Ginsenoside Compound K Ameliorates Development of Diabetic Kidney Disease through Inhibiting TLR4 Activation Induced by Microbially Produced Imidazole Propionate.

Diabetic kidney disease (DKD) is a common and devastating complication in diabetic patients, which is recognized as a large and growing problem leading to end-stage kidney disease. As dietary-mediated therapies are gradually becoming more acceptable to patients with DKD, we planned to find active compounds on preventing DKD progression from dietary material. The present paper reports the renoprotective properties and underlying mechanisms of ginsenoside compound K (CK), a major metabolite in serum after oral administration of ginseng. CK supplementation for 16 weeks could improve urine microalbumin, the ratio of urinary albumin/creatinine and renal morphological abnormal changes in db/db mice. In addition, CK supplementation reshaped the gut microbiota by decreasing the contents of Bacteroides and Paraprevotella and increasing the contents of Lactobacillu and Akkermansia at the genus level, as well as reduced histidine-derived microbial metabolite imidazole propionate (IMP) in the serum. We first found that IMP played a significant role in the progression of DKD through activating toll-like receptor 4 (TLR4). We also confirmed CK supplementation can down-regulate IMP-induced protein expression of the TLR4 signaling pathway in vivo and in vitro. This study suggests that dietary CK could offer a better health benefit in the early intervention of DKD. From a nutrition perspective, CK or dietary material containing CK can possibly be developed as new adjuvant therapy products for DKD.

Astragaloside â £ negatively regulates Gpr97-TPL2 signaling to protect against hyperhomocysteine-exacerbated sepsis associated acute kidney injury.

BACKGROUND: Hyperhomocysteine (HHcy) plays an important role in promoting inflammation and cell death of tubular epithelial cells. However, the role of HHcy and Astragaloside IV (AS-IV) in sepsis associated acute kidney injury (S-AKI) remain unclear. PURPOSE: A significant aspect of this study aimed to elucidate the effect of AS-Ⅳ treatment on HHcy-exacerbated S-AKI and reveal its potential mechanism. METHODS: Male C57BL/6 J mice fed with specific diet containing 2% methionine were established as in vivo models, and AS-Ⅳ was orally administrated continuously for 3 weeks, and then LPS (10 mg·kg-1 bodyweight) was given by a single intraperitoneal injection. The renal morphological changes were evaluated by HE and PAS staining. RNA-sequencing analysis was applied to select key signaling. The NRK-52E cells exposed to Hcy or combined with LPS were used as in vitro models. The mRNA and protein expression levels of Gpr97-TPL2 signaling were examined by qRT-PCR and western blotting assays. RESULTS: In vivo, HHcy mice developed more severe renal injury and prevalent tubular inflammation after LPS injection. In vitro, the levels of NGAL, Gpr97 and TPL2 were significantly increased in NRK-52E cells induced by Hcy (1.6 mM) or in combination with LPS. Notably, the effects of Hcy on TPL2 signaling was abolished by transfecting TPL2 siRNA or treating TPL2 inhibitor, without alterations in Gpr97. However, the enhancement of Gpr97-TPL2 signaling induced by Hcy was counteracted by Gpr97 siRNA. Subsequently, our findings demonstrated that AS-Ⅳ treatment can improve renal function in HHcy-exacerbated S-AKI mice. Mechanistically, AS-Ⅳ alleviated renal tubular damage characterized by abnormal increases in KIM-1, NGAL, TPL2, Gpr97, Sema3A and TNF-α, and decreases in survivin in vivo and in vitro mainly through suppressing the activation of Gpr97-TPL2 signaling. CONCLUSION: The present study suggested that HHcy-exacerbated S-AKI was mediated mechanically by activation of Gpr97-TPL2 signaling for the first time. Furthermore, our research also illustrated that AS-Ⅳ protected against HHcy-exacerbated S-AKI by attenuating renal tubular epithelial cells damage through negatively regulating Gpr97-TPL2 signaling, proposing a natural product treatment strategy for HHcy-exacerbated S-AKI.

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease.

Diabetic kidney disease (DKD) occurs in 25-40% of patients with diabetes. Individuals with DKD are at a significant risk of progression to end-stage kidney disease morbidity and mortality. At present, although renal function-decline can be retarded by intensive glucose lowering and strict blood pressure control, these current treatments have shown no beneficial impact on preventing progression to kidney failure. Recently, in addition to control of blood sugar and pressure, a dietary approach has been recommended for management of DKD. Amino acids (AAs) are both biomarkers and causal factors of DKD progression. AA homeostasis contributes to renal hemodynamic response and glomerular hyperfiltration alteration in diabetic patients. This review discusses the links between progressive kidney dysfunction and the metabolic homeostasis of histidine, tryptophan, methionine, glutamine, tyrosine, and branched-chain AAs. In addition, we emphasize the regulation effects of special metabolites on DKD progression, with a focus on causality and potential mechanisms. This paper may offer an optimized protein diet strategy with concomitant management of AA homeostasis to reduce the risks of DKD in a setting of hyperglycemia.

Shenyan Kangfu tablet alleviates diabetic kidney disease through attenuating inflammation and modulating the gut microbiota.

Inflammation plays a predominant role in the pathogenesis of diabetic kidney disease (DKD). The Shenyan Kangfu tablet (SYKFT) is a prescription of traditional Chinese medicine for treating chronic kidney disease. However, the concrete mechanism is still unclear. According to previous clinical trial, we explored the effects and potential mechanism on DKD in db/db model supplemented with SYKFT. As a result, SYKFT reduced stimulated blood glucose and HbA1c levels, alleviated renal dysfunction, glomerular and tubular damage, and renal inflammation (TNF-α and IL-1ß) in db/db mice. The primary mechanistic study illustrated that SYKFT improved renal injury mainly associated with inhibition of NF-κB in vivo and in vitro. This study further observed that SYKFT increased relative abundance of Firmicutes and decreased Bacteroidetes, showing direct correlation between representative microbiota relative abundance and renal function parameters. SYKFT effectively decreased the relative abundance of Bacteroides, and positive correlation between the relative abundance and protein expression of NF-κB, TNF-α and IL-1ß predicted that anti-inflammatory activity of SYKFT was associated with modulating the gut microbiota. Therefore, we first demonstrated SYKFT alleviated DKD through regulating renal inflammatory signaling cascades and intestinal microbiota and also pointed out the role of specific gut microbiota in the development of DKD.

[Study on N-acetylated chitosans by FTIR and XRD].

The degree of N-deacetylation (DD) is an important property of chitosan. In the present article the reaction of N-acetylation was applied to prepare six chitosan samples with various DDs. The samples were studied by FTIR and XRD to investigate their IR absorbance characteristics and crystallinity, from which the DDs and crystallinity index (CrI) of chitosans were also determined respectively. The influence of N-acetylation on DD and CrI was also discussed, and it could be found from FTIR that the N-acetylation reaction became difficult for the remaining amino group in chitosan molecule as the reaction proceeded. XRD also indicated that the crystalline zone was broken by N-acetylation gradually, and another kind of crystal form appeared instead.

[FTIR analysis of the enzymatic degradation of chitosan blend membranes].

Chitosan blend membranes were prepared by casting the mixture solution of highly deacetylated chitosan (HDC) and moderately deacetylated chitosan (MDC). FTIR was used to investigate the components of the blend membranes before and after lysozymic degradation. It was found that the ratio of MDC in the blen d membranes had a linear relation with the degree of deacetylation (DD) of the membranes. In enzymatic degradation process, DD of the membranes exhibited an increasing tendency. The FTIR data indicate that MDC component in the blend membranes can be removed by selective enzymatic degradation. This also suggests that FTIR can be used as an efficient and rapid method to investigate the degradation process of chitosan.

The enzymatic degradation and swelling properties of chitosan matrices with different degrees of N-acetylation.

In the design of chitosan-based drug delivery systems and implantable scaffolds, the biodegradation rate of the chitosan matrix represents a promising strategy for drug delivery and the function of carriers. In this study, we have investigated the degradation of chitosan with different degrees of N-acetylation, with respect to weight loss, water absorption, swelling behavior, molecular weight loss of bulk materials, and reducing sugar content in the media. Chitosan matrices were prepared by compression molding. The results revealed that the initial degradation rate, equilibrium water absorption, and swelling degree increased with decreasing degree of deacetylation (DD) and a dramatic rise began as DD of the chitosan matrix decreased to 62.4%. Chitosan matrices with DD of 52.6%, 56.1%, and 62.4% had the weight half-life of 9.8, 27.3, and more than 56 days, respectively, and the weight half-life of average molecular weight 8.4, 8.8, and 20.0 days, respectively. For chitosan matrices with DD of 71.7%, 81.7%, and 93.5%, both types of half-life exceeded 84 days because of the much slower degradation rate. The dimension of chitosan matrices during degradation was determined by the process of swelling and degradation. These findings may help to design chitosan-based biomedical materials with predetermined degradation timed from several days to months and proper swelling behaviors.

[Study on homogeneity of enzymatic degradation of chitosan as biomaterials by gel permeation chromatography].

Chitosan is an important biomedical material, and its degree of deacetylation is a main parameter of its biodegradation. Gel permeation chromatography was used to investigate the lysozymic degradation of two types of chitosan samples (A and B) with similar degree of deacetylation and relative molecular mass but with different distributions of two units of N-acetyl-D-glucosamine and D-glucosamine. Weight average relative molecular mass, polydispersity and gel permeation chromatograms during the degradation process were obtained. It was found that chitosan sample A with random distribution of the two units underwent a homogeneous degradation process while chitosan sample B with block distribution underwent a heterogeneous degradation process. The results suggest that the homogeneity of the degradation of chitosan materials by lysozyme depends on the distribution type of the two units, which can help to design chitosan-based biomedical devices.