Article:New Insights into the Mechanisms of Chinese Herbal Products on Diabetes: A Focus on the "Bacteria-Mucosal Immunity-Inflammation-Diabetes" Axis. (5661076)

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Journal Information

Title: Journal of Immunology Research

New Insights into the Mechanisms of Chinese Herbal Products on Diabetes: A Focus on the “Bacteria-Mucosal Immunity-Inflammation-Diabetes” Axis

  • Zezheng Gao
  • Qingwei Li
  • Xuemin Wu
  • Xuemin Zhao
  • Linhua Zhao
  • Xiaolin Tong

1Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100054, China

2Shenzhen Hospital, Guangzhou University of Chinese Medicine, Guangzhou 518034, China

3Laboratory of Molecular Biology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China

Publication date (ppub): /2017

Publication date (epub): 10/2017

Abstract

Diabetes, especially type 2, has been rapidly increasing all over the world. Although many drugs have been developed and used to treat diabetes, side effects and long-term efficacy are of great challenge. Therefore, natural health product and dietary supplements have been of increasing interest alternatively. In this regard, Chinese herbs and herbal products have been considered a rich resource of product development. Although increasing evidence has been produced from various scientific studies, the mechanisms of action are lacking. Here, we have proposed that many herbal monomers and formulae improve glucose homeostasis and diabetes through the BMID axis; B represents gut microbiota, M means mucosal immunity, I represents inflammation, and D represents diabetes. Chinese herbs have been traditionally used to treat diabetes, with minimal side and toxic effects. Here, we reviewed monomers such as berberine, ginsenoside, M. charantia extract, and curcumin and herbal formulae such as Gegen Qinlian Decoction, Danggui Liuhuang Decoction, and Huanglian Wendan Decoction. This review was intended to provide new perspectives and strategies for future diabetes research and product.

Paper

1. Introduction

In July 2015, the International Diabetes Federation (IDF) released the seventh edition of “IDF diabetes map,” which showed that China had approximately 1.096 million diabetes cases in 2015, ranking the highest in the world. According to the current development trend, the number of diabetes cases in China is projected to reach 150.7 million in 2040. The incidence of diabetes is estimated to increase by 69% in developing countries and 20% in developed countries from 2010 to 2030. Thus, schemes in preventing and treating diabetes are warranted. Currently, Chinese herbs for the prevention and treatment of diabetes and its minimal complications are considered advantageous, and a large number of evidence-based clinical studies have confirmed these effects [[1][7]].

Modern medical technology provides a new way and direction for the prevention and treatment of diabetes. Chinese herbs have been historically and traditionally used in the treatment of diabetes, which dates back to the Qin dynasty (221 to 207 BC). Globalization and progress in medical science rejuvenate the ancient Chinese herbs, and an increasing number of studies have shown that various specific monomers and Chinese formulae can be used in the prevention and treatment of diabetes through the “Bacteria-Mucosal Immunity-Inflammation-Diabetes” axis (BMID axis). We retrieved the literature and screened out more than 40 relevant Chinese herbs and its derivatives that have been used to treat diabetes regulating multiple targets. We have chosen some of them which have been widely studied and characterized, including monomers and prescriptions. The specific monomers include berberine, M. charantia extract, ginsenoside, and curcumin, and prescriptions include Gegen Qinlian Decoction (GGQLD), Danggui Liuhuang Decoction (DGLHD), and Huanglian Wendan Decoction (HLWDD). Here, we attempt to explore the possible mechanisms of action of these in diabetic treatment from the perspective of immunology and provide potentially novel therapeutic strategies that may improve clinical treatment on diabetes.

2. New Insights into Diabetes: “Bacteria-Mucosal Immunity-Inflammation-Diabetes” Axis

The gut microbiota represents a microbial community located in the intestine, composed of over a trillion microorganisms with hundreds of species, which play an important role in digestion and intestinal mucosal immunity. There is increasing evidence that confirms that the changes in gut microbiota are associated with insulin resistance and diabetes.

2.1. Diabetes Is Associated with Imbalance of Gut Microbiota

In mice and humans, there are two main bacterial phyla, Bacteroidetes and Firmicutes, which are found in the gut through metagenomic analysis [[8]]. The normal mice keep a relative balance among these two bacterial phyla, but the bacterial phylum Firmicutes is increased in obese mice observably [[9]]. A study has shown that a high-fat diet (HFD) can reduce the number of Bifidobacterium species (spp.), resulting in the development of endotoxemia and diabetes; an oligosaccharide-rich diet increases the number of Bifidobacterium species (spp.) and subsequently reduces the level of inflammation and improves glucose intolerance [[10]]. The metagenomic analysis revealed that patients with type 2 diabetes had moderate levels of gut microbiota dysbiosis, characterized by the decrease in the abundance of some universal butyrate-producing bacteria and the increase in the abundance of some bacteria which reduce sulfate and antioxidant stress [[11]]. A human study showed that the number of Faecalibacterium prausnitzii, which was associated with the production of short-chain fatty acids and butyrate, is increased [[12]]. Gut microbiota of diabetic patients and mice changed significantly, indicating that reversing this change may reduce the incidence of insulin resistance and diabetes.

2.2. Disorder of Mucosal Immunity Leads to Diabetes

Gut microbiota affects insulin resistance and type 2 diabetes mellitus (T2DM) by altering the intestinal epithelial barrier and intestinal mucosal immunity. The main function of the intestinal epithelial barrier is to limit intestinal contents such as water, chyme, and gut microbiota and also to regulate immune responses. The epithelial barrier needs a continuous epithelial cell layer, and the tight junctions are the major characteristic. The tight junctions consist of a complex network of transmembrane proteins, cytoplasmic proteins, and regulatory proteins. There are two pathways: “pore” and “leak”. The “pore” pathway is a high-capacity, size-selective, and charge-selective route, and the “leak” pathway refers to a low-capacity pathway that has limited selectivity [[13]]. In HFD-induced mice, intestinal bacteria or bacterial products cause the elevation of tumor necrosis factor (TNF) and interleukin- (IL-) 13. These inflammatory factors increase transcription and activity of the myosin light-chain kinase (MLCK) and IL-13-dependent claudin-2 and subsequently increase permeability of “pore” and “leak” pathways and the pass of lipopolysaccharide (LPS) [[14][16]]. This change leads to an increase in chronic inflammation in the liver, fat, and other tissues and other metabolic diseases. In addition to the intestinal bacterial products, the gut microbiota can also directly pass the intestinal barrier and translocate to the pancreatic lymph nodes, activate NOD-like receptors 2 (NOD2), and contribute to diabetes [[17]].

The intestinal mucosal immunity is the most important line of defense against intestinal infection through the functions of goblet cells, intestinal epithelial cells (IEC), innate lymphoid cells (ILC), and other rapid responsive immune cells, such as macrophages and neutrophils. The goblet cells and IEC can produce antimicrobial peptides (AMPs) and mucin to prevent pathogens from penetrating the intestine [[18]]. IEC can secrete anti-inflammatory mediators such as IL-25, IL-33, and transforming growth factor-β (TGF-β). These mediators can influence micro-associated molecular patterns (MAMPs) by binding to Toll-like receptors 5 (TLR5) and NOD2. ILC inhibits the body's chronic low-level inflammation through the secretion of IL-22, IL-17A, IL-17F, and so forth [[19]]. HFD can reduce the diversity and alter the distribution balance of gut microbiota and thus reduce the production of mucin and other antimicrobial factors. Invasive bacteria and the associated products alter the intestinal mucosal immunity, and that contributes to the development of T2DM [[20]].

2.3. Inflammation Affects Diabetes through Multiple Pathways

The alternation of intestinal mucosal immunity and increased production of inflammatory factors have been considered to be linked to the development of T2DM. The pathophysiological processes are proposed to mainly include three pathways: (1) The nuclear factor kappa-B (NF-κB) pathway are activated by the inhibitor of nuclear factor kappa-B kinase (IKK) and proinflammatory cytokines such as TNF-α, IL-1, and IL-6. The activated IKK and proinflammatory cytokines phosphorylate the inhibitor of NF-κB (IκB). When IκB is phosphorylated, IκB and NF-κB are dissociated, resulting in NF-κB degradation. Then, NF-κB enters the nucleus, thereby mediating the expression of a variety of inflammatory genes [[21], [22]]. (2) IKK regulates insulin receptor substrate serine/threonine phosphorylation, interfering with normal tyrosine phosphorylation and weakening the insulin signal transduction. IKK is currently considered the link between inflammation and insulin resistance (IR). TNF-α and free fatty acid (FFA) activate Jun N-terminal kinase (JNK) and product insulin receptor substrate number 307 serine, which interferes with the insulin signal transduction via the IR/IRS/PI3K pathway. (3) The SOCS family of the cytokine signaling factor (SOCS) pathway mediates cytokine-induced IR. SOCS-1, SOCS-3, and SOCS-6 are involved, which predominantly inhibit the phosphorylation of IRS1 and IRS2 tyrosine residues and accelerate the degradation of IRS1 and IRS2 [[23], [24]].

2.4. “Bacteria-Mucosal Immunity-Inflammation-Diabetes” Axis

It has been shown that gut microbiota affects the intestinal epithelial barrier and intestinal mucosal immunity, alters the level of inflammation, and influences insulin resistance and diabetes. This potential pathogenesis of diabetes is referred to as the “BMID” axis, “B” represents gut microbiota, “M” represents mucosal immunity, “I” represents inflammation, and of course, “D” represents diabetes. This axis is like a “line” to string most antidiabetic agents together and may provide new perspectives and strategies for future research on diabetes and the development of hypoglycemic drugs.

3. Herbal Monomers

Herbal monomers are major effective constituents of Chinese herbs. Studies on monomers are increasing in recent years, because they have specific molecular structure and are easier to be used in mechanism research and observing effective targets of Chinese herbs. Here, we screened out five representative monomers to find out their different functions based on the BMID axis. They have been widely researched and applied in treating diabetes for a long time.

3.1. Berberine

Rhizoma coptidis has been used for centuries in traditional Chinese medicine (TCM) as an antipyretic and alexipharmacons, and its main active component is berberine (BBR, Figure 1) [[25]]. BBR is an isoquinoline and found in many plants of the berberidaceae family. Recent studies have shown that BBR and its derivatives possess a variety of disease-fighting activities, they regulate the immune system, inhibit inflammation, and reduce insulin resistance [[26], [27]], and they have an anticancer effect likewise; it was reported that BBR inhibits the progression of pancreatic, colon, and breast cancer [[28][31]].

3.1.1. Effect of BBR on Diabetes

Insulin resistance (IR) is a metabolic state in which insulin inefficiently regulates the tissue and cell for their uptake and utilization of glucose. Nod-like receptor family pyrin domain containing 3 (NLRP3) contributes to obesity-induced inflammation and insulin resistance [[32]]. A recent study showed that BBR inhibited saturated fatty acid palmitate- (PA-) induced activation of NLRP3 and release of interleukin-1β (IL-1β) in macrophages by activating AMPK-dependent autophagy, thus reducing inflammation and insulin resistance [[26]]. An animal study showed that BBR reduced blood TNF-α, IL-6, and MCP-1 levels of JNK and IKKβ phosphorylation in obese mice fed with a high-fat diet, as well as indicated that BBR improves insulin resistance possibly through inhibiting the activation of macrophages in adipose tissue [[33]].

3.1.2. Effect of BBR on Gut Microbiota and Intestinal Mucosal Immunity

Intestinal barrier integrity and immune tolerance are associated with the pathogenesis of diabetes. Defects in the integrity of the mucosal barriers and leakage of the gut microbiome can contribute to the low-grade inflammation of tissues, which is well known to be associated with glucose metabolism in the muscle, liver, and adipose tissue and causes glucose intolerance and T2DM [[17], [34]]. Recent studies have shown that BBR imparts beneficial effects on the immune cells of the intestinal immune system and influences the expression of intestinal immune factors. It also inhibits the expression of IL-1β, IL-4, IL-10, MIF, and TNF-α mRNA and reduces the low-grade inflammation [[35]].

Intestinal microflora is an important factor in mediating the development of obesity-related metabolic disorders (including type 2 diabetes). The current results suggest that BBR can regulate the intestinal microflora, restore the intestinal barrier, reduce metabolic endotoxemia and systemic inflammation, and improve gut peptide levels in high-fat diet-fed rats; it indicates that BBR is possibly an effective agent for the treatment of obesity and diabetes [[36]]. A study showed that BBR improved metabolic disorders induced by high-fat diets by modulating the gut-intestinal-brain axis, including changes in the distribution and diversity of microbes, elevation of serum glucagon-like peptide-1 and neuropeptide Y, decrease in orexin A, and upregulation of glucagon-like peptide-1 receptor mRNA [[37]].

3.1.3. BBR Reduces Inflammatory Response in Diabetes Mellitus

The anti-inflammatory activity of BBR has been observed in in vitro and in vivo studies. In immunocytes (macrophages) [[26], [38]], cultured metabolic cells (adipocytes and hepatocytes) [[39], [40]], or pancreatic β cells [[41]], BBR treatment reduces the production of TNF-α, IL-6, IL-1β, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), matrix metalloprotease 9 (MMP9), monocyte chemoattractant protein-1 (MCP-1), and CRP and haptoglobin (HP) increases the transcription of Nrf2-targeted antioxidative genes [NADPH quinone oxidoreductase-1 (NQO-1), heme oxygenase-1 (HO-1)] [[37][41]]. The insulin-sensitizing effect of HepG2 cells is closely related to its anti-inflammatory activity. BBR administration significantly decreased serine phosphorylation and increased tyrosine phosphorylation of IRS in HepG2 cells, which improved insulin signaling and thus in turn ameliorated insulin resistance [[40]]. BBR inhibited inflammation, ameliorated insulin resistance, and reduced the production of proinflammatory cytokines such as IL-6, IL-17, TNF-α, and interferon-γ (IFNγ) in NOD mice [[42], [43]]. Furthermore, BBR increased the ratios of anti-inflammatory/proinflammatory cytokines, such as IL-10/IL-6, IL-10/IL-1β, and IL-10/TNF-α [[43]].

3.2. M. charantia

M. charantia, also known as bitter melon, has been used for centuries in TCM as an antipyretic and alexipharmacon herb. Recent studies have shown that M. charantia can ameliorate oxidative stress, hyperlipidemia [[44]], inflammation [[45]], and apoptosis [[46]]. It also regulates glucose metabolism by acting as a “plant insulin” [[47]] and presents antidiabetic and antioxidant activities [[48]].

3.2.1. Effect of M. charantia on Diabetes

Momordica charantia (M. charantia) is a widely used traditional remedy for diabetes. It has been proven to be beneficial to insulin resistance, prediabetes, weight losing, and glycemic control in cultured cells, animal models, and human studies [[49]]. M. charantia can repair damaged beta cells, increase insulin levels, and also enhance insulin sensitivity. It inhibits the intestinal glucose absorption by inhibiting glucosidase and enterotoxin activities. It also stimulates the synthesis and release of thyroid hormones and adiponectin and enhances the activity of AMP-activated protein kinase (AMPK) [[50]]. A recent study showed that compared with metformin, the application of M. charantia in diabetes patients had lower probability of hypoglycemia although it is less effective than metformin in lowering blood glucose [[51]]. In addition, M. charantia has a superposition effect when taken with other hypoglycemic agents at the same time, and thus, patients may achieve better management of blood glucose [[52]]. M. charantia also reduces the obesity of rats fed with a high-fat diet [[53], [54]].

3.2.2. M. charantia Changes Gut Microbiota

The effect of M. charantia on intestinal flora and inflammation has been reported in obese rats fed with high-fat diets. A result showed that although the exact effect of M. charantia on intestinal flora was not yet known, the intestinal flora is considered to play an important role through which M. charantia improves obesity and metabolic diseases (including diabetes) and is worth the sustained attention [[54]]. It was reported that BLSP (a bitter melon formulation) treatment reduced the ratio of Firmicutes and Bacteroidetes in the intestinal microflora of diabetic rats, while the relative abundance of Ruminococcaceae, Bacteroides, and Ruminococcus was significantly lower in BLSP-treated rats than in diabetic rats. These demonstrate that BLSP can alter the proportion of specific intestinal microflora in diabetic rats [[55]].

3.2.3. M. charantia Reduces Inflammatory Response in Diabetes Mellitus

M. charantia possesses antioxidant activities; it enhances the activity of superoxide dismutase, catalase, and nonprotein sulfhydryls and decreases lipid peroxidation. Moreover, M. charantia can inhibit the expression of proinflammatory cytokines (TNF-α, IL-6, and IL-10), inflammatory markers (NO, inducible nitric oxide synthase, and myeloperoxidase), and apoptotic markers (BAX and caspase-3) and upregulate Bcl-2 expression [[46]]. By suppressing the activation of NF-κB by inhibiting NF-κB alpha (IκBα) degradation and phosphorylation of JNK/p38 mitogen-activated protein kinases (JNK/p38 MAPKs), M. charantia can inhibit inflammation and improve the insulin signaling pathway, thereby ameliorating insulin resistance [[54]]. M. charantia has been reported to inhibit inflammation and the development of diabetes mellitus in rats and mice [[54], [56]]. After weeks of treatment with M. charantia, fasting glucose, insulin, HOMA-IR index, serum lipid levels, fat cell size of epididymal adipose tissues, blood TNF-α, IL-6, and IL-10 levels, and local endotoxin levels decreased in high-fat diet-induced obese rats [[54]]. Further studies have shown that M. charantia lowers mast cell recruitment in epididymal adipose tissues (EAT) and downregulates proinflammatory cytokines monocyte chemotactic protein-1 (MCP-1), IL-6, and TNF-α in EAT [[56]].

3.3. Curcumin

Curcumin is the active component of rhizomes of Curcuma longa, a plant in the ginger family. The chemical structure of curcumin is (1E,6E)-1,7-bis(4-hydroxy-3- methoxyphenyl)hepta-1,6-diene-3,5-dione (Figure 2) [[57]]. Curcumin has been used as medicine for thousands of years. Recent years, extensive research on curcumin has found that curcumin has multiple biological activities, such as anticancer, anti-inflammation, antioxidation, antidiabetes, cardioprotective properties, and antiarthritis [[58]].

3.3.1. Effect of Curcumin on Diabetes

In different experimental animal models, such as rats with alloxan-, streptozotocin- (STZ-), or STZ-nicotinamide-induced diabetes [[59]], oral administration of curcumin resulted in a reduction in body weight, blood glucose, and glycosylated hemoglobin levels [[60]] and improvement of insulin sensitivity [[61]]. In diabetic patients, curcumin treatment lowered blood levels of glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) and improved the pancreatic β cell function, as indicated by homeostasis model assessment-β (HOMA-β), C-peptide, and proinsulin/insulin ratio. Besides, curcumin can reduce the outcome of inflammatory cytokine [[62]] and improve relevant metabolic profiles in type 2 diabetic population [[63]].

3.3.2. Effect of Curcumin on Gut Microbiota and Mucosal Immunity

Curcumin changes the gut microbiota. Through high-throughput sequencing, at the phylum level, Spirochaetae, Tenericutes, and Elusimicrobia were decreased and Actinobacteria was increased after curcumin treatment. At the genus level, curcumin increased the abundance of Collinsella, Streptococcus, Sutterella, Gemella, Thalassospira, Gordonibacter, and Actinomyces [[64]].

Curcumin treatment can increase the protein expression of occludin and zonula occluden-1 (ZO-1), which maintain intestinal tight junction and regulate the permeability of the intestinal epithelial barrier [[16], [65]]. Curcumin treatment also induces differentiation of naive CD4+ T cells into CD4+CD25+Foxp3+ Tregs and IL-10-producing Tr1 cells and increases the secretion of IL-10, TGF-β, and retinoic acid in the intestinal lamina propria [[66]]. Curcumin can also stimulate the intestinal epithelial cells and innate lymphoid cells to increase the secretion of IL-25, IL-33, IL-22, and IL-17 and play a role in anti-inflammatory activity [[67]].

3.3.3. Curcumin Reduces Inflammatory Response in Diabetes

Curcumin suppresses inflammation through complex mechanisms and multiple targets, such as inflammatory cytokines, protein kinases, and transcription factors. Inflammatory cytokines affected by curcumin include interleukins, TNF, IFN, and COX-2. Protein kinases include Janus kinase 1/2 (JAK1/2), JNK, extracellular signal-regulated kinase 1/2 (ERK1/2), IKK, and MAPK. Transcription factors include NF-κB [[58]].

Curcumin can reduce the production of inducible nitric oxide synthase (iNOS) and cyclooxygenase- (COX-) 2 by inhibiting LPS-induced iNOS and COX-2 gene expression [[68]]. iNOS, as an inflammatory signaling factor, mediated inflammation by multiple pathways. Excessive expression of iNOS in cells causes the inflammation and insulin resistance of metabolic organs [[69]]. COX-2 is a key enzyme in the synthesis of prostaglandins, which contributes to low-grade inflammation of tissues. It was found that curcumin exhibited anti-inflammatory activity by inhibiting the JNK/NF-κB activation and the gene expression of TNF-α, IL-10, and IL-6 [[70]].

3.4. Ginsenoside

Panax ginseng has been used for centuries in TCM as an herbal remedy. It is one of the best chosen medical plants to replenish vitality/energy, nourish body fluid, and calm the nerves [[71]]. The active components of ginseng have been identified as a group of saponins called ginsenosides. According to the chemical structure, ginsenosides can be divided into ginseng diol saponins, ginseng triol saponins, and oleanolic acid saponins (Figure 3). Recent studies have shown that Panax ginseng and its monomers have a variety of pharmacologic action such as antioxidation [[72], [73]], antitumor [[74]], anti-inflammation [[75], [76]], immune regulation [[77]], antidiabetes [[78], [79]], and myocardial protection [[80], [81]]. It can improve the immune system; inhibit inflammatory factors; protect cardiac function; lower blood glucose; inhibit rectal, liver, and breast cancers [[74], [82], [83]]; repair neurons; and delay the development of Parkinson's disease and Alzheimer's disease [[84], [85]].

3.4.1. Benefits of Ginsenosides to Diabetes

Studies have shown that ginsenoside Rg1 can improve glucose and lipid metabolisms and reduce blood glucose levels and insulin resistance indices in T2DM rats [[86]]. Ginsenoside Ge can improve hyperglycemia by improving cholinergic and antioxidant systems in the brain of C57BL/6 mice and improve high-fat diet-induced insulin resistance, reducing triglycerides and cholesterol [[72]]. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that play important roles in regulating glucose and lipid metabolisms and the development of atherosclerosis. A clinical study showed that ginsenosides could improve PPARγ expression and lipid metabolism, thereby reducing blood glucose [[87]]. Another study has shown that ginsenoside Rb1 activates the insulin signaling pathway, upregulates the expression and translocation of glucose transporters in adipose tissue, and thus increases glucose uptake in adipocytes, thereby reducing blood glucose levels and improving insulin resistance [[88]].

3.4.2. Ginsenoside Reduces the Inflammatory Response in Diabetes Mellitus

Studies have shown that inflammatory factors such as TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1) interfere with the insulin signal transduction pathway and cause insulin resistance. They can also directly damage pancreatic β cells [[89][92]]. It is reported that ginsenoside Rb1 reduces the expression of TNF-α and MCP-1 in 3T3-L1 cells through regulating the IKK/NF-κB signaling pathway [[93], [94]]. In addition, ginsenoside Rb1 suppresses lipid accumulation and increases the lipolysis in 3T3-L1 adipocytes induced by TNF-α [[94], [95]]. Ginsenoside Rb1 reduced free fatty acids in the blood and fat content, improved lipid metabolism and insulin resistance, and inhibited TNF-α, IL-6, and other inflammatory factors in obese mice [[96][99]].

3.5. Mulberry Leaf Extract (MLE)

1-Deoxynojirimycin (DNJ, Figure 4) and Kuwanon G (KWG, Figure 5) are the effective constituents of mulberry leaf, which belongs to the genus Morus of the Moraceae family. The chemical structure of DNJ is a glucose analogue with an NH group substituting for the oxygen atom of the pyranose ring [[100]]. Mulberry leaf, as a traditional Chinese medicine, has been used to treat fever and inflammation for thousands of years. Recent research revealed that MLE have multiple biological activities, such as antidiabetes, antidyslipidemia, and anticancer [[101]].

3.5.1. Benefits of MLE to Diabetes

It is reported that 1-deoxynojirimycin (DNJ) is an important component of MLE that is beneficial to the diabetes. In rats with STZ- or alloxan-induced diabetes, DNJ treatment markedly reduced blood levels of glucose and glycosylated hemoglobin and prevented the dysfunction of pancreatic β cells [[102], [103]]. A large number of studies have shown that DNJ is a competitive α-glucosidase inhibitor, which is present in the intestinal epithelial cells. The function of this enzyme is to hydrolyze the disaccharides to monosaccharides for absorption. DNJ inhibits the glucose absorption through competitive inhibition of α-glucosidase [[104]]. In db/db mice, DNJ treatment improved insulin resistance via the activation of the insulin signaling PI3K/AKT pathway in skeletal muscle [[100]] and the activation of the PKB/GSK-3β signaling pathway in the liver [[105]].

3.5.2. Effects of MLE on the Intestinal Epithelial Barrier and Inflammation

Kuwanon G (KWG) which is essential in MLE is reported to protect the intestinal epithelial barrier. LPS can cause the disruption of the intestinal epithelial barrier and decrease the expression of intercellular junction protein. KWG treatment can increase the protein expression levels of occludin and intercellular adhesion molecule-1 [[106]].

Mulberry leaf has been used to treat fever and inflammation for thousands of years, and its extract also has anti-inflammatory effects. A study showed that MLE inhibited the expression of inflammatory cytokines IL-I, IL-6, and TNF-α [[107]] and C-reactive protein (CRP) and MLE reduced the production of iNOS [[108]]. The decrease in inflammatory factors is indicative of reduced chronic inflammation and results in the improvement of insulin resistance.

3.6. Other Herbal Monomers

In addition to the five monomers described above, many other monomers are also found to be closely related to the BMID axis, including tetrandrine [[109]], notoginsenoside [[110]], Lycium barbarum polysaccharide [[111]], allicin [[112]], astragaloside IV [[113], [114]], quercetin [[115]], and resveratrol [[116]].

Among these monomers, astragaloside IV [[117]], quercetin [[118]], and resveratrol [[119]] affect gut microbiota, and notoginsenoside [[120]], Lycium barbarum polysaccharide [[121]], and allicin [[122]] affect the function of alleviating intestinal mucosal immunity; the anti-inflammatory monomers are tetrandrine [[123]], Lycium barbarum polysaccharide [[124]], allicin [[125]], astragaloside IV [[126], [127]], quercetin [[128]], resveratrol [[116]], and the effect and possible mechanism of these monomers are summarized in Table 1.

4. Formulae

A formula consists of multiple Chinese herbs, which are selected under the guidance of TCM theory. In the treatment of diabetes, a formula simultaneously affects multiple targets and regulates the homeostasis, and thus, the application of formulae attracted more focus. But the mechanism research of formulae is limited. The BMID axis will provide a new perspective and make it easier for further studies.

4.1. Gegen Qinlian Decoction (GGQLD)

GGQLD has a very long history as a TCM formula, with the earliest record being found in the book Treatise on Febrile and Miscellaneous Diseases compiled by Zhongjing Zhang. GGQLD consists of extracts of Gegen (Puerariae lobataeradix), Huangqin (Scutellariae radix), Huanglian (Coptidis rhizoma), and Zhigancao (Glycyrrhizae radix et Rhizoma Praeparata cum Melle) [[129]]. In clinic, GGQLD is often used to treat ulcerative colitis and diabetes. Studies showed that GGQLD inhibits the inflammatory signaling pathway, enhances antioxidant effect, and thus improves ulcerative colitis. In addition, GGQLD improves glucose metabolism disorder, increases the insulin sensitivity index, and protects pancreatic β cells, playing a positive role in the treatment of diabetes [[130][132]].

4.1.1. GGQLD Improves Diabetes

In some clinical observations and animal trials, GGQLD has been reported to have beneficial effects on diabetes. For example, in STZ- and HFD-induced diabetic SD rats, GGQLD significantly reduced FBG, HbA1c, and insulin resistance index. In 3T3-L1 adipocytes, GGQLD at 4%, 8%, and 16% was found to increase glucose consumption and decrease triglyceride in a dose-dependent manner [[131]]. In an observational study, T2DM patients treated with a high dose of modified GGQLD reduced blood HbA1c to 1.79% from the initial level of 9.2% [[4]]. Although limited, available information has demonstrated that GGQLD is beneficial to glucose metabolism and homeostasis.

4.1.2. GGQLD Alters Gut Microbiota

There is an established connection between an altered gut microbiota and metabolic disorders such as obesity and diabetes [[133], [134]]. After treatment with GGQLD, the relative abundance of intestinal beneficial bacteria such as Lachnospiracea incertae sedis, Gemmiger, Bifidobacterium, and Faecalibacterium was significantly higher while harmful bacteria such as F. prausnitzii, Alistipes, Pseudobutyrivibrio, and Parabacteroides decreased. GGQLD increases butyrate production and protects the integrity of the mucosal barriers, thereby exerting anti-inflammatory effects which are beneficial to diabetes [[135]]. A study showed that GGQLD induces compositional changes in the intestinal microflora, increases beneficial bacteria, such as Faecalibacterium spp., and thus exerts an antidiabetic effect [[135]].

4.2. Danggui Liuhuang Decoction (DGLHD)

DGLHD is an old Chinese herbal formula which comes from the book Lan Shi Mi Cang written by Gao Li 741 years ago. DGLHD prescription consists of Dangui (Angelica sinensis), Shengdihuang (Radix rehmanniae preparata), Huangqin (Radix scutellariae), Huanglian (Rhizoma coptidis), Huangbo (Cortex phellodendri), and Huangqi (Radix astragali). Researches indicate that DGLHD decreases FBG and HbA1c levels and protects pancreatic β cells [[136]].

Recent studies have demonstrated that DGLHD possesses antidiabetic and immunomodulatory effects. For instance, DGLHD enhances glucose uptake in HepG2 cells, inhibits T lymphocyte proliferation, and suppresses the function of dendritic cells. After 16 weeks of treatment, DGLHD promotes insulin secretion, increases insulin sensitivity, and decreases the range of lymphocyte infiltration to inhibit insulitis as well as to protect pancreatic β cells in NOD mice [[137]].

DGLHD inhibited LPS-induced production of NO and IL-6 and the expression of iNOS and COX-2. Furthermore, DGLHD suppressed LPS-induced phosphorylation of ERK1/2 [[138]]. CD4+CD25+Foxp3+ Tregs exhibit immune regulatory activity and protect against autoimmune diabetes development. With oral intake of DGLHD, forkhead box transcription factor (Foxp3) mRNA expression in the pancreas and spleen increased. Foxp3 is essential for the differentiation and function of Tregs; thus, DGLHD increases the percentage of CD4+CD25+Foxp3+ Tregs in spleen lymphocytes, therefore inhibiting the low-grade inflammation in the pancreas. DGLHD also regulates the maturation and function of dendritic cells, increasing the expression of programmed death ligand-1 and decreasing the percentage of merocytic dendritic cell subset, which in turn decreases T cell-mediated inflammation and ameliorates diabetes [[137]].

4.3. Huanglian Wendan Decoction (HLWDD)

HLWDD is a Chinese herbal formula recorded in the book Liu Yin Tiao Bian [[139]]. It consists of root and rhizome of Coptis deltoidea C. Y. Cheng & P. K. Hsiao (family: Ranunculaceae), cortex of Bambusa textilis McClure (family: Poaceae), caulis of Pinellia ternata (Thunb.) Makino (family: Araceae), fructus of Citrus aurantium L. (family: Rutaceae), pericarpium of Citrus reticulata Blanco (family: Rutaceae), dried sclerotia of Poria cocos (Schw.) Wolf (family: Polyporaceae), root and rhizome of Glycyrrhiza uralensis Fisch (family: Leguminosae), and root and rhizome of Zingiber officinale Roscoe (family: Zingiberaceae). It has been used clinically to treat diabetes and its complications [[140]].

A recent study showed that treatment with HLWDD (6 g·kg−1 body weight) for 30 days increased the body weight and decreased FBG, triglycerides, and cholesterol compared with the diabetic model group. HLWDD decreases the release of proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β, and inhibits the phosphorylation of IRS1 at the Ser307 and JNK signal pathway. Through these mechanisms, HLWDD inhibits inflammatory responses and thus improves the insulin signaling pathway [[141]].

5. Conclusions

Diabetes and its complications seriously affect human health and impose increasingly a heavy burden on the health care in many countries. Chinese herbs are inexpensive, less toxic, and tolerable than drugs. Therefore, they have been attracting increased attention in the field of diabetic prevention and treatment. Although clinical efficacy of Chinese herbs or herbal formulae is supported by emerging evidence, the mechanism is still lacking.

Through the analysis of a large number of studies on diabetic pathogenesis and treatment, we proposed the “Bacteria-Mucosal Immunity-Inflammation-Diabetes” (BMID) axis through which we attempted to explain how herbal monomers and formulae improve diabetes. Evidence has demonstrated that monomers and formulae improve diabetes and insulin function via multiple targets. Moreover, the majority of the current studies of TCM on diabetes were focused on inflammation and limited gut microbiota and intestinal mucosal immunity. Furthermore, most studies were aimed to a single target.

Functional food and natural health products have been of great interest to patients, doctors, and researchers for over a decade. Chinese herbs and herbal products are critical and a rich resource of information for the development of health products and precision medicine. Although increasing scientific evidence has been generated from clinical, preclinical, and in vitro studies, the information is still limited and lacks systemic evaluation. The mechanisms of action are particularly a weak area that needs an increased attention. BMID is our first attempt to integrate information and results of various studies and inspire a focus of future direction at which future studies can be conducted to support and improve it. We hope that this review will provide new perspectives and strategies for future research on Chinese herbal products for the prevention and treatment of diabetes and further product development.

References

  1. Y. ZhangX. LiD. ZouTreatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberineThe Journal of Clinical Endocrinology and Metabolism20089372559256510.1210/jc.2007-24042-s2.0-4754910086418397984
  2. L. JiX. TongH. WangEfficacy and safety of traditional Chinese medicine for diabetes: a double-blind, randomised, controlled trialPLoS One20138210.1371/journal.pone.00567032-s2.0-8487451210323460810
  3. X. L. TongS. T. WuF. M. LianThe safety and effectiveness of TM81, a Chinese herbal medicine, in the treatment of type 2 diabetes: a randomized double-blind placebo-controlled trialDiabetes, Obesity & Metabolism201315544845410.1111/dom.120512-s2.0-8487634268923231379
  4. X. L. TongL. H. ZhaoF. M. LianClinical observations on the dose-effect relationship of Gegen Qin Lian decoction on 54 out-patients with type 2 diabetesJournal of Traditional Chinese Medicine2011311565921563509
  5. B. GodmanR. E. MalmströmE. DiogeneAre new models needed to optimize the utilization of new medicines to sustain healthcare systems?Expert Review of Clinical Pharmacology201581779410.1586/17512433.2015.9903802-s2.0-8491693188025487078
  6. J. E. ShawR. A. SicreeP. Z. ZimmetGlobal estimates of the prevalence of diabetes for 2010 and 2030Diabetes Research and Clinical Practice201087141410.1016/j.diabres.2009.10.0072-s2.0-7374908348119896746
  7. H. CaiG. LiP. ZhangD. XuL. ChenEffect of exercise on the quality of life in type 2 diabetes mellitus: a systematic reviewQuality of Life Research201726351553010.1007/s11136-016-1481-52-s2.0-8500636534127990609
  8. S. R. GillM. PopR. T. DeboyMetagenomic analysis of the human distal gut microbiomeScience200631257781355135910.1126/science.11242342-s2.0-3374480429916741115
  9. R. E. LeyF. BäckhedP. TurnbaughC. A. LozuponeR. D. KnightJ. I. GordonObesity alters gut microbial ecologyProceedings of the National Academy of Sciences of the United States of America200510231110701107510.1073/pnas.05049781022-s2.0-2334444212016033867
  10. P. D. CaniA. M. NeyrinckF. FavaSelective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemiaDiabetologia200750112374238310.1007/s00125-007-0791-02-s2.0-3484891262717823788
  11. J. QinY. LiZ. CaiA metagenome-wide association study of gut microbiota in type 2 diabetesNature20124907418556010.1038/nature114502-s2.0-8486707483123023125
  12. E. Le ChatelierT. NielsenJ. QinRichness of human gut microbiome correlates with metabolic markersNature2013500746454154610.1038/nature125062-s2.0-8488311088023985870
  13. M. A. OdenwaldJ. R. TurnerThe intestinal epithelial barrier: a therapeutic target?Nature Reviews Gastroenterology & Hepatology201714192110.1038/nrgastro.2016.16927848962
  14. J. AmarC. ChaboA. WagetIntestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatmentEMBO Molecular Medicine20113955957210.1002/emmm.2011001592-s2.0-8005227849721735552
  15. P. D. CaniJ. AmarM. A. IglesiasMetabolic endotoxemia initiates obesity and insulin resistanceDiabetes20075671761177210.2337/db06-14912-s2.0-3434739956317456850
  16. P. D. CaniR. BibiloniC. KnaufChanges in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in miceDiabetes20085761470148110.2337/db07-14032-s2.0-4824912586218305141
  17. F. R. CostaM. C. FrançozoG. G. de OliveiraGut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onsetThe Journal of Experimental Medicine201621371223123910.1084/jem.201507442-s2.0-8497762542127325889
  18. S. FukudaH. TohK. HaseBifidobacteria can protect from enteropathogenic infection through production of acetateNature2011469733154354710.1038/nature096462-s2.0-7925158406621270894
  19. C. L. MaynardC. O. ElsonR. D. HattonC. T. WeaverReciprocal interactions of the intestinal microbiota and immune systemNature2012489741523124110.1038/nature115512-s2.0-8486616749722972296
  20. L. GaridouC. PomiéP. KloppThe gut microbiota regulates intestinal CD4 T cells expressing RORgt and controls metabolic diseaseCell Metabolism201522110011210.1016/j.cmet.2015.06.0012-s2.0-8493740777326154056
  21. M. KassanS. K. ChoiM. GalánEnhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetesDiabetes20136262078208710.2337/db12-13742-s2.0-8487825057923349490
  22. I. HameedS. R. MasoodiS. A. MirM. NabiK. GhazanfarB. A. GanaiType 2 diabetes mellitus: from a metabolic disorder to an inflammatory conditionWorld Journal of Diabetes20156459861210.4239/wjd.v6.i4.59825987957
  23. Z. T. BloomgardenInflammation and insulin resistanceDiabetes Care20032661922610.1172/JCI290692-s2.0-3374586130012766135
  24. I. A. ZolotnikT. Y. FigueroaInsulin receptor and IRS-1 co-immunoprecipitation with SOCS-3, and IKKα/β phosphorylation are increased in obese Zucker rat skeletal muscleLife Sciences20129115-16p. 81610.1016/j.lfs.2012.08.0382-s2.0-8486733437222982470
  25. X. JinX. SongY. B. CaoY. Y. JiangQ. Y. SunResearch progress in structural modification and pharmacological activities of berberineJournal of Pharmacy Practice201432171175
  26. H. ZhouL. FengF. XuBerberine inhibits palmitate-induced NLRP3 inflammasome activation by triggering autophagy in macrophages: a new mechanism linking berberine to insulin resistance improvementBiomedicine & Pharmacotherapy20178986487410.1016/j.biopha.2017.03.00328282788
  27. L. M. OrtizP. LombardiM. TillhonA. ScovassiBerberine, an epiphany against cancerMolecules201419123491236710.3390/molecules1908123492-s2.0-8490669506925153862
  28. Y. SunK. XunY. WangX. ChenA systematic review of the anticancer properties of berberine: a natural product from Chinese herbsAnti-Cancer Drugs20091375776910.1097/CAD.0b013e328330d95b2-s2.0-7034908537019704371
  29. J. TangY. FengS. TsaoN. WangR. CurtainY. WangBerberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigationsJournal of Ethnopharmacology20091351710.1016/j.jep.2009.08.0092-s2.0-7034997173219686830
  30. M. MingJ. Sinnett-SmithJ. WangDose-dependent AMPK-dependent and independent mechanisms of berberine and metformin inhibition of mTORC1, ERK, DNA synthesis and proliferation in pancreatic cancer cellsPLoS One201491210.1371/journal.pone.01145732-s2.0-8491689462025493642
  31. P. Jabbarzadeh KaboliA. RahmatP. IsmailK. H. LingTargets and mechanisms of berberine, a natural drug with potential to treat cancer with special focus on breast cancerEuropean Journal of Pharmacology201474058459510.1016/j.ejphar.2014.06.0252-s2.0-8491066173424973693
  32. B. VandanmagsarY. H. YoumA. RavussinThe NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistanceNature Medicine201117217918810.1038/nm.22792-s2.0-7975151246321217695
  33. L. YeL. ShuG. ChaoInhibition of M1 macrophage activation in adipose tissue by berberine improves insulin resistanceLife Sciences2016166829110.1016/j.lfs.2016.09.0252-s2.0-8499241729027702567
  34. X. WangN. OtaP. ManzanilloInterleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetesNature2014514752123724110.1038/nature135642-s2.0-8490831182125119041
  35. J. GongM. HuZ. HuangBerberine attenuates intestinal mucosal barrier dysfunction in type 2 diabetic ratsFrontiers in Pharmacology201738p. 4210.3389/fphar.2017.0004228217099
  36. J. H. XuX. Z. LiuW. PanD. J. ZouBerberine protects against diet-induced obesity through regulating metabolic endotoxemia and gut hormone levelsMolecular Medicine Reports20171552765278710.3892/mmr.2017.632128447763
  37. H. SunN. WangC. ZhenModulation of microbiota-gut-brain axis by berberine resulting in improved metabolic status in high-fat diet-fed ratsObesity Facts201696p. 36510.1159/0004495072-s2.0-8500091622727898425
  38. C. MoL. WangJ. ZhangThe crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked miceAntioxidants & Redox Signaling201420457458810.1089/ars.2012.51162-s2.0-8489291172123875776
  39. B.-H. ChoiI.-S. AhnY.-H. KimBerberine reduces the expression of adipogenic enzymes and inflammatory molecules of 3T3-L1 adipocyteExperimental and Molecular Medicine200638659960510.1038/emm.2006.7117202835
  40. T. LouZ. ZhangZ. XiBerberine inhibits inflammatory response and ameliorates insulin resistance in hepatocytesInflammation201134665966710.1038/emm.2006.7121110076
  41. Y. WangAttenuation of berberine on lipopolysaccharide-induced inflammatory and apoptosis responses in β-cells via TLR4-independent JNK/NF-κB pathwayPharmaceutical Biology201352410.3109/13880209.2013.8408512-s2.0-8492459625524188583
  42. G. CuiX. QinY. ZhangZ. GongB. GeY. Q. ZangBerberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic miceThe Journal of Biological Chemistry200928441284202842910.1074/jbc.M109.0126742-s2.0-7035051882919661066
  43. W.-H. ChuehJ.-Y. LinProtective effect of isoquinoline alkaloid berberine on spontaneous inflammation in the spleen, liver and kidney of non-obese diabetic mice through downregulating gene expression ratios of pro-/anti-inflammatory and Th1/Th2 cytokinesFood Chemistry201213141263127110.1016/j.foodchem.2011.09.1162-s2.0-81855221952
  44. N. P. FernandesC. V. LagishettyV. S. PandaS. R. NaikAn experimental evaluation of the antidiabetic and antilipidemic properties of a standardized Momordica charantia fruit extractBMC Complementary and Alternative Medicine20077p. 2910.1186/1472-6882-7-292-s2.0-3574894196117892543
  45. J. S. YuJ. H. KimS. LeeK. JungK. H. KimJ. Y. ChoSrc/Syk-targeted anti-inflammatory actions of triterpenoidal saponins from Gac (Momordica cochinchinensis) seedsThe American Journal of Chinese Medicine2017211510.1142/S0192415X1750028828367713
  46. M. RaishMomordica charantia polysaccharides ameliorate oxidative stress, hyperlipidemia, inflammation, and apoptosis during myocardial infarction by inhibiting the NF-κB signaling pathwayInternational Journal of Biological Macromolecules20179754455110.1016/j.ijbiomac.2017.01.07428109806
  47. P. KhannaS. C. JainA. PanagariyaV. P. DixitHypoglycemic activity of polypeptide-p from a plant sourceJournal of Natural Products1981446486557334382
  48. M. F. MahmoudF. E. El AshryN. N. El MaraghyA. FahmyStudies on the antidiabetic activities of Momordica charantia fruit juice in streptozotocin-induced diabetic ratsPharmaceutical Biology201755175876510.1080/13880209.2016.127502628064559
  49. M. B. KrawinkelG. B. KedingBitter gourd (Momordica charantia): a dietary approach to hyperglycemiaNutrition Reviews20066433133716910221
  50. P. ChaturvediAntidiabetic potentials of Momordica charantia: multiple mechanisms behind the effectsJournal of Medicinal Food2012152p. 10110.1089/jmf.2010.02582-s2.0-8485629593622191631
  51. A. FuangchanP. SonthisombatT. SeubnukarnHypoglycemic effect of bitter melon compared with metformin in newly diagnosed type 2 diabetes patientsJournal of Ethnopharmacology2011134242242810.1016/j.jep.2010.12.0452-s2.0-7995270216021211558
  52. E. BaschS. GabardiC. UlbrichtBitter melon (Momordica charantia): a review of efficacy and safetyAmerican Journal of Health-System Pharmacy20036035635912625217
  53. H. HuiG. TangV. L. W. GoHypoglycemic herbs and their action mechanismsChinese Medicine200941p. 1110.1186/1749-8546-4-112-s2.0-6765027088119523223
  54. J. BaiY. ZhuY. DongResponse of gut microbiota and inflammatory status to bitter melon (Momordica charantia L.) in high fat diet induced obese ratsJournal of Ethnopharmacology201619471772610.1016/j.jep.2016.10.0432-s2.0-8499425298527751827
  55. Y. ZhuJ. BaiY. ZhangX. XiaoY. DongEffects of bitter melon (Momordica charantia L.) on the gut microbiota in high fat diet and low dose streptozocin-induced ratsInternational Journal of Food Sciences & Nutrition2016676p. 68610.1080/09637486.2016.11971852-s2.0-8497712590827352776
  56. B. BaoY. G. ChenL. ZhangMomordica charantia (bitter melon) reduces obesity-associated macrophage and mast cell infiltration as well as inflammatory cytokine expression in adipose tissuesPLoS One2013812, article e8407510.1371/journal.pone.00840752-s2.0-8489293488024358329
  57. A. S. PithadiaA. BhuniaR. SribalanV. PadminiC. A. FierkeA. RamamoorthyInfluence of a curcumin derivative on hIAPP aggregation in the absence and presence of lipid membranesChemical Communications (Camb)201652594294510.1039/c5cc07792c2-s2.0-8495412873726587568
  58. S. PrasadS. C. GuptaA. K. TyagiB. B. AggarwalCurcumin, a component of golden spice: from bedside to bench and backBiotechnology Advances20143261053106410.1016/j.biotechadv.2014.04.0042-s2.0-8492153568324793420
  59. L. PariP. MuruganTetrahydrocurcumin prevents brain lipid peroxidation in streptozotocin-induced diabetic ratsJournal of Medicinal Food20071032332910.1089/jmf.2006.0582-s2.0-3454710658517651069
  60. N. ArunN. NaliniEfficacy of turmeric on blood sugar and polyol pathway in diabetic albino ratsPlant Foods for Human Nutrition200257415211855620
  61. P. MuruganL. PariInfluence of tetrahydrocurcumin on hepatic and renal functional markers and protein levels in experimental type 2 diabetic ratsBasic & Clinical Pharmacology & Toxicology200710124124510.1111/j.1742-7843.2007.00109.x2-s2.0-3664903600017845505
  62. S. ChuengsamarnS. RattanamongkolgulR. LuechapudipornC. PhisalaphongS. JirawatnotaiCurcumin extract for prevention of type 2 diabetesDiabetes Care201235112121212710.2337/dc12-01162-s2.0-8486815002122773702
  63. S. ChuengsamarnS. RattanamongkolgulB. PhonratReduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: a randomized controlled trialThe Journal of Nutritional Biochemistry20142514415010.1016/j.jnutbio.2013.09.0132-s2.0-8489252791424445038
  64. W. FengH. WangP. ZhangModulation of gut microbiota contributes to curcumin-mediated attenuation of hepatic steatosis in ratsBiochimica et Biophysica Acta2017186171801181210.1016/j.bbagen.2017.03.01728341485
  65. R. Al-SadiS. GuoD. YeT. Y. MaTNF-alpha modulation of intestinal epithelial tight junction barrier is regulated by ERK1/2 activation of Elk-1The American Journal of Pathology20131831871188410.1016/j.ajpath.2013.09.0012-s2.0-8488826318624121020
  66. Y. CongL. WangA. KonradT. SchoebC. O. ElsonCurcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine-protective regulatory T cellsEuropean Journal of Immunology200939113134314610.1002/eji.2009390522-s2.0-7044935346419839007
  67. J. WangS. S. GhoshS. GhoshCurcumin improves intestinal barrier function: modulation of intracellular signaling and 2 organization of tight junctionsAmerican Journal of Physiology - Cell Physiology20173124C438C44510.1152/ajpcell.00235.201628249988
  68. S. GafnerS. K. LeeM. CuendetBiologic evaluation of curcumin and structural derivatives in cancer chemoprevention model systemsPhytochemistry2004652849285910.1016/j.phytochem.2004.08.0082-s2.0-1384426972115501252
  69. K. M. SakthivelC. GuruvayoorappanAcacia ferruginea inhibits inflammation by regulating inflammatory iNOS and COX-2Journal of Immunotoxicology201613112713510.3109/1547691X.2015.10176252-s2.0-8494594279725738525
  70. Y. PanY. WangL. CaiInhibition of high glucose-induced inflammatory response and macrophage infiltration by a novel curcumin derivative prevents renal injury in diabetic ratsBritish Journal of Pharmacology201216631169118210.1111/j.1476-5381.2012.01854.x2-s2.0-8486087391322242942
  71. J. YinH. ZhangJ. YeTraditional Chinese medicine in treatment of metabolic syndromeEndocrine Metabolic & Immune Disorders Drug Targets200882p. 9918537696
  72. J. M. KimC. H. ParkS. K. ParkGinsenoside Re ameliorates brain insulin resistance and cognitive dysfunction in high-fat diet-induced C57BL/6 miceJournal of Agricultural & Food Chemistry201765132719272928314104
  73. C. LuZ. ShiL. DongExploring the effect of ginsenoside Rh1 in a sleep deprivation-induced mouse memory impairment modelPhytotherapy Research (PTR)201731576377010.1021/acs.jafc.7b0029728244162
  74. D. DaiC. F. ZhangS. WilliamsC. S. YuanC. Z. WangGinseng on cancer: potential role in modulating inflammation-mediated angiogenesisAmerican Journal of Chinese Medicine2017451132210.1142/S0192415X1750002128068835
  75. I. S. LeeI. J. UhK. S. KimAnti-inflammatory effects of ginsenoside Rg3 via NF-κB pathway in A549 cells and human asthmatic lung tissueJournal of Immunology Research2016201611752160110.1155/2016/752160128116321
  76. S. AhnM. H. SiddiqiV. C. AceitunoS. Y. SimuD. C. YangSuppression of MAPKs/NF-κB activation induces intestinal anti-inflammatory action of ginsenoside Rf in HT-29 and RAW264.7 cellsImmunological Investigations2016455p. 439
  77. S. BaoZ. YunW. BingGinsenoside Rg1 improves lipopolysaccharide-induced acute lung injury by inhibiting inflammatory responses and modulating infiltration of M2 macrophagesInternational Immunopharmacology201528142943410.1016/j.intimp.2015.06.0222-s2.0-8493699652326122136
  78. Q. T. BuW. Y. ZhangQ. C. ChenAnti-diabetic effect of ginsenoside Rb(3) in alloxan-induced diabetic miceMedicinal Chemistry20128593494122741793
  79. Y. C. HwangD. H. OhM. C. ChoiCompound K attenuates glucose intolerance and hepatic steatosis through AMPK-dependent pathways in type 2 diabetic OLETF ratsKorean Journal of Internal Medicine201710.3904/kjim.2015.20828142230
  80. Y. J. ZhangX. L. ZhangM. H. LiThe ginsenoside Rg1 prevents transverse aortic constriction-induced left ventricular hypertrophy and cardiac dysfunction by inhibiting fibrosis and enhancing angiogenesisJournal of Cardiovascular Pharmacology2013621p. 5010.1097/FJC.0b013e31828f8d452-s2.0-8488054301523846802
  81. H. YuJ. ZhenY. YangJ. GuS. WuQ. LiuGinsenoside Rg1 ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress-induced apoptosis in a streptozotocin-induced diabetes rat modelJournal of Cellular & Molecular Medicine2016204p. 62310.1111/jcmm.127392-s2.0-8496121066826869403
  82. L. U. PingS. U. WeiZ. H. MiaoH. R. NiuJ. LiuQ. L. HuaEffect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancerChinese Journal of Integrative Medicine2008141333610.1007/s11655-007-900218219455
  83. Z. YuanH. JiangX. ZhuX. LiuJ. LiGinsenoside Rg3 promotes cytotoxicity of paclitaxel through inhibiting NF-κB signaling and regulating Bax/Bcl-2 expression on triple-negative breast cancerBiomedicine & Pharmacotherapy20178922723210.1016/j.biopha.2017.02.03828231544
  84. X. ZhangY. WangC. MaGinsenoside Rd and ginsenoside Re offer neuroprotection in a novel model of Parkinson’s diseaseAmerican Journal of Neurodegenerative Disease201651p. 5227073742
  85. F. LiX. WuJ. LiQ. NiuGinsenoside Rg1 ameliorates hippocampal long-term potentiation and memory in an Alzheimer’s disease modelMolecular Medicine Reports2016136p. 490410.3892/mmr.2016.51032-s2.0-8496655322327082952
  86. W. TianL. ChenL. ZhangEffects of ginsenoside Rg1 on glucose metabolism and liver injury in streptozotocin-induced type 2 diabetic ratsGenetics & Molecular Research Gmr201716110.4238/gmr1601946328362999
  87. H. X. NiN. J. YuX. H. YangThe study of ginsenoside on PPARgamma expression of mononuclear macrophage in type 2 diabetesMolecular Biology Reports2010376p. 297510.1007/s11033-009-9864-02-s2.0-7795565440819821054
  88. W. B. ShangC. GuoJ. ZhaoX. Z. YuH. ZhangGinsenoside Rb1 upregulates expressions of GLUTs to promote glucose consumption in adiopcytesZhongguo Zhong Yao Za Zhi20143922p. 44825850283
  89. K. WaughJ. SnellbergeonA. MichelsIncreased inflammation is associated with islet autoimmunity and type 1 diabetes in the Diabetes Autoimmunity Study in the Young (DAISY)PLoS One2017124, article e017484010.1371/journal.pone.017484028380011
  90. J. Z. Q. LuoJ. W. KimL. LuoEffects of ginseng and its four purifed ginsenosides (Rb2, Re, Rg1, Rd) on human pancreatic islet β cell in vitroEuropean Journal Pharmaceutical & Medical Research201631p. 11027547829
  91. S. S. KimH. J. JangM. Y. OhGinsenoside Rg3 enhances islet cell function and attenuates apoptosis in mouse isletsTransplantation Proceedings20144641150115510.1016/j.transproceed.2013.12.0282-s2.0-8490031603924815149
  92. K. EguchiR. NagaiIslet inflammation in type 2 diabetes and physiologyJournal of Clinical Investigation20171271p. 1410.1172/JCI8887728045399
  93. W. ShangY. YangL. ZhouB. JiangH. JinM. ChenGinsenoside Rb1 stimulates glucose uptake through insulin-like signaling pathway in 3T3-L1 adipocytesJournal of Endocrinology20081983p. 56110.1677/JOE-08-01042-s2.0-5334914148318550785
  94. Q. MuX. FangX. LiGinsenoside Rb1 promotes browning through regulation of PPARγ in 3T3-L1 adipocytesBiochemical & Biophysical Research Communications2015466353053510.1016/j.bbrc.2015.09.0642-s2.0-8494323580826381176
  95. Y. GaoM. F. YangY. P. SuGinsenoside Re reduces insulin resistance through activation of PPAR-γ pathway and inhibition of TNF-α productionJournal of Ethnopharmacology2013147250951610.1016/j.jep.2013.03.0572-s2.0-8487691117623545455
  96. L. ZhangL. ZhangX. WangH. SiAnti-adipogenic effects and mechanisms of ginsenoside Rg3 in pre-adipocytes and obese miceFrontiers in Pharmacology20178p. 11310.3389/fphar.2017.0011328337143
  97. Y. WuY. YuA. SzaboM. HanX. F. HuangCentral inflammation and leptin resistance are attenuated by ginsenoside Rb1 treatment in obese mice fed a high-fat dietPLoS One20149310.1371/journal.pone.00926182-s2.0-8489980344024675731
  98. X. M. ZhangS. C. QuD. Y. SuiX. F. YuZ. Z. LvEffects of ginsenoside-Rb on blood lipid metabolism and anti-oxidation in hyperlipidemia ratsChina Journal of Chinese Materia Medica200429111085108815656146
  99. S. YuX. ZhouF. LiMicrobial transformation of ginsenoside Rb1, Re and Rg1 and its contribution to the improved anti-inflammatory activity of ginsengScientific Reports201771p. 13810.1038/s41598-017-00262-028273939
  100. Q. LiuX. LiC. LiY. ZhengG. Peng1-Deoxynojirimycin alleviates insulin resistance via activation of insulin signaling PI3K/AKT pathway in skeletal muscle of db/db miceMolecules20152012217002171410.3390/molecules2012197942-s2.0-8495435715026690098
  101. Y. LiuX. LiC. XiePrevention effects and possible molecular mechanism of mulberry leaf extract and its formulation on rats with insulin-insensitivityPLoS One201611410.1371/journal.pone.01527282-s2.0-8496353286427054886
  102. V. SainiMolecular mechanisms of insulin resistance in type 2 diabetes mellitusWorld Journal of Diabetes201013687510.4239/wjd.v1.i3.6821537430
  103. A. AzizS. WheatcroftInsulin resistance in type 2 diabetes and obesity: implications for endothelial functionExpert Review of Cardiovascular Therapy20119440340710.1586/erc.11.202-s2.0-7995549725521517723
  104. A. HatanoY. KannoY. KondoSynthesis and characterization of novel, conjugated, fluorescent DNJ derivatives for α-glucosidase recognitionBioorganic & Medicinal Chemistry201725277377810.1016/j.bmc.2016.11.05327956035
  105. Q. LiuX. LiC. Li1-Deoxynojirimycin alleviates liver injury and improves hepatic glucose metabolism in db/db miceMolecules2016213p. 27910.3390/molecules210302792-s2.0-8496457816726927057
  106. H. GuoY. XuW. HuangKuwanon G preserves LPS-induced disruption of gut epithelial barrier in vitroMolecules2016211110.3390/molecules211115972-s2.0-8499761133027879681
  107. H. N. NaS. ParkH. J. JeonH. B. KimJ. H. NamReduction of adenovirus 36-induced obesity and inflammation by mulberry extractMicrobiology and Immunology201458530330610.1111/1348-0421.121462-s2.0-8489997511424580367
  108. H. H. LimS. O. LeeS. Y. KimS. J. YangY. LimAnti-inflammatory and antiobesity effects of mulberry leaf and fruit extract on high fat diet-induced obesityExperimental Biology and Medicine (Maywood, N.J.)2013238101160116910.1177/15353702134989822-s2.0-8488463387924000381
  109. C. SongY. JiG. ZouC. WanTetrandrine down-regulates expression of miRNA-155 to inhibit signal-induced NF-κB activation in a rat model of diabetes mellitusInternational Journal of Clinical and Experimental Medicine2015834024403026064305
  110. E. ZhangB. GaoL. YangNotoginsenoside Ft1 promotes fibroblast proliferation via PI3K/Akt/mTOR signaling pathway and benefits wound healing in genetically diabetic miceThe Journal of Pharmacology and Experimental Therapeutics2016356232433210.1124/jpet.115.2293692-s2.0-8495896293126567319
  111. M. DuX. HuL. KouB. ZhangC. ZhangLycium barbarum polysaccharide mediated the antidiabetic and antinephritic effects in diet-streptozotocin-induced diabetic Sprague Dawley rats via regulation of NF-κBBioMed Research International201620169314029010.1155/2016/31402902-s2.0-8497138536727200371
  112. A. HosseiniH. HosseinzadehA review on the effects of Allium sativum (garlic) in metabolic syndromeJournal of Endocrinological Investigation201538111147115710.1007/s40618-015-0313-82-s2.0-8494406291626036599
  113. R. ZhuJ. ZhengL. ChenB. GuS. HuangAstragaloside IV facilitates glucose transport in C2C12 myotubes through the IRS1/AKT pathway and suppresses the palmitate-induced activation of the IKK/IκBα pathwayInternational Journal of Molecular Medicine20163761697170510.3892/ijmm.2016.25552-s2.0-8497888092227082050
  114. D. GuiJ. HuangY. GuoAstragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-κB-mediated inflammatory genes expressionCytokine201361397097910.1016/j.cyto.2013.01.0082-s2.0-8487537809623434274
  115. L. DuM. HaoC. LiQuercetin inhibited epithelial mesenchymal transition in diabetic rats, high-glucose-cultured lens, and SRA01/04 cells through transforming growth factor-β2/phosphoinositide 3-kinase/Akt pathwayMolecular and Cellular Endocrinology2017452445610.1016/j.mce.2017.05.01128501572
  116. Y. QiaoK. GaoY. WangX. WangB. CuiResveratrol ameliorates diabetic nephropathy in rats through negative regulation of the p38 MAPK/TGF-β1 pathwayExperimental and Therapeutic Medicine20171363223323010.3892/etm.2017.442028588674
  117. Y. JinX. GuoB. YuanDisposition of astragaloside IV via enterohepatic circulation is affected by the activity of the intestinal microbiomeJournal of Agricultural and Food Chemistry201563266084609310.1021/acs.jafc.5b001682-s2.0-8493680322226066785
  118. J. FirrmanL. LiuL. ZhangThe effect of quercetin on genetic expression of the commensal gut microbes Bifidobacterium catenulatum, Enterococcus caccae and Ruminococcus gauvreauiiAnaerobe20164213014110.1016/j.anaerobe.2016.10.0042-s2.0-8499172854827742572
  119. M. M. SungT. T. KimE. DenouImproved glucose homeostasis in obese mice treated with resveratrol is associated with alterations in the gut microbiomeDiabetes201766241842510.2337/db16-068027903747
  120. X. P. ZhangJ. JiangQ. H. ChengProtective effects of Ligustrazine, Kakonein and Panax Notoginsenoside on the small intestine and immune organs of rats with severe acute pancreatitisHepatobiliary & Pancreatic Diseases International201110663263722146628
  121. L. ZhaoH. WuA. ZhaoThe in vivo and in vitro study of polysaccharides from a two-herb formula on ulcerative colitis and potential mechanism of actionJournal of Ethnopharmacology2014153115115910.1016/j.jep.2014.02.0082-s2.0-8489695873924548752
  122. A. LangM. LahavE. SakhniniAllicin inhibits spontaneous and TNF-alpha induced secretion of proinflammatory cytokines and chemokines from intestinal epithelial cellsClinical Nutrition20042351199120810.1016/j.clnu.2004.03.0112-s2.0-454422687815380914
  123. H. S. ChoiH. S. KimK. R. MinAnti-inflammatory effects of fangchinoline and tetrandrineJournal of Ethnopharmacology200069217317910687873
  124. Y. C. OhW. K. ChoG. Y. ImAnti-inflammatory effect of Lycium fruit water extract in lipopolysaccharide-stimulated RAW 264.7 macrophage cellsInternational Immunopharmacology201213218118910.1016/j.intimp.2012.03.0202-s2.0-8486053088622483979
  125. L. F. CardozoL. M. PedruzziP. StenvinkelNutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2Biochimie20139581525153310.1016/j.biochi.2013.04.0122-s2.0-8487968854723643732
  126. X. ZhouX. SunX. GongAstragaloside IV from Astragalus membranaceus ameliorates renal interstitial fibrosis by inhibiting inflammation via TLR4/NF-κB in vivo and in vitroInternational Immunopharmacology201742182410.1016/j.intimp.2016.11.00627855303
  127. Z. CaiJ. LiuH. BianJ. CaiAstragaloside IV ameliorates necrotizing enterocolitis by attenuating oxidative stress and suppressing inflammation via the vitamin D3-upregulated protein 1/NF-κB signaling pathwayExperimental and Therapeutic Medicine20161242702270810.3892/etm.2016.36292-s2.0-8498797337127698775
  128. H. IskenderE. DokumaciogluT. M. SenI. InceY. KanbayS. SaralThe effect of hesperidin and quercetin on oxidative stress, NF-κB and SIRT1 levels in a STZ-induced experimental diabetes modelBiomedicine & Pharmacotherapy20179050050810.1016/j.biopha.2017.03.10228395272
  129. K. A. KangS. ChaeY. S. KohProtective effect of puerariae radix on oxidative stress induced by hydrogen peroxide and streptozotocinBiological and Pharmaceutical Bulletin2005281154116015997089
  130. R. LiY. ChenM. ShiGegen Qinlian decoction alleviates experimental colitis via suppressing TLR4/NF-κB signaling and enhancing antioxidant effectPhytomedicine201623101012102010.1016/j.phymed.2016.06.0102-s2.0-8497813642127444346
  131. C. H. ZhangG. L. XuY. H. LiuAnti-diabetic activities of Gegen Qinlian decoction in high-fat diet combined with streptozotocin-induced diabetic rats and in 3T3-L1 adipocytesPhytomedicine2013203-422122910.1016/j.phymed.2012.11.0022-s2.0-8487371474123219338
  132. Y. M. LiX. M. FanY. M. WangQ. L. LiangG. A. LuoTherapeutic effects of Gegen Qinlian decoction and its mechanism of action on type 2 diabetic ratsActa Pharmaceutica Sinica2013489p. 141524358775
  133. V. TremaroliF. BackhedFunctional interactions between the gut microbiota and host metabolismNature201248924224910.1038/nature115522-s2.0-8486616889422972297
  134. P. J. TurnbaughR. E. LeyM. A. MahowaldV. MagriniE. R. MardisJ. I. GordonAn obesity-associated gut microbiome with increased capacity for energy harvestNature20064441027103110.1038/nature054142-s2.0-3384587410117183312
  135. J. XuF. LianL. ZhaoStructural modulation of gut microbiota during alleviation of type 2 diabetes with a Chinese herbal formulaISME Journal201593p. 55210.1038/ismej.2014.1772-s2.0-8492354580425279787
  136. L. ZhengY. H. QuanExperience of treating side effects of antibiotic abuses by professor Quan Yihong’s Dangguiliuhuang decoctionJournal of Hubei University of Chinese Medicine201416107109
  137. T. LiuH. CaoY. JiInteraction of dendritic cells and T lymphocytes for the therapeutic effect of Dangguiliuhuang decoction to autoimmune diabetesScientific Reports2015510.1038/srep139822-s2.0-8494158536726358493
  138. S. B. KimO. H. KangJ. H. KeumAnti-inflammatory effects of Danggui Liuhuang decoction in RAW 264.7 cellsChinese Journal of Integrative Medicine201210.1007/s11655-012-1237-123212570
  139. G. BaorongG. LiangqingClinical observation of Huanglian Wendan Heji (Huanglian Wendan mixture) in treatment of damp-heat type of gerontic diabetes gastroparesisWorld Journal of Traditional Chinese Medicine20072p. 008
  140. L. LiuY. SuiThe effect of Huanglianwendan decoction on insulin resistance and adipocytokines in metabolic syndrome ratsLiaoning Journal of Traditional Chinese Medicine20113p. 002
  141. Y. B. LiW. H. ZhangH. D. LiuZ. LiuS. P. MaProtective effects of Huanglian Wendan decoction aganist cognitive deficits and neuronal damages in rats with diabetic encephalopathy by inhibiting the release of inflammatory cytokines and repairing insulin signaling pathway in hippocampusChinese Journal of Natural Medicines2016141181382210.1016/S1875-5364(16)30098-X2-s2.0-8499888191727914525
The underlying source XML for this text is taken from https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5661076/fullTextXML. The license for the article is Creative Commons Attribution 4.0 International. The main subject has been identified as maturity-onset diabetes of the young.