lignans and Diabetic-Nephropathies

Diabetes mellitus is a chronic metabolic disease characterized by disturbances in carbohydrate, protein, and lipid metabolism, often accompanied by oxidative stress. Diabetes treatment is a complicated process in which, in addition to the standard pharmacological action, it is necessary to append a comprehensive approach. Introducing the aspect of non-pharmacological treatment of diabetes allows one to alleviate its many adverse complications. Therefore, it seems important to look for substances that, when included in the daily diet, can improve diabetic parameters. Magnolol, a polyphenolic compound found in magnolia bark, is known for its health-promoting activities and multidirectional beneficial effects on the body. Accordingly, the goal of this review is to systematize the available scientific literature on its beneficial effects on type 2 diabetes and its complications. Taking the above into consideration, the article collects data on the favorable effects of magnolol on parameters related to glycemia, lipid metabolism, or oxidative stress in the course of diabetes. After careful analysis of many scientific articles, it can be concluded that this lignan is a promising agent supporting the conventional therapies with antidiabetic drugs in order to manage diabetes and diabetes-related diseases.

Topics: Animals; Biphenyl Compounds; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eye Diseases; Homeostasis; Humans; Hypoglycemic Agents; Inflammation; Lignans; Lipid Metabolism; Magnolia; Mice; Oxidative Stress; Plant Bark; Polyphenols; Treatment Outcome

Arctigenin (AR) and its glycoside, arctiin, are two major active ingredients of Arctium lappa L (A lappa), a popular medicinal herb and health supplement frequently used in Asia. In the past several decades, bioactive components from A lappa have attracted the attention of researchers due to their promising therapeutic effects. In the current article, we aimed to provide an overview of the pharmacology of AR and arctiin, focusing on their anti-inflammatory effects, pharmacokinetics properties and clinical efficacies. Compared to acrtiin, AR was reported as the most potent bioactive component of A lappa in the majority of studies. AR exhibits potent anti-inflammatory activities by inhibiting inducible nitric oxide synthase (iNOS) via modulation of several cytokines. Due to its potent anti-inflammatory effects, AR may serve as a potential therapeutic compound against both acute inflammation and various chronic diseases. However, pharmacokinetic studies demonstrated the extensive glucuronidation and hydrolysis of AR in liver, intestine and plasma, which might hinder its in vivo and clinical efficacy after oral administration. Based on the reviewed pharmacological and pharmacokinetic characteristics of AR, further pharmacokinetic and pharmacodynamic studies of AR via alternative administration routes are suggested to promote its ability to serve as a therapeutic agent as well as an ideal bioactive marker for A lappa.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Arctium; Cell Line, Tumor; Diabetic Nephropathies; Furans; Glucosides; Humans; Lignans; Neuroprotective Agents; Pancreatic Neoplasms

Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus; Diabetic Nephropathies; Eucommiaceae; Lignans; Molecular Docking Simulation; NF-E2-Related Factor 2; Rats; Tandem Mass Spectrometry

More effective treatments for diabetic nephropathy remain a major unmet clinical need. Increased oxidative stress is one of the most important pathological mechanisms that lead to kidney damage and functional impairment induced by diabetes. Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase and critically regulates cellular reactive oxygen species (ROS) production and detoxification. Honokiol is a natural biphenolic compound that, by activating mitochondrial SIRT3, can carry out anti-oxidant, anti-inflammatory and anti-fibrotic activities. Here, we sought to investigate the renoprotective effects of honokiol in BTBR ob/ob mice with type 2 diabetes. Diabetic mice were treated with vehicle or honokiol between the ages of 8 and 14 weeks. Wild-type mice served as controls. Renal Sirt3 expression was significantly reduced in BTBR ob/ob mice, and this was associated with a reduction in its activity and increased ROS levels. Selective activation of SIRT3 through honokiol administration translated into the attenuation of albuminuria, amelioration of glomerular damage, and a reduction in podocyte injury. SIRT3 activation preserved mitochondrial wellness through the activation of SOD2 and the restoration of PGC-1α expression in glomerular cells. Additionally, the protective role of SIRT3 in glomerular changes was associated with enhanced tubular Sirt3 expression and upregulated renal Nampt levels, indicating a possible tubule-glomerulus retrograde interplay, which resulted in improved glomerular SIRT3 activity. Our results demonstrate the hitherto unknown renoprotective effect of SIRT3 against diabetic glomerular disease and suggest that the pharmacological modulation of SIRT3 activity is a possible novel approach to treating diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents; Antioxidants; Biphenyl Compounds; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Kidney Glomerulus; Lignans; Male; Mice; Mice, Obese; Mitochondria; Nicotinamide Phosphoribosyltransferase; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Podocytes; Reactive Oxygen Species; Sirtuin 3; Superoxide Dismutase

Transforming growth factor-β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFβ1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the

Topics: Animals; Base Sequence; Diabetic Nephropathies; Disease Progression; DNA; Furans; Humans; Lignans; Male; Mesangial Cells; Mice, Inbred C57BL; NF-E2-Related Factor 2; Promoter Regions, Genetic; Protein Binding; Transcription, Genetic; Transforming Growth Factor beta1; Up-Regulation; YY1 Transcription Factor

Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduced proteinuria in diabetic patients. However, whether ATG specifically provides renoprotection in DKD is not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2 A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression.

Topics: Animals; Arctium; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Progression; Furans; Humans; Lignans; Male; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Nitric Oxide Synthase Type III; Podocytes; Protein Phosphatase 2; Streptozocin; Treatment Outcome

Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients, with inflammation and oxidative stress implicated as crucial pathogenic factors. There is an urgent need to develop effective therapeutic drug. Natural medicines are rich resources for active lead compounds. They would provide new opportunities for the treatment of DN. The present study was designed to investigate the protective effects of Schisandrin B (SchB) on DN and to delineate the underlying mechanism. Oral administration of SchB in the diabetic mouse model significantly alleviated hyperglycemia-induced renal injury, which was accompanied by maintenance of urine creatinine and albumin levels at similar to those of control non-diabetic mice. Histological examination of renal tissue indicated that both development of fibrosis and renal cell apoptosis were dramatically inhibited by SchB. The protective effect of SchB on DN associated with suppression of inflammatory response and oxidative stress. These results strongly suggested that SchB could be a potential therapeutic agent for treatment of DN. Moreover, our findings provided a fuller understanding of the regulatory role of NF-κB and Nrf2 in DN, indicating that they could be important therapeutic targets.

Topics: Animals; Cyclooctanes; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Inflammation; Lignans; Mice; Mice, Inbred C57BL; Molecular Conformation; Oxidative Stress; Polycyclic Compounds; Reactive Oxygen Species; Streptozocin

Diabetic nephropathy (DN) is one of the most serious long-term complications of type 2 diabetes (T2D). 4-O-methylhonokiol (MH) is one of the biologically active ingredients extracted from the Magnolia stem bark. In this study, we aim to elucidate whether treatment with MH can ameliorate or slow-down progression of DN in a T2D murine model and, if so, whether the protective response of MH correlates with AMPK-associated anti-oxidant and anti-inflammatory effects. To induce T2D, mice were fed normal diet (ND) or high fat diet (HFD) for 3 months to induce insulin resistance, followed by an intraperitoneal injection of STZ to induce hyperglycemia. Both T2D and control mice received gavage containing vehicle or MH once diabetes onset for 3 months. Once completing 3-month MH treatment, five mice from each group were sacrificed as 3 month time-point. The rest mice in each group were sacrificed 3 months later as 6 month time-point. In T2D mice, the typical DN symptoms were induced as expected, reflected by increased proteinuria, renal lipid accumulation and lipotoxic effects inducing oxidative stress, and inflammatory reactions, and final fibrosis. However, these typical DN changes were significantly prevented by MH treatment for 3 months and even at 3 months post-MH withdrawal. Mechanistically, MH renal-protection from DN may be related to lipid metabolic improvement and oxidative stress attenuation along with increases in AMPK/PGC-1α/CPT1B-mediated fatty acid oxidation and Nrf2/SOD2-mediated anti-oxidative stress. Results showed the preventive effect of MH on the renal oxidative stress and inflammation in DN.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet, High-Fat; Enzyme Activation; Fatty Acids; Insulin Resistance; Kidney; Lignans; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Phytotherapy

Diabetic nephropathy (DN) is the most common complication of diabetes mellitus. Endoplasmic reticulum (ER) plays an important role in the development and progression of DN. Arctigenin (ATG), a lignan extract from Fructus Arctii, exhibits anti-inflammatory, anticarcinogenic, anti-oxidative stress and immunomodulatory properties. The present research aimed to investigate whether ATG could protect against diabetes-related renal injury and inhibit ER stress in db/db mice.. Male db/db mice were randomly divided into two groups: DN group and ATG treatment group (DN + ATG). db/m mice were defined as the normal control group (NC). ATG was dissolved in 0.5% carboxymethyl cellulose sodium salt solution and administered orally at a dose of 80 mg/kg to mice in the DN + ATG group once daily for 8 consecutive weeks. HK2 cells were used to determine the effects of ATG on ER stress and cell apoptosis in vitro.. ATG administration significantly reduced blood glucose, urine albumin excretion, and urine albumin to creatinine ratio, and attenuated renal pathological injury when compared with untreated db/db mice. These changes were accompanied by decreased expression of both ER stress-related markers and caspase 12 level in the kidneys of db/db mice. In vitro, high glucose activated ER stress signal transduction pathway and induced cell apoptosis in HK2 cells, which were blocked by ATG.. Our results suggest that ATG exerts renoprotective effects on diabetes-related renal injury in db/db mice and cytoprotective effects on high glucose induced cell apoptosis and inhibits ER stress.

Topics: Animals; Apoptosis; Arctium; Cell Culture Techniques; Cell Line; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endoplasmic Reticulum Stress; Epithelial Cells; Furans; Humans; Hypoglycemic Agents; Kidney; Lignans; Male; Mice, Inbred C57BL

Glomerular hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy (DN). High glucose-induced oxidative stress is implicated in the etiology of DN. This study aims to investigate the effect of eleutheroside E (EE) on high glucose mediated rat mesangial cells (MCs) proliferation and monocyte chemoattractant protein-1 (MCP-1) expression and the underlying mechanism. MCs proliferation was assessed by MTT assay. Reactive oxygen species (ROS) level and MCP-1 expression were evaluated by ELISA kit. The protein expression of p47, NF-κB p65, p-NF-κB p65, IκBα, p-IκBα, IKKβ and p-IKKβ were determined by Western blot. The results showed that treatment with EE markedly attenuated high glucose induced MCs proliferation and in a dose-dependent manner. Intervention with EE also significantly blocked high glucose induced intracellular ROS production by decreasing NADPH oxidase activity. Meanwhile, EE administration could effectively alleviate the high glucose-stimulated activation of NF-κB, the degradation of IκBα and the expression of MCP-1. These results demonstrate that high glucose enhances MCs proliferation and MCP-1 expression by activating the ROS/NF-κB pathway and can be inhibited by EE. Our findings provide a new perspective for the clinical treatment of DN.

Topics: Animals; Cell Proliferation; Chemokine CCL2; Diabetic Nephropathies; Disease Models, Animal; Gene Expression Regulation; Glucose; Glucosides; Humans; I-kappa B Proteins; Lignans; Mesangial Cells; NADPH Oxidases; NF-kappa B; NF-KappaB Inhibitor alpha; Rats; Reactive Oxygen Species; Signal Transduction; Transcription Factor RelA

Euryale ferox seed is consumed medicinally or for food in China. The present study revealed it to contain significant antioxidant activity, which may be associated with its medical applications as a proteinuria inhibitor of diabetic nephropathy. This study resulted in the identification of 3 new sesquineolignans, named euryalins A-C (1-3), and 16 known compounds, which were all first isolated from this plant apart from 5,7,4-trihydroxy-flavanone. The antioxidant potential of the partial isolates was evaluated using the DPPH radical scavenging assay and mesangial cellular assay. Compounds 2, rel-(2α,3β)-7-O-methylcedrusin (4), syringylglycerol-8-O-4-(sinapyl alcohol) ether (5), and (+)-syringaresinol (7) were found to be most active on DPPH assay, whereas compounds 2, 4, 7, (1R,2R,5R,6S)-2-(3,4-dimethoxyphenyl)-6-(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, and buddlenol E could significantly inhibit high glucose-stimulated reactive oxygen species production in mesangial cells. The results suggested that E. ferox seed could be considered as an excellent source of natural antioxidants and is useful in the prevention of diabetic nephropathy.

Topics: Animals; Antioxidants; Biphenyl Compounds; Cell Line; Diabetic Nephropathies; Glomerular Mesangium; Glucose; Lignans; Nymphaeaceae; Phytotherapy; Picrates; Plant Extracts; Proteinuria; Rats; Reactive Oxygen Species; Seeds

We investigated the effect of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl), a marker compound isolated from the cortex of Magnolia officinalis, in non-obese type 2 diabetic Goto-Kakizaki (GK) rats. The rats were treated orally with magnolol (100 mg/kg body weight) once a day for 13 weeks. In magnolol-treated GK rats, fasting blood glucose and plasma insulin were significantly decreased, and the pancreatic islets also showed strong insulin antigen positivity. Urinary protein and creatinine clearance (Ccr) were significantly decreased. Pathological examination revealed the prevention of the glomeruli enlargement in magnolol-treated GK rats. The overproduction of renal sorbitol, advanced glycation endproducts (AGEs), type IV collagen, and TGF-beta1 mRNA were significantly reduced in magnolol-treated GK rats. Thus based on our findings, the use of magnolol could result in good blood glucose control and prevent or retard development of diabetic complications such as diabetic nephropathy.

Topics: Animals; Biphenyl Compounds; Blood Glucose; Collagen Type IV; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycation End Products, Advanced; Hypoglycemic Agents; Immunohistochemistry; Insulin; Islets of Langerhans; Kidney Cortex; Lignans; Magnolia; Male; Plant Bark; Plant Roots; Proteinuria; Rats; Rats, Inbred Strains; Sorbitol; Transforming Growth Factor beta1