Modelling and experimental studies on mass transport of multiple cryoprotective agents in articular cartilage.

Cartilage transplantation is an effective way to repair, reconstruct, and replace damaged articular cartilage (AC) but its use is limited by the inability to preserve AC for long periods of time. Vitrification is an ideal choice for long-term storage of AC, and multiple cryoprotective agents (CPAs) with high concentration are usually used. To obtain high cell viability, chondrocytes at all locations inside AC should be protected properly by the CPAs during cooling and rewarming. Hence, it is important to know the mass transport properties of multiple CPAs as they synergistically infiltrate AC. In this study, a mathematical model to describe the mass transport behavior of multiple CPAs in AC was developed based on the mixture-averaged diffusion model. In addition, a methodology for the simultaneous determination of dimethyl sulfoxide, glycerol, ethylene glycol, and propylene glycol by carbon-13 nuclear magnetic resonance was established. The model is applicable for predicting single- and multiple-CPA permeation into AC, and its accuracy was verified by a massive experimental dataset. Simulation results showed reverse diffusion in the multiple-CPA permeation process, which was not found in the single-CPA permeation process. This curious phenomenon shows the sharp contrast between the diffusion behavior of a binary mixture and a multicomponent mixture.

Urolithin A ameliorates diabetic retinopathy via activation of the Nrf2/HO-1 pathway.

Diabetic retinopathy (DR) is a progressive microvascular complication of diabetes mellitus and is characterised by excessive inflammation and oxidative stress. Urolithin A (UA), a major metabolite of ellagic acid, exerts anti-inflammatory and antioxidant functions in various human diseases. This study, for the first time, uncovered the role of UA in DR pathogenesis. Streptozotocin-induced diabetic rats were used to determine the effects of UA on blood glucose levels, retinal structures, inflammation, and oxidative stress. High glucose (HG)-induced human retinal endothelial cells (HRECs) were used to elucidate the anti-inflammatory and antioxidant mechanisms of UA in DR in vitro. The in vivo experiments demonstrated that UA injection reduced blood glucose levels, decreased albumin and vascular endothelial growth factor concentrations, and ameliorated the injured retinal structures caused by DR. UA administration also inhibited inflammation and oxidative damage in the retinal tissues of diabetic rats. Similar anti-inflammatory and antioxidant effects of UA were observed in HRECs induced by HG. Furthermore, we found that UA elevated the levels of nuclear Nrf2 and HO-1 both in vivo and in vitro. Nrf2 silencing reversed the inhibitory effects of UA on inflammation and oxidative stress during DR progression. Together, our findings indicate that UA can ameliorate DR by repressing inflammation and oxidative stress via the Nrf2/HO-1 pathway, which suggests that UA could be an effective drug for clinical DR treatment.

Resource Mapping Allocation Scheme in 6G Satellite Twin Network.

The sixth generation (6G) satellite twin network is an important solution to achieve seamless global coverage of 6G. The deterministic geometric topology and the randomness of the communication behaviors of 6G networks limit the realism and transparency of cross-platform and cross-object communication, twin, and computing co-simulation networks. Meanwhile, the parallel-based serverless architecture has a high redundancy of computational resource allocation. Therefore, for the first time, we present a new hypergraph hierarchical nested kriging model, which provides theoretical analysis and modeling of integrated relationships for communication, twin, and computing. We explore the hierarchical unified characterization method which joins heterogeneous topologies. A basis function matrix for local flexible connectivity of the global network is designed for the connection of huge heterogeneous systems to decouple the resource mapping among heterogeneous networks. To improve the efficiency of resource allocation in communication, twin, and computing integrated network, a multi-constraint multi-objective genetic algorithm (MMGA) based on the common requirements of operations, storage, interaction, and multi-layer optimal solution conflict is proposed for the first time. The effectiveness of the algorithm and architecture is verified through simulation and testing.

[The effect of different types of exercise on the intestinal mechanical barrier and related regulatory factors in type 2 diabetic mice].

The aim of this study was to investigate the effects of different types of exercise on intestinal mechanical barrier and related regulatory factors in mice with type 2 diabetes mellitus (T2DM). The model was established by high-fat diet feeding and intraperitoneal injection of streptozocin (STZ). The mice were divided into control group, model group (free exercise), resistance exercise group (tail load-bearing ladder climbing, 5 times a week), aerobic exercise group (non-load-bearing platform running, 5 times a week at a speed of 10-15 m/min), and combined exercise group (aerobic exercise was performed on the first, third and fifth days of each week, and resistance exercise on the second and fourth days of each week). After 8 weeks of intervention, the serum lipid levels and inflammatory cytokines were measured by corresponding kits. The pathological changes of ileum were detected by HE and PAS staining. The mRNA and protein expression levels of tight junction-related proteins were detected by real-time qPCR and Western blot, respectively. Moreover, the protein expression levels of hypoxia inducible factor-1α (HIF-1α) and myosin light chain kinase (MLCK) were detected by Western blot. The results showed that all three types of exercise decreased blood glucose and body weight compared to the model group. Aerobic exercise and combined exercise decreased serum lipid (triglycerides and total cholesterol) levels, up-regulated the expression levels of ileal tight junction-related proteins and HIF-1α, improved the intestinal alkaline phosphatase (AKP) activity, reduced serum lipopolysaccharide (LPS), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and diamine oxidase (DAO) levels, and down-regulated MLCK protein expression level. These results suggest that all three types of exercise can reduce blood glucose and body weight of T2DM mice, and aerobic exercise and combined exercise can restore the damaged intestinal mechanical barrier by a mechanism involving HIF-1α-MLCK pathway.

Long non-coding RNA PWRN2 regulates cytotoxicity in an in vitro model of age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) may lead to irreversibly vision loss among aging populations. In this work, in an in vitro AMD cell model, we examined the expression and function of long non-coding RNA, Prader-Willi Region Non-Protein Coding RNA 2 (PWRN2) in injured human retinal pigment epithelial cells. METHOD: ARPE-19 cell line was maintained in vitro and treated with multi-module stressful conditions, including hydrogen peroxide (H2O2) tert-butylhydroperoxide (t-BuOOH) and ultraviolet B (UVB). Multi-module-stressor-induced cell death was monitored by a viability assay, and PWRN2 expression by qRT-PCR. PWRN2 was either downregulated or upregulated in ARPE-19 cells. The effects of PWRN2 downregulation or upregulation on t-BuOOH-induced cell death, cellular apoptosis and mitochondrial injuries were then quantitatively evaluated. RESULTS: Multi-module stressful conditions induced cell death and PWRN2 upregulation in ARPE-19 cells in vitro. We created ARPE-19 subpopulations with either downregulated or upregulated PWRN2 expressions. Quantitative assays demonstrated that, PWRN2 downregulation effectively alleviated t-BuOOH-induced cell death, apoptosis and various-type of mitochondrial injuries. On the other hand, PWRN2 upregulation worsened t-BuOOH-induced cellular damages in ARPE-19 cells. CONCLUSION: We demonstrated that downregulating PWRN2 protected multi-module-stressor-induced cell death, apoptosis and mitochondrial injuries in human retinal pigment epithelial cells, suggesting PWRN2 may be an active factor in human AMD.

The Hypoglycemic Effect of Berberine and Berberrubine Involves Modulation of Intestinal Farnesoid X Receptor Signaling Pathway and Inhibition of Hepatic Gluconeogenesis.

Our previous study suggests that berberine (BBR) lowers lipids by modulating bile acids and activating intestinal farnesoid X receptor (FXR). However, to what extent this pathway contributes to the hypoglycemic effect of BBR has not been determined. In this study, the glucose-lowering effects of BBR and its primary metabolites, berberrubine (M1) and demethyleneberberine, in a high-fat diet-induced obese mouse model were studied, and their modulation of the global metabolic profile of mouse livers and systemic bile acids was determined. The results revealed that BBR (150 mg/kg) and M1 (50 mg/kg) decreased mouse serum glucose levels by 23.15% and 48.14%, respectively. Both BBR and M1 markedly modulated the hepatic expression of genes involved in gluconeogenesis and metabolism of amino acids, fatty acids, and purine. BBR showed a stronger modulatory effect on systemic bile acids than its metabolites. Moreover, molecular docking and gene expression analysis in vivo and in vitro suggest that BBR and M1 are FXR agonists. The mRNA levels of gluconeogenesis genes in the liver, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were significantly decreased by BBR and M1. In summary, BBR and M1 modulate systemic bile acids and activate the intestinal FXR signaling pathway, which reduces hepatic gluconeogenesis by inhibiting the gene expression of gluconeogenesis genes, achieving a hypoglycemic effect. BBR and M1 may function as new, natural, and intestinal-specific FXR agonists with a potential clinical application to treat hyperglycemia and obesity. SIGNIFICANCE STATEMENT: This investigation revealed that BBR and its metabolite, berberrubine, significantly lowered blood glucose, mainly through activating intestinal farnesoid X receptor signaling pathway, either directly by themselves or indirectly by modulating the composition of systemic bile acids, thus inhibiting the expression of gluconeogenic genes in the liver and, finally, reducing hepatic gluconeogenesis and lowering blood glucose. The results will help elucidate the mechanism of BBR and provide a reference for mechanism interpretation of other natural products with low bioavailability.

Targeting MDM2 for novel molecular therapy: Beyond oncology.

The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.

Plastic optical fiber sensor for temperature-independent high-sensitivity detection of humidity.

A simple U-shaped plastic optical fiber evanescent-wave sensor was fabricated for temperature-independent highly sensitive detection of humidity. The sensing region of the sensor was subjected to five cycles of heating-cooling to improve temperature independence. The effects of the polyimide (PI) coating thickness, number of graphene oxide (GO) coating layers, and alternate PI-GO coating sequence were investigated to optimize sensitivity. The fabricated sensor exhibited high-temperature independence and good sensitivity of 0.17×10-2 (% relative humidity)-1 in the temperature range of 10°C to 70°C.

Long noncoding RNA IGF2AS regulates high-glucose induced apoptosis in human retinal pigment epithelial cells.

High-glucose-induced retinal tissue impairment is the major pathological phenotype of diabetic retinopathy. In an in vitro diabetic apoptosis cell model, we evaluated the function of long noncoding RNA, insulin growth factor 2 antisense (IGF2-AS) in high-glucose-injured human retinal pigment epithelial cells. A human retinal pigment epithelial cell line, ARPE-19 was incubated with high-glucose in vitro to induce apoptosis. SiRNA-mediated IGF2-AS downregulation was conducted in ARPE-19 cells to evaluate its effect on high-glucose induced apoptosis, assessed by a TUNEL assay. qRT-PCR and western blot assays were applied to examine the functional effect of IGF2-AS on IGF2/AKT/Casp-9 expressions in glucose-injured ARPE-19 cells. ART was further knocked down, specifically in IGF2-AS-downregualted ARPE-19 cells, to investigate its functional involvement in IGF2-AS-inhibition-mediated apoptotic protection in glucose-injured ARPE-19 cells. High-glucose induced apoptosis in ARPE-19 cells, and upregulated IGF-2AS in a dose-dependent manner. SiRNA-mediated IGF2-AS downregulation ameliorated apoptosis, upregulated IGF2/AKT and decreased Casp-9, in high-glucose-treated ARPE-19 cells. AKT knockdown was shown to dramatically reverse the preventive effect of IGF2-AS-downregulation on high-glucose-induced apoptosis in ARPE-19 cells. Moreover, it was demonstrated that AKT knockdown directly upregulated Casp-9 in IGF2-AS-downregulated and high-glucose-treated ARPE-19 cells. We demonstrated that inhibiting IGF2-AS, possibly also through activation of AKT signaling pathway, has a protective function in high-glucose-induced apoptosis in human retinal pigment epithelial cells in diabetic retinopathy.

Purine Catabolism Shows a Dampened Circadian Rhythmicity in a High-fat Diet-Induced Mouse Model of Obesity.

High-calorie diet, circadian rhythms and metabolic features are intimately linked. However, the mediator(s) between nutritional status, circadian rhythms and metabolism remain largely unknown. This article aims to clarify the key metabolic pathways bridging nutritional status and circadian rhythms based on a combination of metabolomics and molecular biological techniques. A mouse model of high-fat diet-induced obesity was established and serum samples were collected in obese and normal mice at different zeitgeber times. Gas chromatography/mass spectrometry, multivariate/univariate data analyses and metabolic pathway analysis were used to reveal changes in metabolism. Metabolites involved in the metabolism of purines, carbohydrates, fatty acids and amino acids were markedly perturbed in accordance with circadian related variations, among which purine catabolism showed a typical oscillation. What's more, the rhythmicity of purine catabolism dampened in the high-fat diet group. The expressions of clock genes and metabolic enzymes in the liver were measured. The mRNA expression of Xanthine oxidase (Xor) was highly correlated with the rhythmicity of Clock, Rev-erbα and Bmal1, as well as the metabolites involved in purine catabolism. These data showed that a high-fat diet altered the circadian rhythm of metabolic pathways, especially purine catabolism. It had an obvious circadian oscillation and a high-fat diet dampened its circadian rhythmicity. It was suggested that circadian rhythmicity of purine catabolism is related to circadian oscillations of expression of Xor, Uox and corresponding clock genes.

7,8-Dihydroxyflavone ameliorates high-glucose induced diabetic apoptosis in human retinal pigment epithelial cells by activating TrkB.

BACKGROUND: In diabetic retinopathy, prolonged high-level blood glucose induced significant impairments among various retinal tissues, including retinal pigment epithelial (RPE) cells. In an in vitro model of human RPE cells, we evaluated whether 7,8-Dihydroxyflavone (DHF) may effectively prevent high glucose-induced diabetic apoptosis among human RPE cells. METHOD: ARPE-19 cells, a Human RPE cell line, were treated with d-glucose (50 mM) to induce apoptosis in vitro. Prior to glucose, ARPE-19 cells were pre-incubated with various concentrations of DHF. The effect of DHF on d-glucose-induced apoptosis was examined by TUNEL assay, in a concentration-dependent manner. The biological effects of DHF on Caspase-9 (Casp-9) and TrkB signaling pathways in d-glucose-injured ARPE-19 cells were evaluated by qRT-PCR and western blot (WB) assays. A TrkB antagonist, K252a, was also applied in DHF and d-glucose treated ARPE-19 cells. Possible effect of K252a blocking TrkB signaling pathway, thus reversing DHF-modulated apoptosis prevention was also examined by TUNEL and WB assays. RESULTS: DHF ameliorated d-glucose-induced diabetic apoptosis in ARPE-19 cells. Apoptotic factor Casp-9, at both mRNA and protein levels, were drastically inhibited by DHF in d-glucose-injured ARPE-19 cells. Also, DHF activated TrkB signaling pathway through phosphorylation. K252a dramatically reversed the preventive effect of DHF on d-glucose-induced apoptosis in ARPE-19 cells. Further investigation showed that K252a functioned through de-activating or de-phosphorylating TrkB signaling pathway. CONCLUSION: This work demonstrates that DHF, through activation of TrkB signaling pathway, has a preventive function in d-glucose-induced apoptosis in PRE cells in diabetic retinopathy.

Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway.

Previous studies suggest that the lipid-lowering effect of berberine (BBR) involves actions on the low-density lipoprotein receptor and the AMP-activated protein kinase signaling pathways. However, the implication of these mechanisms is unclear because of the low bioavailability of BBR. Because the main action site of BBR is the gut and intestinal farnesoid X receptor (FXR) plays a pivotal role in the regulation of lipid metabolism, we hypothesized that the effects of BBR on intestinal FXR signaling pathway might account for its pharmacological effectiveness. Using wild type (WT) and intestine-specific FXR knockout (FXRint-/-) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXRint-/- mice. BBR increased conjugated bile acids in serum and their excretion in feces. Furthermore, BBR inhibited bile salt hydrolase (BSH) activity in gut microbiota, and significantly increased the levels of tauro-conjugated bile acids, especially tauro-cholic acid(TCA), in the intestine. Both BBR and TCA treatment activated the intestinal FXR pathway and reduced the expression of fatty-acid translocase Cd36 in the liver. These results indicate that BBR may exert its lipid-lowering effect primarily in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway. In summary, we provide the first evidence to suggest a new mechanism of BBR action in the intestine that involves, sequentially, inhibiting BSH, elevating TCA, and activating FXR, which lead to the suppression of hepatic expression of Cd36 that results in reduced uptake of long-chain fatty acids in the liver.

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-ß-D-glucuronide, an active metabolite of berberrubine.

Berberrubine (BRB) is the primary metabolite of berberine (BBR) that has shown a stronger glucose-lowering effect than BBR in vivo. On the other hand, BRB is quickly and extensively metabolized into berberrubine-9-O-ß-D-glucuronide (BRBG) in rats after oral administration. In this study we compared the pharmacokinetic properties of BRB and BRBG in rats, and explored the mechanisms underlying their glucose-lowering activities. C57BL/6 mice with HFD-induced hyperglycemia were administered BRB (50 mg·kg-1·d-1, ig) for 6 weeks, which caused greater reduction in the plasma glucose levels than those caused by BBR (120 mg·kg-1·d-1) or BRB (25 mg·kg-1·d-1). In addition, BRB dose-dependently decreased the activity of α-glucosidase in gut of the mice. After oral administration of BRB in rats, the exposures of BRBG in plasma at 3 different dosages (10, 40, 80 mg/kg) and in urine at different time intervals (0-4, 4-10, 10-24 h) were dramatically greater than those of BRB. In order to determine the effectiveness of BRBG in reducing glucose levels, we prepared BRBG from the urine pool of rats, and identified and confirmed it through LC-MS-IT-TOF and NMR spectra. In human normal liver cell line L-O2 in vitro, treatment with BRB or BRBG (5, 20, 50 µmol/L) increased glucose consumption, enhanced glycogenesis, stimulated the uptake of the glucose analog 2-NBDG, and modulated the mRNA levels of glucose-6-phosphatase and hexokinase. However, both BBR and BRB improved 2-NBDG uptake in insulin-resistant L-O2 cells, while BRBG has no effect. In conclusion, BRB exerts a stronger glucose-lowering effect than BBR in HFD-induced hyperglycemia mice. Although BRB significantly stimulated the insulin sensitivity and glycolysis in vitro, BRBG may have a greater contribution to the glucose-lowering effect because it has much greater system exposure than BRB after oral administration of BRB. The results suggest that BRBG is a potential agent for reducing glucose levels.

Modulation of the pentose phosphate pathway alters phase I metabolism of testosterone and dextromethorphan in HepG2 cells.

AIM: The pentose phosphate pathway (PPP) is involved in the activity of glucose-6-phosphate dehydrogenase (G6PD) and generation of NADPH, which plays a key role in drug metabolism. The aim of this study was to investigate the effects of modulation of the PPP on drug metabolism capacity in vitro. METHODS: A pair of hepatic cell lines, ie, the cancerous HepG2 cells and normal L02 cells, was used. The expression of CYP450 enzymes, p53 and G6PD in the cells were analyzed. The metabolism of testosterone (TEST, 10 µmol/L) and dextromethorphan (DEM, 1 µmol/L), the two typical substrates for CYP3A4 and CYP2D6, in the cells was examined in the presence of different agents. RESULTS: Both the expression and metabolic activities of CYP3A4 and CYP2D6 were considerably higher in HepG2 cells than in L02 cells. The metabolism of TEST and DEM in HepG2 cells was dose-dependently inhibited by the specific CYP3A4 inhibitor ketoconazole and CYP2D6 inhibitor quinidine. Addition of the p53 inhibitor cyclic PFT-α (5, 25 µmol/L) in HepG2 cells dose-dependently enhanced the metabolism of DEM and TEST, whereas addition of the p53 activator NSC 66811 (3, 10, 25 µmol/L) dose-dependently inhibited the metabolism. Furthermore, addition of the G6PD inhibitor 6-aminonicotinamide (5, 15 µmol/L) in HepG2 cells dose-dependently inhibited the metabolism of DEM and TEST, whereas addition of the PPP activity stimulator menadione (1, 5, 15 µmol/L) dose-dependently enhanced the metabolism. CONCLUSION: Modulation of p53 and the PPP alters the metabolism of DEM and TEST, suggesting that the metabolic flux pattern of PPP may be closely involved in drug metabolism and the individual variance.

Simultaneous treatment of pterygium complicated with conjunctivochalasis: analysis of pterygium excision and conjunctival autotransplantation combined with sclera fixation.

BACKGROUND: This prospective study investigated the safety and efficacy of a therapeutic method of treating pterygium complicated with conjunctivochalasis, using pterygium excision and conjunctival autotransplantation combined with sclera fixation, followed by therapeutic contact lens application. METHODS: Fifty-seven patients (83 eyes) diagnosed as pterygium complicated with conjunctivochalasis, at our hospital from July 2011 to June 2012, were selected. Patients were treated with pterygium excision and conjunctival autotransplantation combined with sclera fixation surgery, then therapeutic bandage contact lenses were applied. The efficacy of simultaneous surgery was evaluated based on vision changes, tear dynamics, and other complications. Histopathological changes were investigated on removed bulbar conjunctival tissue, using hematoxylin eosin (HE) and Masson's trichrome staining. RESULTS: (1) Three months after the operation, the success of simultaneous surgery in the treatment of pterygium was 97.6 %, and the recurrence was 2.4 %. Based on subjective evaluation, the success of the simultaneous treatment of conjunctivochalasis was 95.2 %, and failure was 4.8 %. Based on objective evaluation, the success rate was 94.0 % and the recurrence rate was 6.0 %. (2) Visual acuity of the 83 eyes was significantly improved after surgery, and was statistically significant (X 2 = 10.29, P < 0.05). (3) Three months after surgery, the height and integrity of the tear meniscus, tear film break-up time, and chloramphenicol test results of the 83 eyes were significantly improved and there was a statistically significant difference (X 2 the height and integrity of tear meniscus = 147.24, X 2 tear film break-up time = 81.17, X 2 chloramphenicol test = 17.41, P < 0.01). (4) Complications after the operation such as granulation hyperplasia, constrictive fornix, oculomotor defect, and other complications were not observed. (5) Pathological observations, using HE and Masson's trichrome staining of removed bulbar conjunctival tissue, showed several pathological changes, including obvious squamous epithelial hyperplasia, parakeratosis, basal cell pigmentation, lamina propria hemorrhage, infiltration of lymphocytes, and reduction of elastic fibers and collagen fibers. CONCLUSION: Pterygium excision and conjunctival autotransplantation, combined with sclera fixation followed by therapeutic contact lens use was safe, effective, and suitable for simultaneous treatment of pterygium complicated with conjunctivochalasis.

[Metabolomic approach to evaluating the effect of the mixed decoction of kelp and licorice on system metabolism of SD rats].

The aim of the study is to evaluate the effects of the single and mixed decoction of Thallus laminariae (kelp) and Glycyrrhiza glabra (licorice) on the metabolism and their difference. The mixed decoction of kelp and licorice and the single decoction were made and intragastrically administered to the SD rats. The effect on system metabolism, the toxicity of liver and kidney were assessed by GC-MS profiling of the endogenous molecules in serum, routine biochemical assays and histographic inspection of tissues from SD rats, separately. The mixed decoction of kelp and licorice induced more obvious pathological abnormalities in SD rats than a single decoction of kelp, while the extracts of licorice did not show any pathological change. Neither the mixed, nor the single decoction showed abnormal histopathology. After intragastric administration of extracts for 5 days, the mixed decoction induced a decrease of ALT (no significant change in the groups of single decoction) and an increase of BUN (so did the single decoction of kelp). Metabolomic profile of the molecules in serum revealed that the metabolic patterns were all obviously affected for the three groups, i.e., the mixed and single decoction of kelp and licorice. The rats given with the single decoction of kelp showed a similar pattern to that of the mixed decoction, indicating that the kelp primarily contributed the perturbation of metabolism for the mixed decoction. All three groups induced a decrease of branched chain amino acids, TCA cycle intermediates and glycolysis intermediates (e.g., pyruvic acid and lactic acid) and an increase of 3-hydroxybutyric acid. Kelp decoction showed stronger potential in reducing TCA cycle intermediates and glycolysis intermediates than the other two groups, while the levels of branched chain amino acids were the lowest after licorice extracts were given. These results suggested that the effect of the mixed decoction on metabolism was closely associated with both kelp and licorice. The continuous administration of single decoction of kelp and the mixed decoction of licorice and kelp resulted in pathological abnormalities in kidney of SD rats. The mixed decoction of kelp and licorice distinctly perturbed sera molecules and hence system metabolism, which showed associated with those of kelp and licorice. Although the metabolic effect was associated with both kelp and licorice, the results suggested kelp contributed to it primarily.

An in vitro metabolic system of gut flora and the metabolism of ginsenoside Rg3 and cholic acid.

For orally administered drugs, the metabolism of a drug by the gut flora plays an important role in the bioavailability, activation and disposition of the drug in vivo. However, no in vitro system is currently available to evaluate the metabolism of a drug by the gut flora before the drug is absorbed into the body. This paper presents an in vitro metabolic system in an anaerobic environment that could be used to evaluate the metabolism of an endogenous compound, cholic acid, and a xenobiotic compound, ginsenoside Rg3. We showed that the proliferation of the anaerobic bacteria of the gut content of hamsters produced a similar composition of gut flora in a culture medium for yeast to that in vivo. Incubation of ginsenoside Rg3 and cholic acid in the anaerobic in vitro system efficiently produced the metabolites Rh2 and deoxycholic acid, respectively, similar to those seen in the gut content in vivo. In comparison with in vivo analysis, this anaerobic in vitro metabolic system is convenient, reproducible, economic and animal saving, and can easily be applied to assess the transformation and disposition of a drug before it enters into the circulatory system.

Identification and validation of ferroptosis-related genes for diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of blindness, and ferroptosis may be an essential component of the pathological process of DR. In this study, we aimed to screen five hub genes (TLR4, CAV1, HMOX1, TP53, and IL-1B) using bioinformatics analysis and experimentally verify their expression and effects on ferroptosis and cell function. The online Gene Expression Omnibus microarray expression profiling datasets GSE60436 and GSE1025485 were selected for investigation. Ferroptosis-related genes that might be differentially expressed in DR were identified. Then, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analyses were conducted to characterize the differentially-expressed ferroptosis-related genes. After tissue-specific analyses and external dataset validation of hub genes, the mRNA and protein levels of hub genes in retinal microvascular endothelial cells (HRMECs) symbiotic with high glucose were verified using real-time quantitative PCR (qRT-PCR) and immunocytochemistry (ICC). Finally, hub genes were knocked down using siRNA, and changes in ferroptosis and cell function were observed. Based on the differential expression analysis, 19 ferroptosis-related genes were identified. GO and KEGG enrichment analyses showed that ferroptosis-related genes were significantly enriched in reactive oxygen species metabolic processes, necrotic cell death, hypoxia responses, iron ion responses, positive regulation of cell migration involved in sprouting angiogenesis, NF-kappa B signaling pathway, ferroptosis, fluid shear stress, and atherosclerosis. Subsequently, PPI network analysis and critical module construction were used to identify five hub genes. Based on bioinformatics analysis of mRNA microarrays, qRT-PCR confirmed higher mRNA expression of five genes in the DR model, and immunocytochemistry confirmed their higher protein expression. Finally, siRNA interference was used to verify the effects of five genes on ferroptosis and cell function. Based on bioinformatics analysis, five potential genes related to ferroptosis were identified, and their upregulation may affect the onset or progression of DR. This study sheds new light on the pathogenesis of DR.

The efficacy of endoscopic dacryocystorhinostomy in the treatment of dacryocystitis: A systematic review and meta-analysis.

BACKGROUND: This article aimed to discuss the efficacy and safety of endoscopic dacryocystorhinostomy (EDCR) versus external dacryocystorhinostomy (EX-DCR) for the treatment of dacryocystitis by meta-analysis. METHODS: All randomized controlled trials that met the inclusion and exclusion criteria were collected by searching the following databases: PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang, from the establishment of the database to June 2023. Meta-analysis was performed using Stata 17.0 software and review manager 5.4 software. In the collected trials, the observation group was treated with EDCR, whereas the control group was treated with EX-DCR. RESULTS: A total of 10 studies involving 969 patients were included in this analysis. There was a similar surgical success rate in the treatment of dacryocystitis between the 2 groups (RR = 1.021, 95% CI [0. 803, 1.297], P = 0. 865). However, compared with the control group, patients in the observation group had a higher total effective rate of treatment (RR = 1. 195, 95% CI [1. 063, 1.343], P = .003), and shorter operative time (WMD = -23.640, 95% CI [-35.533, -11.747], P < .001), and less intraoperative blood loss (WMD = -50.797, 95% CI [-80.339, -21.255], P = .001), shorter length of hospital stays (WMD = -4.570, 95% CI [-5.992, -3.148], P < .001), and lower incidence of adverse events (RR = 0.295, 95% CI [0.173, 0.504], P < .001). CONCLUSION: EDCR is an effective and safe surgical procedure for the treatment of dacryocystitis and can be used as an alternative to EX-DCR.

Air Gap Fiber Bragg Grating for Simultaneous Strain and Temperature Measurement.

We propose an air gap fiber Bragg grating (g-FBG) sensor that can measure strain and temperature simultaneously. The sensor is made by aligning two fiber Bragg gratings (FBGs), and an air gap exists between these two sub-gratings. This sensor's architecture allows it to form a spectrum with phase-shifted fiber Bragg grating (PSFBG) spectroscopy and Fabry-Perot interference (FPI) spectroscopy. Since the sensitivity of PSFBG and FPI spectra is different for strain and temperature, it is possible to measure both strain and temperature by measuring one of the reflected dips of PSFBG and the interference dip of FPI. The experimental results show that the strain sensitivity is about 11.95 pm/µÎµ via the dip wavelength detection of FPI, and the temperature sensitivity is about 9.64 pm/°C via the dip wavelength detection of PSFBG. The g-FBG sensor demonstrates a resolution of approximately ±3.7 µÎµ within the strain range of 0 to 1000 µÎµ and about ±0.6 °C within the temperature range of 25 °C to 120 °C. The proposed g-FBG sensor, characterized by its simple structure, compact size, and cost-effectiveness, exhibits significant potential in the field of multi-parameter measurements.