Corrigendum] Differential regulation of the biosynthesis of glucose transporters by the PI3‑K and MAPK pathways of insulin signaling by treatment with novel compounds from Liriope platyphylla.

The herb Liriope platyphylla (LP) has been considered to have curative properties for diabetes, asthma and neurodegenerative disorders. To examine the effects of steaming time and frequency of manufactured red LP (RLP) on the nerve growth factor (NGF) secretion ability and NGF receptor signaling pathway, the NGF concentration, cell differentiation, NGF signaling pathway and calcium concentration were analyzed in neuronal cells treated with several types of LPs manufactured under different conditions. The maximum NGF secretion was observed in B35 cells treated with 50 µg/ml LP extract steamed for 9 h (9-SLP) and with two repeated steps (3 h steaming and 24 h air-dried) carried out 7 times (7-SALP). No significant changes in viability were detected in any of the cells treated with the various LPs, with the exception of 0-SLP and 0-SALP. In addition, PC12 cell differentiation was induced by treatment with the NGF-containing conditional medium (CM) collected from the RLP-treated cells. The levels of TrkA and extracellular signal-regulated kinase (ERK) phosphorylation in the high affinity NGF receptor signaling pathway were significantly higher in the cells treated with 3-SLP or 1-SALP/3-SALP CM compared with those treated with the vehicle CM. In the low affinity NGF receptor pathway, the expression levels of most components were higher in the 9-, 15- and 24-SALP CM-treated cells compared with the vehicle CM-treated cells. However, this level was significantly altered in cells treated with 3-SALP CM. Furthermore, an examination of the RLP function on calcium regulation revealed that only the LP- or RLP-treated cells exhibited changes in intracellular and extracellular calcium levels. RLP induced a significant decrease in the intracellular calcium levels and an increase in the extracellular calcium levels. These results suggest the possibility that steaming-processed LP may aid in the relief of neurodegenerative diseases through the NGF secretion ability and NGF signaling pathway.

The insulin signaling pathway, involving protein kinase B (PKB) and mitogen-activated protein kinase (MAPK), mediates the biological response to insulin and several growth factors and cytokines. To investigate the correlation between glucose transporter (Glut) biosynthesis and the insulin signaling pathway activated by novel compounds of Liriope platyphylla (LP9M80-H), alterations in Glut and key protein expression in the insulin signaling pathway were analyzed in the liver and brain of ICR mice treated with LP9M80-H. An in vitro assay showed that the highest level of insulin concentration was observed in the LP9M80-H-treated group, followed by the LP-H, LP-M, LP-E, and LP9M80-C-treated groups. Therefore, LP9M80-H was selected for use in studying the detailed mechanism of the insulin signaling pathway in animal systems. In an in vivo experiment, LP9M80-H induced a significant increase in glucose levels and a decrease of insulin concentration in the blood of mice, while their body weight remained constant over 5 days. The expression level of Glut-3 was down-regulated in the liver, or maintained at the same level in the brain of LP9MH80-H-treated mice. These changes corresponded to the phosphorylation of the p38 protein rather than to ERK and JNK in the MAPK signaling pathway. In addition, the expression level of Glut-1 increased significantly after LP9MH80-H treatment of both insulin target tissues in mice. Western blot analysis showed that Akt in the PI3-K pathway mainly participated in Glut-1 biosynthesis. Thus, these results suggest the possibility that the LP9M80-H-induced regulation of Glut-1 and Glut-3 biosynthesis may be mediated by the Akt and p38 MAPK signaling of the insulin signaling pathway in the liver and brain of mice.

In oriental medicine, Liriope platyphylla (LP) has long been regarded as a curative herb useful for the treatment of diabetes, asthma, and neurodegenerative disorders. The principal objective of this study was to assess the effects of steaming time and frequency for manufactured Red LP (RLP) on insulin secretion ability and insulin receptor signaling pathway. To achieve our goal, several types of LPs manufactured under different conditions were applied to INS cells and streptozotocin (STZ)-induced diabetic ICR mice, after which alterations in insulin concentrations were detected in the culture supernatants and sera. The optimal concentration for the investigation of insulin secretion ability was found to be 50 ug/mL of LP. At this concentration, maximum insulin secretion was observed in the INS cells treated with LP extract steamed for 3 h (3-SLP) with two repeated steps (3 h steaming and 24 h air-dried) carried out 9 times (9-SALP); no significant changes in viability were detected in any of the treated cells. Additionally, the expression and phosphorylation levels of most components in the insulin receptor signaling pathway were increased significantly in the majority of cells treated with steaming-processed LP as compared to the cells treated with LP prepared without steaming. With regard to glucose transporter (GLUT) expression, alterations of steaming time induced similar responses on the expression levels of GLUT-2 and GLUT-3. However, differences in steaming frequency were also shown to induce dose-dependent responses in the expression level of GLUT-2 only; no significant differences in GLUT-3 expression were detected under these conditions. Furthermore, these responses observed in vitro were similarly detected in STZ-induced diabetic mice. 24-SLP and 9-SALP treatment applied for 14 days induced the down-regulation of glucose concentration and upregulation of insulin concentration. Therefore, these results indicated that the steaming processed LP may contribute to the relief of diabetes symptoms and should be regarded as an excellent candidate for a diabetes treatment.

맥문동(Liriope platyphylla)은 동양의학에서 오래 동안 항염증제, 당뇨 혹은 비만 치료제, 그리고 신경세포활성화 약제로 사용되어 왔다. 본 연구에서는 맥문동으로부터 NGF의 발현을 촉진하는 새로운 물질을 개발하고 이들의 작용기전을 밝히기 위하여 맥문동으로부터 13가지의 새로운 추출물을 확보하고 이들의 기능을 세포주와 마우스 실험을 통해 분석하였다. 그 결과, 상대적으로 세포독성이 낮고 NGF의 분비량이 많은 LP-E, LP-M, LP-M50, LP2E17PJ 등 4가지 추출물을 확보하였다. 또한 이들 중에서 LP2E17PJ를 제외한 3가지 추출물에 의해 분비된 NGF는 PC12세포의 neuritic outgrowth를 촉진하였다. 더불어 추출방법과 추출량의 측면에서 효과적인 LP-M을 C57BL/6 마우스에 2주간 투여하여 뇌조직에서 NGF mRNA의 발현을 확인하였다. LP-M은 오직 피질에서만 두 종류의 receptor 중에서 low affinity receptor를 통한 억제신호를 전달하였으며, 해마에서는 유의적인 변화를 유도하지 못했다. 그러나 high affinity receptor를 통한 신호전달은 해마에서만 활성화 신호를 전달하였고 피질에서는 변화를 유도하지 못했다. 이러한 결과는 맥문동 추출물인 LP-M은 마우스 대뇌의 해마에서 high affinity receptor를 통한 신호전달을 통해 neuritic outgrowth를 촉진함을 확인하였다. Liriope platyphylla has been used in oriental medicine as an effective medical plant to improve symptoms of cough, sputum production, neurodegenerative disorders, obesity and diabetes for long time. In order to investigate the effects of novel extracts on nerve growth factors (NGF)-stimulated neuritic outgrowth, the alteration of NGF expression and NGF receptor signaling pathway were detected in neuroblastoma cells and C57BL/6 mice. Of a total of 13 novel extracts, 4 extracts (LP-E, LP-M, LP-M50, LP2E17PJ) showed high viability on MTT assay. Also, all of these extracts induced NGF secretion and NGF mRNA expression in neuroblastoma cells. However, the NGF-induced neuritic outgrowth from PC12 cells was only stimulated by LP-E, LP-M and LP-M50. Furthermore, we selected LP-M as a best candidate, based on method and amounts of extraction, in order to verify its effect in mice. C57BL/6 mice were treated with 50 mg/kg of LP-M for 2 weeks and the effects on NGF regulation were analyzed with various methods. The expression of NGF mRNA was significantly increased in LP-M treated mice compared to vehicle treated mice. Also, the signaling pathway of p75NTR was inhibited in the cortex by LP-M treatment, with no change in the hippocampus of brain. However, the signaling pathway of TrkA was dramatically activated in only hippocampus via LP-M treatment. Therefore, these results suggest that the novel four extracts of L. platyphylla may contribute to the regulation of NGF expression and secretion in neuronal cells. LP-M was especially considered to be an excellent candidate for a neurodegenerative disease-therapeutic drug.

In the present study, the anti-inflammatory and antisepticemic activities of a water extract of Liriope platyphylla (LP) were investigated. We first estimated the scavenging activity of DPPH and the hydroxyl radical and total phenolic contents of LP. Results indicated that LP, a rich source of phenolic compounds, showed a remarkable radical scavenging capacity. A MTT assay showed that LP treatment did not affect the toxicity against the RAW 264.7 macrophage cells, up to the concentration of 500[Formula: see text][Formula: see text]g/mL. Treatment of LP significantly attenuated the production of inflammatory mediators, such as nitric oxide (NO), interleukin-6 (IL-6), tumor-necrosis factor (TNF)-[Formula: see text] and prostaglandin (PG)E2 in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages cells. Moreover, LP contributed to the down-regulation of inducible NO synthase (iNOS) and TNF-[Formula: see text] mRNA expression, as well as cyclooxygenase-2 (COX-2) protein expression. A western blotting assay further showed that LP inhibited activation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-[Formula: see text]B. In an animal experiment using an LPS-induced septicemia model in C57BL/6 mice, oral administration of LP (40[Formula: see text]mg/kg body weight) markedly reduced the level of TNF-[Formula: see text] and IL-6 in serum and protected against LPS-induced lethal shock in mice. Taken together, the results of treatments of LP on inhibited LPS-induced inflammatory responses in both in vitro and in vivo models and indicate it may be a promising neutraceutical or medicinal agent to prevent or cure inflammation-related disease.

Objective To analyze the effects of bone morphogenetic protein 7 (BMP 7) on insulin signaling pathway in mice and its involved molecular mechanisms. Methods To increase BMP7 expression in liver, adenovirus bearing BMP7 was injected into mice via tail vein. The impact of BMP7 overexpression on glucose metabolism was assayed by glucose tolerance test and insulin tolerance test. The levels of proteins involved in insulin signaling pathway and c-Jun N-terminal kinase (JNK) signaling pathway were analyzed by Western blot. Results The blood glucose level was increased by BMP7 overexpression (P<0.05), while the glucose tolerance and insulin tolerance were decreased by BMP7. The p-Akt and p-GSK3β in liver and epididymal white adipose tissue (WAT) were reduced in the BMP7-overexpressed mice (P<0.01), indicating insulin signal transduction was inhibited. In gastrocnemius muscle, the insulin signal transduction was not altered by BMP7. Mechanistically, the JNK pathway was activated by BMP7 in liver and epididymal WAT (P<0.01), while the JNK pathway in skeletal muscle was not changed. Conclusions In mice, BMP7 elevated blood sugar and decreased glucose and insulin tolerance. BMP7 inhibited the insulin signaling pathway in liver and WAT. These inhibitory effects on insulin signaling pathway was likely to be achieved by an activating JNK signaling pathway. (Chin J Endocrinol Metab, 2018, 34: 398-403) Key words: Bone morphogenetic protein 7; Insulin signaling transduction; JNK; Insulin resistance; Diabetes mellitus, experimental

The epithelial sodium channel (ENaC) plays an important role in transepithelial Na(+) absorption; hence its function is essential for maintaining Na(+) and fluid homeostasis and regulating blood pressure. Insulin is one of the hormones that regulates activity of ENaC. In this study, we investigated the contribution of two related protein kinases, Akt (also known as protein kinase B) and the serum- and glucocorticoid-dependent kinase (Sgk), on insulin-induced ENaC activity in Fisher rat thyroid cells expressing ENaC. Overexpression of Akt1 or Sgk1 significantly increased ENaC activity, whereas expression of a dominant-negative construct of Akt1, Akt1(K179M), decreased basal activity of ENaC. Inhibition of the endogenous expression of Akt1 and Sgk1 by short interfering RNA not only inhibited ENaC but also disrupted the stimulatory effect on ENaC of insulin and of the downstream effectors of insulin, phosphatidylinositol 3-kinase and PDK1. Conversely, overexpression of Akt1 or Sgk1 increased expression of ENaC at the cell membrane and overcame the inhibitory effect of Nedd4-2 on ENaC. Furthermore, mutation of consensus phosphorylation sites on Nedd4-2 for Akt1 and Sgk1, Ser(342) and Ser(428), completely abolished the inhibitory effect of Sgk1 and Akt1 on Nedd4-2 action. Together these data suggest that both Akt and Sgk are components of an insulin signaling pathway that increases Na(+) absorption by up-regulating membrane expression of ENaC via a regulatory system that involves inhibition of Nedd4-2.

NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy

Objective To investigate the effects of JNK inhibition on insulin signaling pathway. Methods HepG2 cells were treated with different kinds of JNK inhibitors for 12 h, and then the cells were treated with 10 nmol/L insulin for 5 min to stimulate insulin signaling pathway. Mitogen-activated protein kinases(MAPK)and insulin signaling pathways were analyzed by Western blot using the total cell lysates. Results JNK activity was significantly inhibited by JNK inhibitor JNKi-Ⅷ and results showed that JNKi-Ⅷ treatment could reduce insulin signaling pathway in a dose-dependent manner. Furthermore, other JNK inhibitors including JNKi-Ⅴ, JNKi-Ⅲ, and SP600125 blocked JNK activity in HepG2 cells. Similar to JNKi-Ⅷ, these JNK inhibitors also impaired insulin signaling transduction in a dose-dependent manner. Conclusion In HepG2 hepatocytes, JNK activity inhibition blocks insulin signaling transduction. (Chin J Endocrinol Metab, 2017, 33: 129-134) Key words: JNK; JNK inhibitors; MAPK signaling pathway; Insulin signaling pathway; HepG2 hepatocytes

BackgroundOxidative stress is involved in neuronal cell death and mitochondrial dysfunction in neurodegenerative diseases. Liriope platyphylla (LP) has been suggested to have anti-inflammation, anti-bacterial, and anti-cancer effects. However, whether LP exerts neuroprotective effects on neuronal cells is unknown.MethodsThe present study was performed to investigate the neuroprotective effects of LP extract (LPE) against hydrogen peroxide (H2O2)-induced injury in human neuroblastoma cells SH-SY5Y. To test neuroprotective effects of LPE, we performed cell viability assay, flow cytometry analysis and western blot analysis. In addition, mitochondrial membrane potential (MMP) and oxidative stress were performed to evaluate the anti-apoptotic and anti-oxidant effects.ResultsLPE pretreatment conferred significant protection against the H2O2-induced decrease of SH-SY5Y cell viability. H2O2-induced increases of intracellular oxidative stress and mitochondrial dysfunction were attenuated by LPE pretreatment. Therefore, LPE pretreatment prevented SH-SY5Y cell injury. Treatment with H2O2 significantly induced poly(ADP ribose) polymerase (PARP) and caspase-3 cleavage, which was blocked by LPE. We found that p38 activation was involved in the neuroprotective effects of LPE.ConclusionsCurrent findings suggest that LPE exerts neuroprotective effects against H2O2-induced apoptotic cell death by modulating p38 activation in SH-SY5Y cells. Therefore, LPE has potential anti-apoptotic effects that may be neuroprotective in neurodegenerative diseases and aging-related dementia.

Recent studies have shown that statins can influence insulin resistance (IR) in animal models and in humans.1,2 However, the mechanism by which statins influence the insulin signaling pathway (ISP) remains obscure. It has been proposed that the pleiotropic effects of statins might be involved in regulation of IR. The phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway is the main ISP. Insulin binding to insulin receptor initiates PI3K-Akt pathway by phosphorylates tyrosine residue of IR substrate proteins (IRSs) including IRS-1 and IRS-2. Activation of the PI3K leads to the accumulation of phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 activates serine/threonine kinase (Akt). Glucose transporter-4 (GLUT-4) translocates to plasma membrane from cytosol by serine phosphorylation of Akt and directly regulates glucose metabolism in liver, muscle and adipose tissue (Figure 1). However, an overall mechanism by which statins influence ISP remained obscure.Figure 1.: Insulin signaling pathway.Effect of statins on ISP via regulation of adipocytokines adiponectin Adiponectin, a prototypic adipocytokine, has an anti-inflammatory and anti-insulin resistance function.3 An increment of serum adiponectin level and amelioration of IR has been reported after the administration of pravastatin and pitavastatin.4,5 The adiponectin-deficient mice developed more severe IR within 2 weeks of a high-fat, high-sucrose diet than control group.6 Replenishment of adiponectin significantly ameliorated high-fat diet-induced IR. Adiponectin signaling pathway activates ISP. Leucine zipper containing 1 (APPL1) is an endosomal protein binds to the N-terminal domains of AdipoR1 and AdipoR2. APPL1 activates insulin signaling of PI3K and interferes with Tribble-3 (TRB3) binding which in turn resulted in insulin-stimulated Akt/PKB activation (Figure 2).Figure 2.: Adiponectin signaling pathway activates ISP.Leptin Leptin is a 16-kDa protein produced mainly by adipocytes and encoded by Ob gene. Leptin and insulin may coordinately act to control energy homeostasis. Leptin receptor b (ObRb) activation induces phosphorylation of IRS2 via SH2B1, an interaction partner of JAK2 (Figure 3).7 ObR-deficient rats improved insulin sensitivity in a PI3K-dependent way after expression of the ObRb.8Figure 3.: Leptin signaling pathway activates ISP.It is indicated that there is an interaction between leptin and statins. Atorvastatin was reported to decrease leptin levels in patients with coronary artery disease (CAD).9 Moreover, statins inhibit the leptin expression in vascular smooth muscle cells, adipocytes and human coronary artery endothelial cells.10 Resistin Hyperglycemia, which occurs in type 2 diabetes mellitus, could produce an increased resistin expression. Plasma resistin concentrations were higher in type 2 diabetic patients than in normal subjects.11 Administration of recombinant resistin will lead to glucose intolerance in mice and impaired insulin action in rat's liver.12 Resistin level was significantly decreased after 12 weeks of pitavastatin.13 Simvastatin was also demonstrated to inhibit resistin over-expression. The c-jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family which phosphorylates serine 307 of IRS proteins (Figure 4). JNK pathway mediates the inhibitory effect of resistin on IRS- 1 activity.14 Moreover, resistin disturbs single nucleotide polymorphisms (SNP)-420 which is a gene found to be associated with IR.15Figure 4.: The JNK pathway.RBP4 RBP4, a molecule secreted by adipocytes and liver, contributes to systemic IR. Elevated RBP4 levels have been reported in people with IR and type 2 diabetes mellitus.16 Increased serum RBP4 levels impair postreceptor insulin signaling at the level of PI3K in muscle and liver. Rosuvastatin significantly decreases the level of serum RBP4.17 Thus, statin therapy provides a rationale for improving the IR by lowering RBP4. Visfatin Circulating visfatin, an adipokine interfering with the central regulation of insulin sensitivity, was positively associated with IR. A meta-analysis demonstrated that plasma visfatin concentrations were increased in participants diagnosed with type 2 diabetes mellitus and metabolic syndrome.18 Visfatin show a dose-dependent significant up-regulation in PI3K activity.19 However, atorvastatin and rosuvastatin administration decreased visfatin serum levels significantly.20 Effect of statins on ISP via regulation of inflammatory factors Interleukin-1β The cytokine interleukin 1β has been implicated as a pathogenetic factor in the initial events leading to insulin-dependent diabetes mellitus. However, a study showed JNK can be activated by interleukin-1β indicating that interleukin-1β plays a role in IR and type 2 diabetes mellitus as well.21 Statins are lipid-lowering drugs that exhibit anti-inflammatory and immune-modulatory properties. It is demonstrated that interleukin-1β was significantly decreased in the atorvastatin treated group.22 Therefore, statin treatment inhibits interleukin-1β and prevents activation of JNK. Tumor necrosis factor (TNF)-α TNF-α is also linked to the presentation of IR in humans supported by substantial evidences. Direct exposure to TNF-α impairs ISP and induces IR in myocytes and adipocytes.23 Protein-tyrosine phosphatase (PTP) 1B acts as a negative regulator of insulin signaling by dephosphorylating the phosphotyrosine residues of insulin receptor and IRS-1 (Figure 5). Up-regulation of PTP 1B expression was recently found in cells and animals treated with TNF-α. Consistently, PTP-1B expression is up-regulated in the insulin-resistant hamsters. Moreover, JNK pathway can be activated by TNF-α leading to phosphorylation of serine residue of IRS.Figure 5.: The PTP 1B pathway.Rosuvastatin, simvastatin and pitavastatin lowered plasma levels of TNF-α in patients with type 2 diabetes mellitus.24,25 TNF-α production was also reduced in lipopolysaccharide-activated monocytes from patients treated with atorvastatin.26 Rosuvastatin normalizes elevated PTP-1B protein levels associated with fructose-induced insulin resistance.27 Effect of statins on ISP via reduction of oxidative stress Oxidative stress is enhanced in adipose tissue before diabetes development suggesting that adipose tissue may be a major source of reactive oxygen species (ROS). A study by Wei et al28 claimed that the ISP is impaired in cultured skeletal muscle cells due to ROS. ROS leads to a decrease of Akt phosphorylation by JNK pathway resulted in deterioration of IR.29 Treatment with anti-oxidative agents improves IR and restores adiponectin production.30 In subjects with metabolic syndrome, statins are associated with a reduction in markers of oxidative stress.31 Effect of statins on ISP via inhibition of isoprenoid synthesis Statins by inhibiting the synthesis of isoprenoids, block the activation of small GTPases which are involved in the GLUT4 expression to the plasma membrane of adipocytes.32,33 Lovastatin downregulates GLUT4 expression and decreases the insulin-mediated glucose uptake in adipocytes.33 Atorvastatin was shown to dosedependently inhibit insulin-mediated glucose uptake by inhibiting GLUT4 translocation and phosphorylation of IRS-1 and Akt.34 Effect of statins on ISP via regulation of lipid metabolism Treatment with low-density lipoprotein (LDL) resulted in increased JNK phosphorylation and release of cytokines from macrophages. High-density lipoprotein (HDL) cotreatment reversed phosphorylation of JNK and release of pro-inflammatory cytokines.35 LDL impairs ISP while HDL restores defective glucose uptake. Levels of free fatty acids (FFAs) are increased under obese diabetic conditions with IR. The JNK pathway which leads to IR can be activated by FFAs.36 It is widely accepted that statins can increase HDL, decrease LDL and FFAs level. Statins have multi-targets on ISP and exhibit different effect on IR under different conditions. Statins with different dose, potency and hydrophilicity perform different effect on IR. It is reported that statins increase the risk of new onset of diabetes mellitus.37 The incidence of diabetes mellitus seems to be type and dose dependent on statins.38 Another study drew a conclusion that risk of new onset diabetes is associated with the potency of statins. Compared with low potency statins such as pravastatin, treatment with higher potency statins, especially atorvastatin and simvastatin, is correlated with an increased risk of new onset diabetes.39 Comparison trials also suggest a preferable IR improving effect of the hydrophilic statins pravastatin, rosuvastatin and pitavastatin as compared to lipophilic statins including atorvastatin and simvastatin.40 Hydrophilic statins increased the serum adiponectin level and decreased ox-LDL level after switching from lipophilic statins, indicating that insulin sensitizing effect of hydrophilic statins is more significant than lipophilic statins.41 However, there are opposite voices claiming that statins have no beneficial effect or even adverse effect on IR. A study by Kostapanos et al42 claimed that rosuvastatin therapy was associated with a dosedependent increase in IR. Another study claimed that atorvastatin treatment increased homeostasis model assessment index (HOMA-IR) by 36.1% and pitavastatin increased HOMA-IR by 27.0%.43 Moreover, a few studies indicated no change in the degree of IR was observed with statin therapy. 40 In conclusion, statins play an important role in regulating ISP due to the pleiotropic effect. This effect of statins is mediated by regulation of serum adipocytokines, pro-inflammatory factors, oxidative stress, isoprenoid and lipid metabolism. The views of this article is that statins have opposite effect on ISP. Statins inhibit ISP at the level of IRS2, PI3K and GLUT4 by leptin, visfatin and isoprenoid respectively (Figure 6).Figure 6.: The mechanisms by which statins inhibit ISP.However, Statins also activates ISP by regulating a variety of mediators. Adiponectin is up-regulated by statins and stimulates both PI3K and Akt. HDL level is increased by statins and thus activates IRS1. Resistin, interleukin-1β, TNF-α, ROS, LDL, FFAs interferes with ISP at the level of IRS1 by JNK pathway. TNF-α alone impairs ISP by PTP 1B pathway. In contrast with adiponectin, RBP4 disturbs the activation of PI3K. All of these interferences are suppressed by statin therapy (Figure 7).Figure 7.: The mechanisms by which statins activate ISP.Therefore, our conclusion is that the activation and inhibition of ISP by statins coexist due to the pleiotropic effect. Statins have bidirectional effect on ISP.

Liriope platyphylla (LP) has long been regarded as a curative herb for the treatment of diabetes, asthma, and neurodegenerative disorders. To examine the therapeutic effects of Red LP (RLP) manufactured by steaming process on neurodegenerative disorders, significant alteration of the key factors influencing Alzheimer's Disease (AD) was detected in NSE/hAPPsw transgenic (Tg) mice after RLP treatment. The concentration of nerve growth factor (NGF) in serum increased in RLP-treated NSE/hAPPsw Tg mice compared with vehicle-treated Tg mice. However, downstream effectors of the NGF receptor signaling pathway, including TrkA and p75NTR proteins, were suppressed in RLP-treated NSE/hAPPsw Tg mice. Especially, Tg mice showed decreased levels of TrkA, p75NTR, and RhoA expression. Production of Aβ-42 peptides was lower in RLP-treated NSE/hAPPsw Tg mice than in vehicle-treated Tg mice. Further, analysis of γ-secretase components showed that Aβ-42 peptide expression was downregulated. Of the four components, the expression of APH-1 and Nicastrin (NCT) decreased in RLP-treated NSE/hAPPsw Tg mice, whereas expression of PS-2 and Pen-2 was maintained or increased within the same group. Overall, these results suggest that RLP can help relieve neurodegenerative diseases, especially AD, through upregulation of NGF secretion ability, activation of NGF signaling pathway, downregulation of Aβ-42 peptide deposition, and alteration of γ-secretase components.

Anti-viral effect of a compound isolated from Liriope platyphylla against hepatitis B virus in vitro

An adverse intrauterine environment, induced by a chromium-restricted diet, is a potential cause of metabolic disease in adult life. Up to now, the relative mechanism has not been clear. C57BL female mice were time-mated and fed either a control diet (CD), or a chromium-restricted diet (CR) throughout pregnancy and the lactation period. After weaning, some offspring continued the diet diagram (CD-CD or CR-CR), while other offspring were transferred to another diet diagram (CD-CR or CR-CD). At 32 weeks of age, glucose metabolism parameters were measured, and the liver from CR-CD group and CD-CD group was analyzed using a gene array. Quantitative real-time polymerase chain reaction (qPCR) and Western blot were used to verify the result of the gene array. A maternal chromium-restricted diet resulted in obesity, hyperglycemia, hyperinsulinemia, increased area under the curve (AUC) of glucose in oral glucose tolerance testing and homeostasis model assessment of insulin resistance (HOMA-IR). There were 463 genes that differed significantly (>1.5-fold change, p < 0.05) between CR-CD offspring (264 up-regulated genes, 199 down-regulated genes) and control offspring. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis revealed that the insulin signaling pathway and Wnt signaling pathway were in the center of the gene network. Our study provides the first evidence that maternal chromium deficiency influences glucose metabolism in pups through the regulation of insulin signaling and Wnt signaling pathways.

Discoidin domain receptors (DDRs) DDR1 and DDR2 are receptor tyrosine kinases with the unique ability among receptor tyrosine kinases to respond to collagen. Several signaling molecules have been implicated in DDR signaling, including Shp-2, Src, and MAPK pathways, but a detailed understanding of these pathways and their transcriptional targets is still lacking. Similarly, the regulation of the expression of DDRs is poorly characterized with only a few inflammatory mediators, such as lipopolysaccharide and interleukin-1β identified as playing a role in DDR1 expression. DDRs have been reported to induce the expression of various genes including matrix metalloproteinases and bone morphogenetic proteins, but the regulatory mechanisms underlying DDR-induced gene expression remain to be determined. The aim of the present work was to elucidate the molecular mechanisms implicated in the expression of DDRs and to identify DDR-induced signaling pathways and target genes. Our data show that collagen I induces the expression of DDR1 in a dose- and time-dependent manner in primary human lung fibroblasts. Furthermore, activation of DDR2, JAK2, and ERK1/2 MAPK signaling pathways was essential for collagen I-induced DDR1 and matrix metalloproteinase 10 expression. Finally, inhibition of the ERK1/2 pathway abrogated DDR1 expression by blocking the recruitment of the transcription factor polyoma enhancer A-binding protein 3 to the DDR1 promoter. Our data provide new insights into the molecular mechanisms of collagen I-induced DDR1 expression and demonstrate an important role for ERK1/2 activation and the recruitment of polyoma enhancer-A binding protein 3 to the DDR1 promoter.