exerts effective neurotrophic effects. In both major depressive disorder (MDD) subjects and rat depression models, the hippocampal VEGF and other growth factors are abnormally regulated . Increasing VEGF expression in the hippocampus of rats can improve depression-like behaviors in rats after myocardial infarction (MI) . Deyama et al. confirmed that VEGF signaling plays a crucial role in the antidepressant effects of brain-derived neurotrophic factor (BDNF) and ketamine [86, 87]. The genome-wide association study (GWAS) also proved the role of VEGF in the development of depression . It can be seen that VEGF is closely related to DM and depression. The correlation between INS and DM has long been recognized worldwide, and AKT1, as a key factor in the PI3K-Akt signaling pathway, has been confirmed by many researches on its relationship with DM and depression, which will be discussed in detail below.
The results of KEGG enrichment analysis showed that the active compounds of JTW may play a therapeutic effect on DM and depression by regulating multiple pathways. The intersection targets are mainly enriched in HIF-1 signaling pathway, pathways in cancer, TNF signaling pathway, PI3K-Akt signaling pathway and MAPK signaling pathway, etc. Many studies have shown that HIF-1 signaling pathway is associated with DM and depression. Hypoxia-inducible factor 1-alpha (HIF-1α) is important for maintaining the function and survival of pancreatic β cells  and the expression of hypoxia-inducible factor 1-beta (HIF-1β) mRNA in patients with T2DM is decreased . Glucose-induced inhibition of HIF-1α protein stability may also accelerate the deterioration of β cell function and speed progression to diabetes . Myocyte HIF-1α is necessary for normal muscle glucose uptake and insulin sensitivity . Furthermore, HIF-1 is also associated with diabetic complications such as DR and diabetes kidney disease (DKD) [82, 93, 94]. In conclusion, HIFs play a role in the pathogenesis of β cell dysfunction and diabetes . In terms of depression, Li et al. established a depression model using chronic unpredictable mild stress (CUMS) and found that FG-4592 can reverse depressive behaviors by activating HIF-1 signaling pathway . The study conducted by Shibata et al. indicated that the altered expression of HIF-1 and its target genes mRNA in peripheral blood cells are associated with mood disorders, especially with MDD . Kang et al. also proposed that interventions including the intermittent hypoxia conditioning and hyperbaric oxygen therapy to elevate the level of HIF-1 in the brain might be considered as new additional treatments for depression .
PI3K-Akt signaling pathway is the main downstream molecular pathway of insulin, which plays a crucial role in regulating glucose and lipid metabolism. PI3K-Akt signaling pathway block and abnormal function of downstream target proteins can cause IR . Lots of studies have confirmed that the IR of diabetic mice can be improved by regulating the PI3K-Akt signaling pathway [99–101]. AKT1 has been considered as a key mediator of insulin-stimulated glucose uptake, suppression of apoptosis, stimulation of glycolysis and the activation of glycogen and protein synthesis . The activation of PI3K-Akt pathway can protect pancreatic β cells from the influence of different apoptotic stimuli . What’s more, Cao et al. found that the expression of PI3K in depressed rats were attenuated significantly . The study of Xie et al. showed that Crocin can ameliorate depression via PI3K-Akt mediated suppression of inflammation , these studies illustrate the close connection between PI3K-Akt signaling pathway and depression.
In mammalian cells, MAPK families has been divided into three categories, including p38, extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) . Among them, ERK1/2 play a pivotal role in various neuropsychiatric disorders, including depression . Regulating the CUMS-induced MAPK pathway and NF-κB protein complex activation can alleviate depression-like behavior in mice . Paroxetine combined with fluorouracil, ketamine and ghrelin and other drugs can show antidepressant-like effects via the MAPK signaling pathway [109–111]. In addition, resveratrol can attenuate cardiac dysfunction caused by diabetes, and the effects are related to down-regulation of AT1R-ERK/p38 MAPK signaling pathway . Cui et al. found that Huanglian can alleviate inflammation by regulating the expression of pro-inflammatory cytokines through MAPK signaling pathway, thereby inhibiting the occurrence and development of IR and diabetes . Gelidium elegans extract can ameliorate T2DM via regulation of MAPK and PI3K-Akt signaling pathways .