Lacidophilin tablets alleviate constipation through regulation of intestinal microflora by promoting the colonization of Akkermansia sps.

Constipation is a major health problem worldwide that requires effective and safe treatment options. Increasing evidence indicates that disturbances in gut microbiota may be a risk factor for constipation. Administration of lacidophilin tablets shows promising therapeutic potential in the treatment of inflammatory bowel disease owing to their immunomodulatory properties and regulation of the gut microbiota. The focus of this study was on investigating the ability of lacidophilin tablets to relieve constipation by modulating the gut microbiome. Rats with loperamide hydrochloride induced constipation were treated with lacidophilin tablets via intragastric administration for ten days. The laxative effect of lacidophilin tablets was then evaluated by investigating the regulation of intestinal microflora and the possible underlying molecular mechanism. Our results reveal that treatment with lacidophilin tablets increased the intestinal advancement rate, fecal moisture content, and colonic AQP3 protein expression. It also improved colonic microflora structure in the colonic contents of model rats mainly by increasing Akkermansia muciniphila and decreasing Clostridium_sensu_stricto_1. Transcriptome analysis indicated that treatment with lacidophilin tablets maintains the immune response in the intestine and promotes recovery of the intestinal mechanical barrier in the constipation model. Our study shows that lacidophilin tablets improve constipation, possibly by promoting Akkermansia colonization and by modulating the intestinal immune response.

CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction.

BACKGROUND: Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. Since the geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes, we investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice. METHODS: Control or CMS121-containing diets were supplied ad libitum for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism. RESULTS: The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121. CONCLUSIONS: The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.

Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain.

Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25-31% of the cell population within 8-10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. OBJECTIVES: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. RESULTS: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], -90.90 mg/g, 95% CI, -140.17 to -41.64 mg/g), 24-h urinary protein excretion (WMD, -0.20 g, 95% CI, -0.28 to -0.12 g), estimated glomerular filtration rate (eGFR) (WMD, -1.99 mL/min/1.73 m2, 95% CI, -3.28 to -0.70 mL/min/1.73 m2), chronic renal failure events (RR, 0.86, 95% CI, 0.79-0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77-0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73-2.40) and hypotension (RR, 1.80, 95% CI, 1.41-2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56-0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79-1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57-0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02-1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26-25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22-1.22) increased the risk of breast disorders. CONCLUSIONS: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.

Aspirin intervention before ICU admission reduced the mortality in critically ill patients with acute kidney injury: results from the MIMIC-IV.

Background: Aspirin, with its pleiotropic effects such as anti-inflammatory and anti-platelet aggregation, has been widely used for anti-inflammatory, analgesic, and cardiovascular diseases. However, the association between the use of aspirin before the intensive care unit (ICU) and clinical outcomes in critically ill patients with acute kidney injury (AKI) is unknown. Methods: Patients with AKI in this retrospective observational study were selected from the Marketplace for Medical Information in Intensive Care IV (MIMIC-IV). The association between aspirin intervention and 30-day mortality was assessed using Cox proportional hazards model. Logistic regression models were used to assess the association of aspirin intervention with the risks of intracranial hemorrhage, gastrointestinal bleeding and blood transfusion. The propensity score matching (PSM) method was adopted to balance the baseline variables. Sensitivity analysis was performed to validate the results by multiple interpolations for the missing data. Results: The study included 4237 pre-ICU aspirin users and 9745 non-users. In multivariate models, we found a decreased risk of mortality in those who received aspirin before ICU compared to those who did not (30-day:hazard ratio [HR], 0.70; 95% CI, 0.62-0.79; p < 0.001; 90-day:HR, 0.70; 95% CI, 0.63-0.77, p < 0.001; 180-day:HR, 0.72; 95%CI,0.65-0.79, p < 0.001). This benefit was consistent in the post-PSM analyses, sensitivity analyses, and subgroup analyses. Moreover, aspirin intervention was associated with a reduced risk of intracranial hemorrhage and gastrointestinal bleeding (HR, 0.16; 95% CI, 0.10-0.25; p < 0.001; HR, 0.59; 95% CI, 0.38-0.88, p = 0.012) after being adjusted by relating covariates, whereas with a increased risk of blood transfusion (HR, 1.28; 95% CI, 1.16-1.46; p < 0.001). Conclusion: Patients with AKI treated with aspirin before ICU admission might have reduced 30-day, 90-day and 180-day mortality without increasing the risk of intracranial hemorrhage (ICH) or gastrointestinal bleeding, but may increase the risk of transfusion.

STAT3 modulates CD4+ T mitochondrial dynamics and function in aging.

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging-related cytokine profiles. Our data show the mechanistic link among mitoSTAT3, mitochondrial dynamics, function, and T-cell cytokine production.

Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.

Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate-activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)-FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1-dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis.

The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice.

db/db mice, which lack leptin receptors and exhibit hyperphagia, show disturbances in energy metabolism and are a model of obesity and type 2 diabetes. The geroneuroprotector drug candidate CMS121 has been shown to be effective in animal models of Alzheimer's disease and aging through the modulation of metabolism. Thus, the hypothesis was that CMS121 could protect db/db mice from metabolic defects and thereby reduce liver inflammation and kidney damage. The mice were treated with CMS121 in their diet for 6 months. No changes were observed in food and oxygen consumption, body mass, or locomotor activity compared to control db/db mice, but a 5% reduction in body weight was noted. Improved glucose tolerance and reduced HbA1c and insulin levels were also seen. Blood and liver triglycerides and free fatty acids decreased. Improved metabolism was supported by lower levels of fatty acid metabolites in the urine. Markers of liver inflammation, including NF-κB, IL-18, caspase 3, and C reactive protein, were lowered by the CMS121 treatment. Urine markers of kidney damage were improved, as evidenced by lower urinary levels of NGAL, clusterin, and albumin. Urine metabolomics studies provided further evidence for kidney protection. Mitochondrial protein markers were elevated in db/db mice, but CMS121 restored the renal levels of NDUFB8, UQCRC2, and VDAC. Overall, long-term CMS121 treatment alleviated metabolic imbalances, liver inflammation, and reduced markers of kidney damage. Thus, this study provides promising evidence for the potential therapeutic use of CMS121 in treating metabolic disorders.

Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche.

Maintenance of tissue homeostasis is dependent on the communication between stem cells and supporting cells in the same niche. Regulatory T cells (Treg cells) are emerging as a critical component of the stem-cell niche for supporting their differentiation. How Treg cells sense dynamic signals in this microenvironment and communicate with stem cells is mostly unknown. In the present study, by using hair follicles (HFs) to study Treg cell-stem cell crosstalk, we show an unrecognized function of the steroid hormone glucocorticoid in instructing skin-resident Treg cells to facilitate HF stem-cell (HFSC) activation and HF regeneration. Ablation of the glucocorticoid receptor (GR) in Treg cells blocks hair regeneration without affecting immune homeostasis. Mechanistically, GR and Foxp3 cooperate in Treg cells to induce transforming growth factor ß3 (TGF-ß3), which activates Smad2/3 in HFSCs and facilitates HFSC proliferation. The present study identifies crosstalk between Treg cells and HFSCs mediated by the GR-TGF-ß3 axis, highlighting a possible means of manipulating Treg cells to support tissue regeneration.

Capping protein regulates endosomal trafficking by controlling F-actin density around endocytic vesicles and recruiting RAB5 effectors.

Actin filaments (F-actin) have been implicated in various steps of endosomal trafficking, and the length of F-actin is controlled by actin capping proteins, such as CapZ, which is a stable heterodimeric protein complex consisting of α and ß subunits. However, the role of these capping proteins in endosomal trafficking remains elusive. Here, we found that CapZ docks to endocytic vesicles via its C-terminal actin-binding motif. CapZ knockout significantly increases the F-actin density around immature early endosomes, and this impedes fusion between these vesicles, manifested by the accumulation of small endocytic vesicles in CapZ-knockout cells. CapZ also recruits several RAB5 effectors, such as Rabaptin-5 and Rabex-5, to RAB5-positive early endosomes via its N-terminal domain, and this further activates RAB5. Collectively, our results indicate that CapZ regulates endosomal trafficking by controlling actin density around early endosomes and recruiting RAB5 effectors.

Vacuolin-1 inhibits endosomal trafficking and metastasis via CapZß.

Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zß (CapZß) as a V1 binding protein and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that V1 targets CapZß to inhibit endosomal trafficking and metastasis.

AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation.

Despite being the frontline therapy for type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB, but several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for both the translational and transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment. The hepatic transcriptional response in mice on high-fat diet treated with metformin was largely ablated by AMPK deficiency under the conditions examined, indicating the essential role of this kinase and its targets in metformin action in vivo.

Butyrate rather than LPS subverts gingival epithelial homeostasis by downregulation of intercellular junctions and triggering pyroptosis.

AIM: To investigate the effects of sodium butyrate (NaB) and lipopolysaccharide (LPS) on gingival epithelial barrier. MATERIAL AND METHODS: We cultured human primary gingival epithelial cells and investigated the effects of NaB and LPS on gingival epithelial barrier and involved mechanisms at in vitro and in vivo levels by immunostaining, confocal microscopy, field emission scanning electron microscopy (FE-SEM), transmission electronic microscopy (TEM), transepithelial electrical resistance (TEER), FTIC-dextran flux, flow cytometry, real-time PCR and Western blot assays. RESULTS: Our results showed that NaB, rather than LPS, destroyed the epithelial barrier by breaking down cell-cell junctions and triggering gingival epithelial cell pyroptosis with characteristic morphological changes, including swollen cells, large bubbles, pore formation in the plasma membrane and subcellular organelles changes. The upregulated expression of pyroptosis-related markers, caspase-3 and gasdermin-E (GSDME) contributed to this effect. Pyroptosis aroused by NaB is a pro-inflammatory cell death. Pyroptotic cell death provoked inflammatory responses by upregulation of IL-8 and MCP-1, and releasing intracellular contents into the extracellular microenvironment after pyroptotic rupture of the plasma membrane. CONCLUSIONS: Our new findings indicate that butyrate is a potent destructive factor of gingival epithelial barrier and pro-inflammatory mediator, which shed a new light on our understanding of periodontitis initiation.

Joint analyses of multi-tissue Hi-C and eQTL data demonstrate close spatial proximity between eQTLs and their target genes.

BACKGROUND: Gene regulation is important for cells and tissues to function. It has been studied from two aspects at the genomic level, the identification of expression quantitative trait loci (eQTLs) and identification of long-range chromatin interactions. It is important to understand their relationship, such as whether eQTLs regulate their target genes through physical chromatin interaction. Although chromatin interactions have been widely believed to be one of the main mechanisms underlying eQTLs, most evidence came from studies of cell lines and yet no direct evidence exists for tissues. RESULTS: We performed various joint analyses of eQTL and high-throughput chromatin conformation capture (Hi-C) data from 11 human primary tissue types and 2 human cell lines. We found that chromatin interaction frequency is positively associated with the number of genes that have eQTLs and that eQTLs and their target genes tend to fall into the same topologically associating domain (TAD). These results are consistent across all tissues and cell lines we evaluated. Moreover, in 6 out of 11 tissues (aorta, dorsolateral prefrontal cortex, hippocampus, pancreas, small bowel, and spleen), tissue-specific eQTLs are significantly enriched in tissue-specific frequently interacting regions (FIREs). CONCLUSIONS: Our data have demonstrated the close spatial proximity between eQTLs and their target genes among multiple human primary tissues.

Identification of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor effect against non-small cell lung cancer.

Currently, particular focus is placed on the implication of autophagy in a variety of human diseases, including cancer. Discovery of small-molecule modulators of autophagy as well as their potential use as anti-cancer therapeutic agents would be of great significance. To this end, a series of curcumin analogs previously synthesized in our laboratory were screened. Among these compounds, (3E,5E)-3-(3,4-dimethoxybenzylidene)-5-[(1H-indol-3-yl)methylene]-1-methylpiperidin-4-one (CA-5f) was identified as a potent late-stage macroautophagy/autophagy inhibitor via inhibiting autophagosome-lysosome fusion. We found that CA-5f neither impaired the hydrolytic function nor the quantity of lysosomes. Use of an isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic screen in combination with bioinformatics analysis suggested that treatment of human umbilical vein endothelial cells (HUVECs) with CA-5f for 1 h suppressed the levels of cytoskeletal proteins and membrane traffic proteins. Subsequent studies showed that CA-5f exhibited strong cytotoxicity against A549 non-small cell lung cancer (NSCLC) cells, but low cytotoxicity to normal human umbilical vein endothelial cells (HUVECs), by increasing mitochondrial-derived reactive oxygen species (ROS) production. Moreover, CA-5f effectively suppressed the growth of A549 lung cancer xenograft as a single agent with an excellent tolerance in vivo. Results from western blot, immunofluorescence, and TdT-mediated dUTP nick end labeling (TUNEL) assays showed that CA-5f inhibited autophagic flux, induced apoptosis, and did not affect the level of CTSB (cathepsin B) and CTSD (cathepsin D) in vivo, which were consistent with the in vitro data. Collectively, these results demonstrated that CA-5f is a novel late-stage autophagy inhibitor with potential clinical application for NSCLC therapy. Abbreviations: 3-MA, 3-methyladenine; ANXA5, annexin A5; ATG, autophagy related; CA-5f, (3E,5E)-3-(3,4-dimethoxybenzylidene)-5-[(1H-indol-3-yl)methylene]-1-methylpiperidin-4-one; CQ, chloroquine; CTSB, cathepsin B; CTSD, cathepsin D; DMSO, dimethyl sulfoxide; DNM2, dynamin 2; EBSS, Earle's balanced salt solution; GFP, green fluorescent protein; HCQ, hydroxyl CQ; HEK293, human embryonic kidney 293; HUVEC, human umbilical vein endothelial cells; LAMP1, lysosomal associated membrane protein 1; LC-MS/MS, liquid chromatography coupled to tandem mass spectrometry; LDH, lactic acid dehydrogenase; LMO7, LIM domain 7; MAP1LC3B/LC3B, microtubule associated protein 1 light chain 3 beta; NAC, N-acetyl cysteine; MYO1E, myosin IE; NSCLC, non-small cell lung cancer; PARP1, poly(ADP-ribose) polymerase 1; PI, propidium iodide; RFP, red fluorescent protein; ROS, reactive oxygen species; SQSTM1, sequestosome 1; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.

A digitally guided dual technique for both gingival and bone resection during crown lengthening surgery.

This paper presents a digitally guided dual technique that provides references for gingival and bone resection during crown lengthening surgery. The architecture of the teeth, gingiva, and alveolar bone is scanned and registered to design dual guides consisting of a gingivectomy guide and an alveolectomy guide that are used in periodontal surgery for esthetic rehabilitation.

Simultaneous enhancement of photo- and electroluminescence in white organic light-emitting devices by localized surface plasmons of silver nanoclusters.

White organic light-emitting devices (WOLEDs) with enhanced current efficiency and negligible color shifting equipped with an internal color conversion layer (CCL) were fabricated. They were attained by embedding a single layer of silver nanoclusters (SNCs) between the CCL and light-emitting layer (EML). The simultaneous enhancement of the photoluminescence (PL) of the CCL and electroluminescence (EL) of the EML were realized by controlling the thickness and size of the SNCs to match the localized surface plasmon resonance spectrum with the PL spectrum of the CCL and the EL spectrum of the EML. The WOLED with optimal SNCs demonstrated a 25.81% enhancement in current efficiency at 60 mA cm-2 and good color stability over the entire range of current density.

Identification of resveratrol derivative 3,3',4,4',5,5'-hexamethoxy- trans-stilbene as a novel pro-angiogenic small-molecule compound.

The potential to promote neovascularization in ischemic tissues using exogenous agents is an attractive avenue for therapeutics. To identify novel pro-angiogenic small-molecule compound, we screened a series of resveratrol methylated derivatives and identified 3,3',4,4', 5,5'-hexamethoxy-trans-stilbene (3,3',4,4',5,5'-HMS) potently promotes proliferation, migration, invasion and tube formation of human umbilical vein VECs (HUVECs) in vitro. Furthermore, 3,3',4,4',5,5'-HMS accelerates neo-vessels sprouting of rat aortic rings ex vivo, and neovascularization of chick chorioallantoic membrane (CAM) and mouse matrigel plugs in vivo. Microarray analyses show that the level of early growth response 1 (EGR-1), an inducible pro-angiogenic gene regulatory factor, was upregulated. The upregulation of EGR-1 was confirmed by semiquantitative RT-PCR, quantitative real-time PCR and western blotting analyses. In addition, the levels of several pro-angiogenic factors including transforming growth factor ß1 (TGF-ß1), vascular endothelial growth factor (VEGF), nitric oxide (NO), and the activity of endothelial NO synthase (eNOS) were elevated in 3,3',4,4',5,5'-HMS-treated HUVECs. Inhibition of NO synthase by l-NAME blocked the pro-angiogenic effects of 3,3',4,4',5,5'-HMS. Our research shows that 3,3',4,4',5,5'-HMS dramatically promoted angiogenesis in vitro, ex vivo and in vivo, which might represent a novel potential agent for the development of therapeutic drugs to treat ischemic diseases.

[Effect of 5-hydroxymethyl furfural on BCL-2 and NF-kappaB gene expression of apoptotic rat hippocampal neurons injured by H2O2].

OBJECTIVE: To investigate the effect of 5-hydroxymethyl furfural (5-HMF) on apoptosis and BCL-2, NF-kappaB gene expression of rat hippocampal neurons injured by hydroperoxide (H2O2). METHODS: Hippocampal neurons of newly born rat were cultured in vivo and injured by H2O2. Effect of different concentration of 5-HMF on cell viability was measured by MTT. Flow cytometer (FCM) was used to measure the apoptosis of rat hippocampal neurons pre-cultured with different concentration of 5-HMF,Western blotting was used to measure the expression of BCL-2 and NF-kappaB gene. RESULTS: It revealed that the high and medium dosage of 5-HMF could increase the activity of rat hippocampal. The high, medium and low dosage of 5-HMF also increased the expression of BCL-2 gene and decreased the expression of NF-kappaB gene. CONCLUSION: 5-HMF could restrain the apoptosis of cultured hippocampal neurons injured by H2O2. The mechanism may be related to increasing in BCL-2 level and decreasing in NF-kappaB level.