D-beta-hydroxybutyrate reduced the enhanced cardiac microvascular endothelial FoxO1 to play protective roles in diabetic rats and high glucose-stimulated human cardiac microvascular endothelial cells.

The O subfamily of forkhead (FoxO) 1 may participate in the pathogenesis of diabetic microvascular endothelial injury. However, it is unknown whether D-beta-hydroxybutyrate (BHB) regulates cardiac microvascular endothelial FoxO1 to play protective roles in diabetes. In the study, limb microvascular morphological changes, endothelial distribution of the tight junction protein Claudin-5 and FoxO1, and FoxO1 content in limb tissue from clinical patients were evaluated.

D-beta-hydroxybutyrate protects against microglial activation in lipopolysaccharide-treated mice and BV-2 cells.

Microglial activation is a key event in neuroinflammation, which, in turn, is a central process in neurological disorders. In this study, we investigated the protective effects of D-beta-hydroxybutyrate (BHB) against microglial activation in lipopolysaccharide (LPS)-treated mice and BV-2 cells. The effects of BHB in mice were assessed using behavioral testing, morphological analysis and immunofluorescence labeling for the microglial marker ionizing calcium-binding adaptor molecule 1 (IBA-1) and the inflammatory cytokine interleukin-6 (IL-6) in the hippocampus.

Taurine inhibits KDM3a production and microglia activation in lipopolysaccharide-treated mice and BV-2 cells.

Microglia activation has been suggested as the key factor in neuro-inflammation and thus participates in neurological diseases. Although taurine exhibits anti-inflammatory and neuro-protective effects, its underlying epigenetic mechanism is unknown. In this study, taurine was administered to lipopolysaccharide (LPS)-treated mice and BV-2 cells.

Crocin ameliorates atherosclerosis by promoting the reverse cholesterol transport and inhibiting the foam cell formation via regulating PPARγ/LXR-α.

Crocin (CRO) is feasible in alleviating atherosclerosis (AS), the mechanism of which was therefore explored in the study. High-fat diet (HFD)-induced apolipoprotein E-deficient (ApoE) mice and lysophosphatidic acid (LPA)-treated macrophages received CRO treatment. Treated macrophage viability was determined via MTT assay.

β-Hydroxybutyrate inhibits cardiac microvascular collagen 4 accumulation by attenuating oxidative stress in streptozotocin-induced diabetic rats and high glucose treated cells.

Accumulation of collagen 4 (COL4) and thickened basement membrane are features of diabetic cardiac microvascular fibrosis that may be induced by oxidative stress. The ketone body β-hydroxybutyrate exhibits various cardiovascular protective effects, however its mechanism remains to be clarified. In the current study, the effects of β-hydroxybutyrate on cardiac microvascular fibrosis and COL4 accumulation were evaluated in streptozotocin-induced diabetic rats and in high glucose (HG) treated human cardiac microvascular endothelial cells (HCMECs).

β-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes.

Aims/hypothesis: Microvascular endothelial hyperpermeability, mainly caused by claudin-5 deficiency, is the initial pathological change that occurs in diabetes-associated cardiovascular disease. The ketone body β-hydroxybutyrate (BHB) exerts unique beneficial effects on the cardiovascular system, but the involvement of BHB in promoting the generation of claudin-5 to attenuate cardiac microvascular hyperpermeability in diabetes is poorly understood.

Methods: The effects of BHB on cardiac microvascular endothelial hyperpermeability and claudin-5 generation were evaluated in rats with streptozotocin-induced diabetes and in high glucose (HG)-stimulated human cardiac microvascular endothelial cells (HCMECs).

Tumor supernatant derived from hepatocellular carcinoma cells treated with vincristine sulfate have therapeutic activity.

Vincristine sulfate (VCR), a commonly used chemotherapeutic agent, kills cancer cells as well as the normal cells for its cytotoxicity. But it is still unclear whether it can exert therapeutic effect on untreated cancer cells by changing the supernatant of cancer cells. Here, we explored the subsequent cascade effects of the supernatant of cancer cells that were transiently treated with VCR on untreated tumor cells and its responsible mechanisms.

Up-regulation of MMP-2 by histone H3K9 β-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat.

Aims: Besides energy supply, β-hydroxybutyrate (BHB) acts as a bioactive molecule to play multiple protective roles, even in diabetes and its complications. The aim of this study was to investigate the antagonizing effects of BHB against diabetic glomerulosclerosis and the underlying mechanism.

Methods: Male Sprague-Dawley rats were intraperitoneally injected with streptozotocin to induce diabetes and then treated with different concentrations of β-hydroxybutyrate.

β-hydroxybutyrate antagonizes aortic endothelial injury by promoting generation of VEGF in diabetic rats.

Endothelial injury is regarded as the initial pathological process in diabetic vascular diseases, but effective therapy has not yet been identified. Although β-hydroxybutyrate plays various protective roles in the cardiovascular system, its ability to antagonize diabetic endothelial injury is unclear. β-hydroxybutyrate reportedly causes histone H3K9 β-hydroxybutyrylation (H3K9bhb), which activates gene expression; however, there has been no report regarding the role of H3K9bhb in up-regulation of vascular endothelial growth factor (VEGF), a crucial factor in endothelial integrity and function.

Targeted induction of bone marrow mesenchymal stem cells to have effectiveness on diabetic pancreatic restoration.

Although bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to be effective for the attenuation of diabetes, they have limitations. Whether BMSCs can be target-induced by pancreatic stem cells (PSCs) to have effectiveness for the restoration of diabetic islet injury was unknown. In this study, based on their successful isolation and cultivation, BMSCs were co-cultured with PSCs.

C-peptide prevents SMAD3 binding to alpha promoters to inhibit collagen type IV synthesis.

Activation of transforming growth factor β1 (TGFB1)/SMAD3 signaling may lead to additional synthesis of collagen type IV (COL4), which is a major contributor to extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can attenuate fibrosis to have unique beneficial effects in DN. However, whether and how C-peptide affects TGFB1/SMAD3-activated COL4 synthesis is unclear.

C-peptide prevents NF-κB from recruiting p300 and binding to the inos promoter in diabetic nephropathy.

C-peptide (CP) has demonstrated unique beneficial effects in diabetic nephropathy (DN), but whether and how CP regulates NF-κB and its coactivator, p300, to suppress inducible iNOS and antagonize DN are unknown. iNOS expression, NF-κB nuclear translocation, colocalization and binding of NF-κB to p300, binding of NF-κB to the inos promoter, and the bound NF-κB, p300, and histone 3 lysine 9 acetylation (H3K9ac) at binding sites were measured in high glucose-stimulated mesangial cells. We evaluated pathologic changes, iNOS expression, NF-κB, and p300 contents in diabetic rats.

C-peptide exhibits a late induction effect on matrix metallopeptidase-9 in high glucose-stimulated rat mesangial cells.

Insufficient matrix metalloproteinase (MMP)-9 and MMP-2 is considered to be a contributor of extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can reverse fibrosis, thus exerting a beneficial effect on DN. Whether C-peptide induces MMP-9 and MMP-2 to reverse ECM accumulation is not clear.

Ginsenoside exhibits concentration-dependent dual effects on HepG2 cell proliferation via regulation of c-Myc and HNF-4α.

Although ginsenoside can generally promote cell proliferation, it is reported to have anti-proliferative effects in hepatocellular carcinoma (HCC). Whether ginsenoside has concentration-dependent effects on HCC cell proliferation have not been clarified. Transcription factors c-Myc and hepatocyte nuclear factor (HNF)-4α are the most important opposite controllers of HCC cell proliferation.

High glucose decreases claudins-5 and -11 in cardiac microvascular endothelial cells: Antagonistic effects of tongxinluo.

Unlabelled: Purpose/aim of the study: Claudins-5, -9, and -11 are tight-junction proteins that are mainly expressed in endothelial cells. Their deficiency may lead to cell barrier dysfunction, which is considered as the initiating process and pathological basis of cardiovascular disease in diabetes. We investigated whether high glucose (HG) affects claudins-5, -9, and -11 in human cardiac microvascular endothelial cells (HCMECs), and examined the effects of the traditional Chinese medication tongxinluo (TXL) on these tight junction proteins.

Macrophages Aggravate Hypoxia-Induced Cardiac Microvascular Endothelial Cell Injury via Peroxynitrite: Protection by Tongxinluo.

Activated macrophages contribute to endothelial dysfunction; however, it is unclear how peroxynitrite contributes to macrophage-mediated human cardiac microvascular endothelial cell (HCMEC) injury in hypoxia. In macrophage-HCMEC co-cultures subjected to hypoxia, there was an increase in hypoxia-inducible factor (HIF)-1α, HIF-2α, inducible nitric oxide synthase (iNOS), endothelin-converting enzyme (ECE)-1 and cyclooxygenase-2 (COX-2), and concomitant decrease in prostacyclin synthase (PGIS). This was mimicked by a peroxynitrite donor and attenuated by its decomposition catalyst.

Tongxinluo Reverses the Hypoxia-suppressed Claudin-9 in Cardiac Microvascular Endothelial Cells.

Background: Claudin-5, claudin-9, and claudin-11 are expressed in endothelial cells to constitute tight junctions, and their deficiency may lead to hyperpermeability, which is the initiating process and pathological basis of cardiovascular disease. Although tongxinluo (TXL) has satisfactory antianginal effects, whether and how it modulates claudin-5, claudin-9, and claudin-11 in hypoxia-stimulated human cardiac microvascular endothelial cells (HCMECs) have not been reported.

Methods: In this study, HCMECs were stimulated with CoCl2to mimic hypoxia and treated with TXL.

Developmental Stage-Specific Embryonic Induction of HepG2 Cell Differentiation.

Background: Although hepatocellular carcinoma cells can sometimes undergo differentiation in an embryonic microenvironment, the mechanism is poorly understood.

Aim: The developmental stage-specific embryonic induction of tumor cell differentiation was investigated.

Methods: Both chick and mouse liver extracts and hepatoblast-enriched cells at different developmental stages were used to treat human hepatoma HepG2 cells, and the effects on the induction of differentiation were evaluated.

Tongxinluo inhibits cyclooxygenase-2, inducible nitric oxide synthase, hypoxia-inducible factor-2α/vascular endothelial growth factor to antagonize injury in hypoxia-stimulated cardiac microvascular endothelial cells.

Background: Endothelial dysfunction is considered as the initiating process and pathological basis of cardiovascular disease. Cyclooxygenase-2 (COX-2) and prostacyclin synthase (PGIS), inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) are key enzymes with opposing actions in inflammation and oxidative stress, which are believed to be the major driver of endothelial dysfunction. And in hypoxia (Hx), Hx-inducible factor (HIF)-1α and HIF-2α are predominantly induced to activate vascular endothelial growth factor (VEGF), resulting in abnormal proliferation.

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit.

On the basis of their characteristics, we presume that developmental stage-specific hepatocytes should have the ability to induce maturation of hepatoma cells. A regulatory circuit formed by hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-6 and the upstream stimulatory factor (USF-1) play a key role in the maturation of embryonic hepatocytes; however, it is unclear whether the regulatory circuit mediates the embryonic induction of hepatoma cell maturation. In this study, 12.

Dynamic localization and functional implications of C-peptide might for suppression of iNOS in high glucose-stimulated rat mesangial cells.

Although C-peptide has unique beneficial effects on diabetic nephropathy (DN), its functional localization and molecular mechanism have not been fully clarified. Whether C-peptide exhibits its protective role through the regulation of inducible nitric oxide synthase (iNOS), a key enzyme in oxidative stress, is not clear. In this study, it was revealed that C-peptide could enter the nucleus of high glucose-stimulated mesangial cells, especially in a time-dependent manner by high glucose pretreatment, while no C-peptide was detected in low glucose-cultured mesangial cells.

Regulation of iNOS expression by NF-κB in human lens epithelial cells treated with high levels of glucose.

Purpose: To explore the regulation of inducible nitric oxide synthase (iNOS) expression by nuclear factor kappa B (NF-κB) in human lens epithelial cells (LECs) treated with high levels of glucose, and to elucidate the impact of this in the pathogenesis of cataracts associated with diabetes.

Methods: LECs (SRA01/04) were cultured in vitro. NF-κB nuclear translocation and iNOS expression were measured at different glucose concentrations and at various time points, and the optimal concentration for detecting changes in the patterns of NF-κB nuclear translocation and iNOS expression was chosen.

Protein nitration promotes inducible nitric oxide synthase transcription mediated by NF-κB in high glucose-stimulated human lens epithelial cells.

Although an important event in hyperglycaemia-induced oxidative stress is the nuclear factor-kappa b (NF-κB)-activated inducible nitric oxide synthase (iNOS) expression, the underlying mechanism is not fully characterized. Peroxynitrite, formed from NO and superoxide, can induce multiple proteins nitration, even including NF-κB and iNOS, to alter their functions. In this study, we found high glucose caused conspicuous nitration of nuclear NF-κB p65 and its co-activator p300 in human lens epithelial cells.

Prebiotics and oxidative stress in constipated rats.

Objectives: Constipation can adversely affect children's health, with disorders of host immunity and enhanced oxidative stress. As nondigestible carbohydrates, prebiotics can affect the host with constipation; however, whether the prebiotics have effects on the content of intestinal secretory immunoglobulin A (sIgA) and the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) in constipation has not been fully clarified.

Methods: In the present study, constipation was induced in female Sprague-Dawley rats by diphenoxylate, and the prebiotics dissolved in milk were used as an intervention.