Resveratrol is a non-flavonoid polyphenolic compound. RES and its derivatives are mainly found in plants such as the genus Vitis L, genus Polygonum, genus Arachis, and genus Veratrum. It is an antioxidant produced by many plants when stimulated (Huang J. et al., 2020). Studies have shown that RES has anti-inflammatory, anti-oxidation, anti-aging, and other effects (Moussa et al., 2017; Huang J. et al., 2020). In particular, RES also has the potential to regulate insulin signaling pathways, improve BG, and improve cognitive function.

In DM, RES shows significant therapeutic potential in ameliorating key symptoms of DM as well as the other concurrent indicators. In clinical trials, RES modulates BG (Szkudelska et al., 2021), HA1c, systolic blood pressure, total cholesterol (Bhatt et al., 2012), and low-density lipoprotein levels in patients with T2DM (Asadi et al., 2017). Furthermore, longer RES intervention time (≥ 6 months) increases total antioxidant status levels in a dose-dependent manner in patients with T2DM (Bo et al., 2017). The anti-diabetic effect of RES is mainly manifested as improving the level of insulin resistance, enhancement of glucose uptake and metabolism, and preservation of islet β-cells (Szkudelski and Szkudelska, 2011). RES has some insulin-sensitizing effects, mainly by activating silent information regulator 1 (SIRT1), AMP-activated protein kinase (AMPK), and forkhead box protein O1 (FOXO1) to regulate NADPH, reactive oxygen species (ROS), and peroxisome proliferators-activated receptors (PPAR) levels, thereby improving mitochondrial function and oxidative stress and relieving insulin resistance (Huang D. D. et al., 2020). Moreover, RES may also increase glucose uptake and metabolism by activating insulin receptor substrate (IRS), PI3K/Akt, AMPK signaling pathways, and endogenous GLUT4 translocation (Chi et al., 2007; Sin et al., 2015). In addition, RES can protect islet β-cells by inhibiting the inflammatory and reducing ROS levels, which is related to the regulation of SIRT1, AMPK, FOXO1, Nrf2, and NF-κB (Zheng et al., 2013; Guo et al., 2014). In conclusion, the improvement effect of RES on diabetes is related to the activation of SIRT1 and insulin-related signaling pathways, thereby inhibiting inflammation and oxidative stress, and improving mitochondrial function.

In AD, RES may be effective in the prevention or treatment. In clinical trials (NCT01504854), oral RES can ameliorate cognitive function in subjects with mild to moderate AD, which involves the regulation of neuroinflammation (Moussa et al., 2017). It restores abnormally high levels in the proteolytic activity of the ubiquitin-proteasome system (Labban et al., 2021). On the one hand, it increases levels of neurotrophins, synaptic markers, and SIRT. On the other hand, it decreases the accumulation of Aβ oligomers, the markers of apoptosis, autophagy, endolysosomal degradation, and ubiquitination in the brains of 3 × Tg (Broderick et al., 2020). In vitro, 50 μmol/L RES for 12 h significantly reduces the levels of pS396 and pS199 by regulating CDK5 and GSK-3β activity in the cell (Fang et al., 2021). In another Aβ-induced cell model, RES attenuates Aβ-mediated microglial inflammatory responses by inhibiting the TLR4, NACHT, LRR, NLRP3, and STAT cascade signaling pathways (Capiralla et al., 2012; Feng and Zhang, 2019). Furthermore, it also reduces microglia-dependent Aβ toxicity by activating SIRT1 and inhibiting NF-κB and microglial overactivation (Chen et al., 2005; Steiner et al., 2016; Locatelli et al., 2018). Therefore, Res can delay or prevent key pathological indicators of AD, abnormal Aβ, and tau through anti-oxidation, anti-inflammatory function, and improving mitochondrial function, ultimately improving the spatial learning and memory ability in AD. These functions are similar to its basic mechanism of anti-diabetes and are related to activating SIRT1 and insulin-related signaling pathways.

Proanthocyanidins, a class of polyphenolic compounds, are widely distributed in plants, such as grapes, black wolfberry, and blueberry (Maria, 2014). PCs have antioxidants and anti-cancer, anti-inflammatory, cardioprotective, and antibacterial effects. They are promising in the treatment of chronic metabolic diseases such as cancer, DM, and cardiovascular disease (Valencia-Hernandez et al., 2021). They also play a protective role in neurodegenerative diseases, such as AD and Parkinson's disease (Zhang et al., 2019; Zhao et al., 2019).

In DM, PCs improve the damage induced by the diet in insulin-resistant models, glycemia, and insulin sensitivity. PCs target several tissues involved in glucose homeostasis. In insulin-sensitive tissues, PCs modulate glucose uptake and lipogenesis and improve their oxidative/inflammatory state. In the pancreas, PCs modulate insulin secretion and production and β-cell mass, although the available results are divergent (Gonzalez-Abuin et al., 2015). Since PCs may be extracted from different plants, they can also be differentiated into different PCs, such as apple procyanidins (APCs) and lotus seedpod oligomeric PC (LSOPC). However, their hypoglycemic effects are not the same. Specifically, APCs ameliorate insulin resistance by improving hepatic insulin signaling through the suppression of hepatic inflammation in ob/ob mice (Ogura et al., 2016). Meanwhile, LSOPC and synbiotics may regulate glucose disposal in peripheral target tissues through the p66Shc-mechanistic/mTOR signaling pathway in high fat and streptozotocin (STZ)-induced diabetes (Li X. et al., 2017). Furthermore, A- and B-type PC oligomers from different cinnamon species also improve insulin sensitivity to decrease BG in T2DM (Lu et al., 2011). In addition, A-type PC oligomers mainly improve insulin concentration in the blood and pancreas, whereas B-type PC oligomers promote lipid accumulation in the adipose tissue and the liver (Chen et al., 2012). In conclusion, although various PCs have different mechanisms of action in DM, what these effects have in common is improving insulin resistance and increasing insulin sensitivity, and anti-inflammatory and anti-oxidative stress are at the core of these effects.

In AD, PCs may promote cognitive function and thus be beneficial to alleviate AD. PCs can enhance synaptic plasticity by upregulating SIRT1 to improve cognition (Michán et al., 2010; Yokozawa et al., 2011). Notably, PCs and some of their metabolites stimulate CREB, acting as a molecular switch from short- to long-term memory, based on the interplay of the CREB-SIRT1 axis (Zhao et al., 2019). Grape seed PCs (GSPCs) improve isoflurane-induced cognitive dysfunction by protecting against perturbing antioxidant enzyme activities and the NR2B/CREB pathway (Gong et al., 2020). In addition, the PCs effectively inhibit the aggregation of human islet amyloid polypeptide (hIAPP) and Aβ through hydrophobic and hydrogen bonding interactions and also dissolve the aged fibrils (Xu et al., 2021). LSOPC inhibits the formation of advanced glycation end-products by scavenging reactive carbonyls, helping to prevent age-associated diseases represented by AD (Wu et al., 2013). Overall, based on the strong physicochemical properties and antioxidant capacity of PCs, PCs have potential use in anti-AD treatments, although they are still a long way from being used in clinical drugs, and are also great as a functional food ingredient.

Berberine, one of the alkaloids extracted from a traditional Chinese herb, is mainly isolated from Coptis chinensis, Berberis vulgaris, Hydrastis canadensis, and Phellodendron amurense (Neag et al., 2018). BBR has shown some potential in the treatment of both DM and AD.

Berberine shows great potential in the treatment of DM. First, BBR dramatically reduces serum insulin levels and alleviates insulin resistance (Wang et al., 2018), working through promoting RXRA, reducing KCNQ1 and NR3C1 (Di et al., 2021), and attenuating palmitate-induced mitochondrial injury and apoptotic death. Moreover, BBR significantly prevents β-cell apoptosis and may improve islet β-cell function in T2DM (Li J. et al., 2019). Second, BBR upregulates glucokinase (GK) in liver fractions and liver glycogen content to an anti-diabetic effect by the dissociation of glucokinase GK from GK regulatory protein in db/db mice (Li M. et al., 2019). In addition, BBR is a substrate of P-gp. However, the oral bioavailability of BBR is less than 5%. Therefore, researchers use TET, another P-gp inhibitor, as an adjuvant component to potentiate the hypoglycemic efficacy of BBR (Shan et al., 2013). Finally, intestinal microbiota may serve as a potential target for berberine treatment of T2DM (Li et al., 2017). BBR could alleviate symptoms in T2DM rats by affecting gut microbiota composition and reducing the concentration of aromatic amino acids (Xu et al., 2020; Yao et al., 2020) such as decreasing the Bacteroidetes, Bacteroidetes/Firmicutes ratio, and Muribaculaceae, and increasing Allobaculum (Zhao et al., 2021). Clinical studies related to this also verified the effect. Furthermore, the hypoglycaemic effect of BBR is mediated by the inhibition of deoxycholic acid (DCA) biotransformation by Ruminococcus bromii (NCT0286126) (Zhang Y. et al., 2020). In summary, the anti-DM effect of BBR is related to affecting tissues such as the pancreas and liver and regulating intestinal flora.

At the same time, BBR also has potential in AD treatment. BBR may prevent the formation of NFTs and the disaggregation of Aβ in AD by limiting neuroinflammation and oxidative stress (Hussien et al., 2018; Akbar et al., 2021). In vivo, BBR rescues synapse damage and limits tau hyperphosphorylation in APP/PS1 mice possibly via inhibiting the NF-κB pathway and activating the liver kinase B1 (LKB1)/AMPK pathway, and these attenuate cognitive deficits (He et al., 2017; Cai et al., 2019). It also reduces APP and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and facilitates Aβ clearance via autophagy in vitro (Huang et al., 2017). Furthermore, BBR may inhibit protein kinase (PKR)-like endoplasmic reticulum (ER) kinase (PERK)/eukaryotic initiation factor 2alpha (eIF2α) signaling-mediated BACE1 translation and attenuate ER stress (Liang et al., 2021). Apart from reducing the Aβ accumulation, BBR inhibits the apoptosis of neurons and promotes the formation of microvessels in the mouse brain by enhancing brain platelet endothelial cell adhesion molecule-1, vascular endothelial growth factor, etc. As the result, it promotes the formation of new vessels with a complete structure and perfect function, which in turn promoted the recovery of cerebral blood flow. Ultimately, it ameliorates cognitive deficits in 3 × Tg AD mice (Ye et al., 2021). In vitro, BBR protects neuronal cells against Aβ partly through lncRNA BACE1 antisense (BACE1-AS)/miR-132-3p axis, regulating the circular RNAs histone deacetylase 9 (circHDAC9)/miR-142-5p axis (Ge et al., 2020; Zhang N. et al., 2020). Meanwhile, it can inhibit Aβ-induced microglial activation via modulating the microglial M1/M2 activated state and the suppressor of cytokine signaling1 (SOCS1) mediates the process (Guo et al., 2021). In addition, it attenuates Aβ-induced neuronal damage by regulating miR-188/nitric oxide synthase 1 (NOS1) (Chen et al., 2020). Interestingly, BBR can also alleviate tau hyperphosphorylation and axonopathy associated with diabetic encephalopathy by regulating the PI3K/Akt/GSK-3β signaling pathway (Wang et al., 2018). Based on the role of BBR in DM and AD, it can be found that the basic anti-inflammation and anti-oxidation of BBR are the key to the protective effect, and the regulation of insulin-related signaling pathways and intestinal flora also plays an important role.

As a pharmacologically active ingredient of Dendrobium nobile Lindl. DNLA was originally extracted from D. nobile Lindl, a traditional Chinese herbal medicine and medicinal material of Guizhou province, and has significant protective effects in T2DM and the nervous system, especially in AD.

Our previous studies show that DNLA reduces BG levels in animal models of T2DM such as db/db and KK-Ay mice, improves insulin resistance, and has a protective effect on pancreatic β cells of pancreatic islets in these animals (Zhang, 2016; Chen, 2018; Huang Q. et al., 2019). It increases the p-INSR level, IRS-1, and after that, activates Akt (Chen, 2018). Furthermore, telomere length is shortened in the pancreas of db/db mice, and DNLA can delay shortening telomere length and increase the telomerase activity. The action works may be related to upregulating TERT, TERC mRNA, protein expressions of TRF2, and POT1, and decreasing protein expression of TRF1 in the pancreas (Zhang, 2016). The key to the protective effect of DNLA in DM is to regulate the insulin signaling pathway and improve insulin resistance.

Our previous studies show DNLA can improve the neuronal disruption caused by LPS, oxygen-glucose deprivation, and reperfusion, and decrease neuronal apoptosis in the rat brain (Li L. S. et al., 2017; Zhang et al., 2017; Liu et al., 2021). Furthermore, we observed amelioration of the spatial learning performance in AD model rats induced by Aβ_{25 − 35}, APP/PS1, and SAMP8 mice (Nie et al., 2016; Lv et al., 2020), and this effect may be related to a decrease in the generation of Aβ by regulating APP, α-secretases (ADAM10 and ADAM17), and BACE1 (Huang J. et al., 2019). It also alleviates Aβ_{25 − 35}-induced axonal injury by improving autophagic flux in neurons, increasing Aβ clearance, activation of autophagy activity, and upregulation of Klotho (Li L. S. et al., 2017; Zhang et al., 2017; Lv et al., 2020), possibly via the suppression of ER stress-related PERK signaling pathway, sequentially inhibiting calpain 1, GSK-3β, and Cdk5 activities and eventually reducing the p-tau (Liu et al., 2020). Notably, DNLA improved learning and memory function in elderly normal mice. Based on the results of DNLA in DM and AD, it is shown that DNLA is a potential insulin sensitizer and has neuroprotective effects, which can significantly improve the learning and memory ability of AD model animals. Based on this, we speculate that the anti-AD effect of DNLA is mainly achieved by regulating insulin-related signaling pathways, thereby inhibiting the hyperphosphorylation of tau protein.