Traditional Chinese Medicine (TCM) has recently emerged as a beacon for the treatment of diabetes and its complications. Many TCMs that are commonly used, have the potentially demonstrated significant anti-diabetic effects. The mechanisms of these effects have been extensively discussed using modern techniques, such as genomics, mass spectrometry, and network pharmacology. Studies have demonstrated that TCM can influence glucose metabolism and pancreatic function via a diverse array of mechanisms including PI3K/AKT and AMPK pathways. TCM not only exhibits potential in the treatment of diabetes but also reduces the risk of diabetic complications. It is effective in the treatment of diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic neuropathy (DPN), diabetic cardiomyopathy, and peripheral angiopathy. Research has demonstrated that prescriptions, Chinese herbal medicines, and their extracts play a role in a variety of molecular mechanisms such as antioxidation, apoptosis regulation, hypoxia improvement, autophagy, and promotion of glucose and lipid metabolism. The antioxidant properties of TCM have received considerable attention. Recent studies have demonstrated that they are capable of effectively eliminating free radicals from the body and reducing damage to cells caused by oxidative stress. Consequently, they are crucial in the treatment of diabetes and its associated complications. This review summarizes the ever-expanding scope of TCM applicability in the field of diabetes, providing crucial support and innovative ideas for modern healthcare. TCMs could help seek more effective pharmacological targets in basic study and as well serve as the complement to the strategy of diabetic prevention and treatment benefiting the patients. More and more large series of RCT and clinical investigations will eventually examine the efficacy of specific TCM formulas on the therapeutic effect of DM and its complication where currently treatments could not be satisfied.

Background: Diabetic retinopathy is the most common retinal vascular disease, affecting the retina's blood vessels and causing chronic inflammation, oxidative stress, and, ultimately, vision loss. Diabetes-induced elevated glucose levels increase glycolysis, the main methylglyoxal (MGO) formation pathway. MGO is a highly reactive dicarbonyl and the most rapid glycation compound to form endogenous advanced glycation end products (AGEs). MGO can act both intra- and extracellularly by glycating molecules and activating the receptor for AGEs (RAGE) pathway. Conclusions: This review summarizes the sources of MGO formation and its actions on various cell pathways in retinal cells such as oxidative stress, glycation, autophagy, ER stress, and mitochondrial dysfunction. Finally, the detoxification of MGO by glyoxalases is discussed.

Retinal diseases significantly contribute to the global burden of visual impairment and blindness. The occurrence of retinal diseases is often accompanied by destruction of the blood‒retinal barrier, a vital physiological structure responsible for maintaining the stability of the retinal microenvironment. However, detailed summaries of the factors damage the blood‒retinal barrier and treatment methods involving natural plant medications are lacking.

To comprehensively summarize and analyze the protective effects of active substances in natural plant medications on damage to the blood-retina barrier that occurs when retinal illnesses, particularly diabetic retinopathy, and examine their medicinal value and future development prospects.

In this study, we searched for studies published in the ScienceDirect, PubMed, and Web of Science databases. The keywords used included natural plant medications, plants, natural herbs, blood retinal barrier, retinal diseases, diabetic retinopathy, age-related macular degeneration, and uveitis. Chinese herbal compound articles, non-English articles, warning journals, and duplicates were excluded from the analysis.

The blood‒retinal barrier is susceptible to high glucose, aging, immune responses, and other factors that destroy retinal homeostasis, resulting in pathological changes such as apoptosis and increased vascular permeability. Existing studies have shown that the active compounds or extracts of many natural plants have the effect of repairing blood-retinal barrier dysfunction. Notably, berberine, puerarin, and Lycium barbarum polysaccharides exhibited remarkable therapeutic effects. Additionally, curcumin, astragaloside IV, hesperidin, resveratrol, ginsenoside Rb1, luteolin, and Panax notoginseng saponins can effectively protect the blood‒retinal barrier by interfering with distinct pathways. The active ingredients found in natural plant medications primarily repair the blood‒retinal barrier by modulating pathological factors such as oxidative stress, inflammation, pyroptosis, and autophagy, thereby alleviating retinal diseases.

This review summarizes a series of plant extracts and plant active compounds that can treat retinal diseases by preventing and treating blood‒retinal barrier damage and provides reference for the research of new drugs for treating retinal diseases.

Infections caused by Candida species, especially Candida albicans, threaten the public health and create economic burden. Shortage of antifungals and emergence of drug resistance call for new antifungal therapies while natural products were attractive sources for developing new drugs. In our study, fangchinoline, a bis-benzylisoquinoline alkaloid from Chinese herb Stephania tetrandra S. Moore, exerted antifungal effects on planktonic growth of several Candida species including C. albicans, with MIC no more than 50 μg/mL. In addition, results from microscopic, MTT and XTT reduction assays showed that fangchinoline had inhibitory activities against the multiple virulence factors of C. albicans, such as adhesion, hyphal growth and biofilm formation. Furthermore, this compound could also suppress the metabolic activity of preformed C. albicans biofilms. PI staining, followed by confocal laser scanning microscope (CLSM) analysis showed that fangchinoline can elevate permeability of cell membrane. DCFH-DA staining suggested its anti-Candida mechanism also involved overproduction of intracellular ROS, which was further confirmed by N-acetyl-cysteine rescue tests. Moreover, fangchinoline showed synergy with three antifungal drugs (amphotericin B, fluconazole and caspofungin), further indicating its potential use in treating C. albicans infections. Therefore, these results indicated that fangchinoline could be a potential candidate for developing anti-Candida therapies.

Glycation is an important step in aging and oxidative stress, which can lead to endothelial dysfunction and cause severe damage to the eyes or kidneys of diabetics. Inhibition of the formation of advanced glycation end products (AGEs) and their cell toxicity can be a useful therapeutic strategy in the prevention of diabetic retinopathy (DR). Gardenia jasminoides Ellis (GJE) fruit is a selective inhibitor of AGEs. Genipin is an active compound of GJE fruit, which can be employed to treat diabetes.

To confirm the effect of genipin, a vital component of GJE fruit, in preventing human retinal microvascular endothelial cells (hRMECs) from AGEs damage in DR, to investigate the effect of genipin in the down-regulation of AGEs expression, and to explore the role of the CHGA/UCP2/glucose transporter 1 (GLUT1) signal pathway in this process.

In vitro, cell viability was tested to determine the effects of different doses of glucose and genipin in hRMECs. Cell Counting Kit-8 (CCK-8), colony formation assay, flow cytometry, immunofluorescence, wound healing assay, transwell assay, and tube-forming assay were used to detect the effect of genipin on hRMECs cultured in high glucose conditions. In vivo, streptozotocin (STZ) induced mice were used, and genipin was administered by intraocular injection (IOI). To explore the effect and mechanism of genipin in diabetic-induced retinal dysfunction, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) assays were performed to explore energy metabolism and oxidative stress damage in high glucose-induced hRMECs and STZ mouse retinas. Immunofluorescence and Western blot were used to investigate the expression of inflammatory cytokines [vascular endothelial growth factor (VEGF), SCG3, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-18, and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3 (NLRP3)]. The protein expression of the receptor of AGEs (RAGE) and the mitochondria-related signal molecules CHGA, GLUT1, and UCP2 in high glucose-induced hRMECs and STZ mouse retinas were measured and compared with the genipin-treated group.

The results of CCK-8 and colony formation assay showed that genipin promoted cell viability in high glucose (30 mmol/L D-Glucose)-induced hRMECs, especially at a 0.4 μmol/L dose for 7 d. Flow cytometry results showed that high glucose can increase apoptosis rate by 30%, and genipin alleviated cell apoptosis in AGEs-induced hRMECs. A high glucose environment promoted ATP, ROS, MMP, and 2-NBDG levels, while genipin inhibited these phenotypic abnormalities in AGEs-induced hRMECs. Furthermore, genipin remarkably reduced the levels of the pro-inflammatory cytokines TNF-α, IL-1β, IL-18, and NLRP3 and impeded the expression of VEGF and SCG3 in AGEs-damaged hRMECs. These results showed that genipin can reverse high glucose induced damage with regard to cell proliferation and apoptosis in vitro, while reducing energy metabolism, oxidative stress, and inflammatory injury caused by high glucose. In addition, ROS levels and glucose uptake levels were higher in the retina from the untreated eye than in the genipin-treated eye of STZ mice. The expression of inflammatory cytokines and pathway protein in the untreated eye compared with the genipin-treated eye was significantly increased, as measured by Western blot. These results showed that IOI of genipin reduced the expression of CHGA, UCP2, and GLUT1, maintained the retinal structure, and decreased ROS, glucose uptake, and inflammation levels in vivo. In addition, we found that SCG3 expression might have a higher sensitivity in DR than VEGF as a diagnostic marker at the protein level.

Our study suggested that genipin ameliorates AGEs-induced hRMECs proliferation, apoptosis, energy metabolism, oxidative stress, and inflammatory injury, partially via the CHGA/UCP2/GLUT1 pathway. Control of advanced glycation by IOI of genipin may represent a strategy to prevent severe retinopathy and vision loss.

Diabetic retinopathy (DR) is one of the leading causes of blindness worldwide. Multiple treatment options have been used over time to attempt to modify the natural progression of the disease in both proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). These two retinal complications are the result of microvascular occlusions and vascular hyperpermeability and are considered one of the leading causes of irreversible blindness in patients of working age. It is now well demonstrated that PDR and DME are associated with increased levels of inflammatory and pro-angiogenic factors in the ocular compartment. To date, laser photocoagulation, vascular endothelial growth factor (VEGF) inhibitors, and corticosteroids have demonstrated efficacy in their treatment in large randomized controlled trials and in real-life observational studies. This manuscript aims to provide a comprehensive review of current treatments, including the main drugs used in diabetic pathologic manifestations, as well as new therapeutic alternatives, such as extended-release intraocular devices.

The role of advanced glycation end products (AGEs) is not limited to diabetes and diabetes-related complications. There are multiple modulators, including the receptor for advanced glycation end products, high mobility group box 1, glyoxalase 1, nuclear factor-kappa B, tumor necrosis factor-α, chronic unpredictable stress, reactive oxygen species, and inflammatory cytokines, which interact with AGE signaling and control diabetes, modulating these interacting modulators. The progression of diabetes, as well as related complications, can be controlled and treated. Natural products rich in bioactive constituents can interact with AGEs and their related mediators through various signaling cascades, thereby controlling and preventing the progression of diabetes. This review provides a deeper assessment of the signaling pathway, interactions between phytochemicals and AGEs, and its mediators, to develop a multifold therapeutic approach to prevent and treat diabetes and its related complications.

Diabetes is a metabolic disease characterized by high blood sugar. Its complications may damage multiple organs, such as eyes, kidneys, heart, blood vessels, and nerves, severely threatening human health. Transferrin (Tf) is a major iron transport protein in the body. Recent studies have shown that the degree of non-enzymatic glycated modification of Tf is increased in diabetic patients, and glycated Tf is closely related to the occurrence and development of diabetes and diabetic complications. However, the molecular mechanisms underlying this glycated modification in diabetes and diabetic complications are still unclear. It is speculated that the mechanism may be that glycated modification reduces the binding ability of Tf and its receptor TfR, followed by excessive iron accumulation in the body. Iron overload in the body may further lead to the death of pancreatic beta cells and insulin resistance by increasing oxidative stress, inducing iron death, interfering with the insulin signaling pathway, and causing autophagy deficiency. In addition, non-enzymatic glycation affects the binding of Tf with chromium and reduces the ability of Tf to transport chromium into tissues, resulting in a decrease in the levels of chromium in tissues and ultimately affecting the sensitivity of tissues to insulin. In diabetic patients, the concentrations of glycated Tf in serum were significantly correlated with those of fructosamine.Tf has a shorter half-life, and not affected by anemia or hypoalbuminemia and less negative charge under physiological conditions, while glycated modification could not change the isoelectric point of Tf, which easily passes through the negatively charged basement membrane of the glomerulus. Therefore, compared to glucosamine, HbA1C, etc., glycated Tf may be a future biomarker for evaluating short-term glycemic control and early renal damage in diabetic patients.