Abstract:Conclusively, increased GAGs and CTGF excretion are evident in T1DM normoalbuminuric juveniles, possibly reflecting early renal injury signs, before the initiation of albuminuria.
“…And the loganin related gene, i.e. CTGF was associated with diabetes and diabetic nephropathy 74–78 , which was also consistent with our results.Figure 5The pharmacology network generated for LDW. The innermost circle represented the compounds collected from LDW, the circle in the middle represented the related genes of compounds from LDW, the outermost layer represented the diseases that were related to the genes.…”
With the advancement of systems biology research, we have already seen great progress in pharmacology studies, especially in network pharmacology. Network pharmacology has been proven to be effective for establishing the “compounds-proteins/genes-diseases” network, and revealing the regulation principles of small molecules in a high-throughput manner, thus would be very effective for the analysis of drug combinations, especially for TCM preparations. In this work, we have proposed the TCM-Mesh system, which records TCM-related information collected from various resources and could serve for network pharmacology analysis for TCM preparations in a high-throughput manner (http://mesh.tcm.microbioinformatics.org/). Currently, the database contains 6,235 herbs, 383,840 compounds, 14,298 genes, 6,204 diseases, 144,723 gene-disease associations, 3,440,231 pairs of gene interactions, 163,221 side effect records and 71 toxic records, and web-based software construct a network between herbs and treated diseases, which will help to understand the underlying mechanisms for TCM preparations at molecular levels. We have used 1,293 FDA-approved drugs, as well as compounds from an herbal material Panax ginseng and a patented drug Liuwei Dihuang Wan (LDW) for evaluating our database. By comparison of different databases, as well as checking against literature, we have demonstrated the completeness, effectiveness, and accuracy of our database.
“…And the loganin related gene, i.e. CTGF was associated with diabetes and diabetic nephropathy 74–78 , which was also consistent with our results.Figure 5The pharmacology network generated for LDW. The innermost circle represented the compounds collected from LDW, the circle in the middle represented the related genes of compounds from LDW, the outermost layer represented the diseases that were related to the genes.…”
With the advancement of systems biology research, we have already seen great progress in pharmacology studies, especially in network pharmacology. Network pharmacology has been proven to be effective for establishing the “compounds-proteins/genes-diseases” network, and revealing the regulation principles of small molecules in a high-throughput manner, thus would be very effective for the analysis of drug combinations, especially for TCM preparations. In this work, we have proposed the TCM-Mesh system, which records TCM-related information collected from various resources and could serve for network pharmacology analysis for TCM preparations in a high-throughput manner (http://mesh.tcm.microbioinformatics.org/). Currently, the database contains 6,235 herbs, 383,840 compounds, 14,298 genes, 6,204 diseases, 144,723 gene-disease associations, 3,440,231 pairs of gene interactions, 163,221 side effect records and 71 toxic records, and web-based software construct a network between herbs and treated diseases, which will help to understand the underlying mechanisms for TCM preparations at molecular levels. We have used 1,293 FDA-approved drugs, as well as compounds from an herbal material Panax ginseng and a patented drug Liuwei Dihuang Wan (LDW) for evaluating our database. By comparison of different databases, as well as checking against literature, we have demonstrated the completeness, effectiveness, and accuracy of our database.
“…CTGF (connective tissue growth factor), a member of CCN family of extracellular matrix-associated heparin-binding proteins, has an essential role in cell adhesion, migration, proliferation and angiogenesis 52, 53 . Aberrant CTGF expression is associated with diabetic nephropathy 54 , retinopathy 55 and cardiovascular diseases 56 . GDF1 is a key regulator in the establishment and maintenance of Left-Right (L-R) signals governing asymmetric organogenesis, including the heart and the great vessels 57 .…”
Objectives
Oxidative stress plays a causal role in diabetic embryopathy. Maternal diabetes induces heart defects and impaired transforming growth factor beta (TGFβ) signaling, which is essential for cardiogenesis. We hypothesize that mitigating oxidative stress through superoxide dismutase 1 (SOD1) overexpression in transgenic (Tg) mice reverses maternal hyperglycemia-impaired TGFβ signaling and its downstream effectors.
Study Design
Day 12.5 embryonic hearts from wild-type (WT) and SOD1 overexpressing embryos of nondiabetic (ND) and diabetic mellitus (DM) dams were used for detection of oxidative stress markers: 4-hydroxynonenal (4-HNE) and malondlaldehyde (MDA), and TGFβ1, 2, 3, phosphor (p)-TGFβ receptor II (TβRII), p-Smad2 and p-Smad3. The expression of three TGFβ responsive genes was also assessed. Day 11.5 embryonic hearts were explanted and cultured ex vivo, with or without treatments of a SOD1 mimetic (tempol) or a TGFβ recombinant protein for detection of TGFβ signaling intermediates.
Results
Levels of 4-HNE and MDA were significantly increased by maternal diabetes, and SOD1 overexpression blocked the increase of these two oxidative stress markers. Maternal diabetes suppresses the TGFβ signaling pathway by down-regulating TGFβ1 and TGFβ3 expression. Consequently, phosphorylation of TβRII, Smad2 and Smad3, downstream effectors of TGFβ, and expression of three TGFβ responsive genes were reduced by maternal diabetes, and these reductions were prevented by SOD1 overexpression. Treatment with tempol or TGFβ recombinant protein restored high glucose-suppressed TGFβ signaling intermediates and responsive gene expression.
Conclusions
Oxidative stress mediates the inhibitory effect of hyperglycemia in the developing heart. Antioxidants, TGFβ recombinant proteins or TGFβ agonists may have potential therapeutic values in the prevention of heart defects in diabetic pregnancies.
“…Multiple studies have described an increased urinary GAGs excretion compared to controls, even in normoalbuminuric patients [94–96, 99, 100, 102–111]. But one study found similar urinary GAGs excretions in normoalbuminuric diabetic patients and healthy controls [102].…”
Diabetic nephropathy, the leading cause of renal failure worldwide, affects approximately one-third of all people with diabetes. Microalbuminuria is considered the first sign and the best predictor of progression to renal failure and cardiovascular events. However, albuminuria has several limitations. Therefore, earlier, more sensitive and specific biomarkers with greater predictability are needed. The aim of this paper is to discuss the current literature on biomarkers of glomerular injury that have been implicated in diabetic kidney disease.
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