Mechanism of intestinal microbiota disturbance promoting the occurrence and development of esophageal squamous cell carcinoma--based on microbiomics and metabolomics.

Esophageal squamous cell carcinoma (ESCC) is a high-risk malignant tumor that has been reported in China. Some studies indicate that gut microbiota disorders can affect the occurrence and development of ESCC, but the underlying mechanism remains unclear. In this study, we aimed to explore the possible underlying mechanisms using microbiomics and metabolomics. Fifty ESCC patients and fifty healthy controls were selected as the study subjects according to sex and age, and fecal samples were collected. 16S rDNA sequencing and LC‒MS were used for microbiomics and nontargeted metabolomics analyses. We found significant differences in the composition of the gut microbiota and metabolites between the ESCC patients and control individuals (P < 0.05). ESCC patients exhibited increased abundances of Fusobacteriaceae and Lactobacillus, increased levels of GibberellinA34 and decreased levels of 12-hydroxydodecanoic acid; these metabolites could be diagnostic and predictive markers of ESCC. An increase in the abundance of Enterobacteriaceae and Lactobacillus significantly reduced the content of L-aspartate and pantothenic acid, which may be involved in the occurrence and development of ESCC by downregulating the expression of proteins in the pantothenate and coenzyme A biosynthesis pathways. An imbalance in the intestinal flora may decrease the number of eosinophils in peripheral blood, resulting in the activation of an inflammatory response and immune dysfunction, leading to ESCC deterioration. We hypothesize that this imbalance in the gut microbiota can cause an imbalance in intestinal metabolites, which can activate carcinogenic metabolic pathways, affect inflammation and immune function, and play a role in the occurrence and development of ESCC.

Ultrafine Iridium Nanoparticles Anchored on Co-Based Metal-Organic Framework Nanosheets for Robust Hydrogen Evolution in Alkaline Media.

A highly promising electrocatalyst has been designed and prepared for the hydrogen evolution reaction (HER). This involves incorporating well-dispersed Ir nanoparticles into a cobalt-based metal-organic framework known as Co-BPDC [Co(bpdc)(H2O)2, BPDC: 4,4'-biphenyldicarboxylic acid]. Ir@Co-BPDC demonstrates exceptional HER activity in alkaline media, surpassing both commercial Pt/C and recent noble-metal catalysts. Theoretical results indicate that electron redistribution, induced by interfacial bonds, optimizes the adsorption energy of water and hydrogen, thereby enhancing our understanding of the superior properties of Ir@Co-BPDC for HER.

Anti-Hyperlipidemic Components of the Leaves of Synsepalum dulcificum (Miracle Fruit).

Synsepalum dulcificum (Miracle fruit) is a tropical plant in West and Central Africa, which has been historically used for treating diarrhea in humans and animals. Pharmacological research has shown that the leaves of the plant possess anti-hyperlipidemia activity. However, its anti-hyperlipidemic components have not been reported. In this study, the leaves of S. dulcificum were extracted using 95% ethanol and the extract was fractionated using different polar solvents. The anti-hyperlipidemia activity of the extract and fractions were evaluated using the zebrafish model. The results showed that the ethyl acetate (EA) fraction displayed the best anti-hyperlipidemic effect. A comparison of the high-performance liquid chromatography equipped with diode array detector (HPLC-DAD) profiles of the ethanol extract and different fractions at 350 nm indicated that a peak at 37.4 min has the highest intensity in the EA part, relatively. Then the chemical constituents of the extract and the active fraction were extensively identified using UPLC-Q-Exactive-Orbitrap-MS/MS, showing the main peak was quercitrin and other components in the EA part mainly included quercitrin analogs. Furthermore, the quercitrin was isolated from the plant and its contents in the extract and fractions were determined using high-performance liquid chromatography with ultraviolet detector (HPLC-UV) method. The quantitative results showed that the content of quercitrin in the EA fraction was 10.04% (w/w). Further pharmacological study indicated that quercitrin also possessed potent anti-hyperlipidemia activity (improvement rates of liver fat and total cholesterol were 75.6% and 92.5% at 40 µg/mL, respectively). Besides, quercitrin showed little toxicity to zebrafish embryos.

The Promise of Molecular Imaging: Focus on Central Nervous System Infections.

Central nervous system (CNS) infections can lead to high mortality and severe morbidity. Diagnosis, monitoring, and assessing response to therapy of CNS infections is particularly challenging with traditional tools, such as microbiology, due to the dangers associated with invasive CNS procedures (ie, biopsy or surgical resection) to obtain tissues. Molecular imaging techniques like positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging have long been used to complement anatomic imaging such as computed tomography (CT) and magnetic resonance imaging (MRI), for in vivo evaluation of disease pathophysiology, progression, and treatment response. In this review, we detail the use of molecular imaging to delineate host-pathogen interactions, elucidate antimicrobial pharmacokinetics, and monitor treatment response. We also discuss the utility of pathogen-specific radiotracers to accurately diagnose CNS infections and strategies to develop radiotracers that would cross the blood-brain barrier.

Visualizing Bacterial Infections With Novel Targeted Molecular Imaging Approaches.

Although nearly a century has elapsed since the discovery of penicillin, bacterial infections remain a major global threat. Global antibiotic use resulted in an astounding 42 billion doses of antibiotics administered in 2015 with 128 billion annual doses expected by 2030. This overuse of antibiotics has led to the selection of multidrug-resistant "super-bugs," resulting in increasing numbers of patients being susceptible to life-threatening infections with few available therapeutic options. New clinical tools are therefore urgently needed to identify bacterial infections and monitor response to antibiotics, thereby limiting overuse of antibiotics and improving overall health. Next-generation molecular imaging affords unique opportunities to target and identify bacterial infections, enabling spatial characterization as well as noninvasive, temporal monitoring of the natural course of the disease and response to therapy. These emerging noninvasive imaging approaches could overcome several limitations of current tools in infectious disease, such as the need for biological samples for testing with their associated sampling bias. Imaging of living bacteria can also reveal basic biological insights about their behavior in vivo.

ETNPPL modulates hyperinsulinemia-induced insulin resistance through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocytes.

Hyperinsulinemia is a critical risk factor for the pathogenesis of insulin resistance (IR) in metabolic tissues, including the liver. Ethanolamine phosphate phospholyase (ETNPPL), a newly discovered metabolic enzyme that converts phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde, is abundantly expressed in liver tissue. Whether it plays a role in the regulation of hyperinsulinemia-induced IR in hepatocytes remains elusive. Here, we established an in vitro hyperinsulinemia-induced IR model in the HepG2 human liver cancer cell line and primary mouse hepatocyte via a high dose of insulin treatment. Next, we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL per se on IR without insulin stimulation. To explore the underlying mechanism of ETNPPL mediating hyperinsulinemia-induced IR in HepG2, we performed genome-wide transcriptional analysis using RNA sequencing (RNA-seq) to identify the downstream target gene of ETNPPL. The results showed that ETNPPL expression levels in both mRNA and protein were significantly upregulated in hyperinsulinemia-induced IR in HepG2 and primary mouse hepatocytes. Upon silencing ETNPPL, hyperinsulinemia-induced IR was ameliorated. Under normal conditions without IR in hepatocytes, overexpressing ETNPPL promotes IR, reactive oxygen species (ROS) generation, and AKT inactivation. Transcriptome analysis revealed that salt-inducible kinase 1 (SIK1) is markedly downregulated in the ETNPPL knockdown HepG2 cells. Moreover, disrupting SIK1 prevents ETNPPL-induced ROS accumulation, damage to the PI3K/AKT pathway and IR. Our study reveals that ETNPPL mediates hyperinsulinemia-induced IR through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocyte cells. Targeting ETNPPL may present a potential strategy for hyperinsulinemia-associated metabolic disorders such as type 2 diabetes.

Enterogenic metabolomics signatures of depression: what are the possibilities for the future.

INTRODUCTION: An increasing number of studies indicate that the microbiota-gut-brain axis is an important pathway involved in the onset and progression of depression. The responses of the organism (or its microorganisms) to external cues cannot be separated from a key intermediate element: their metabolites. AREAS COVERED: In recent years, with the rapid development of metabolomics, an increasing amount of metabolites has been detected and studied, especially the gut metabolites. Nevertheless, the increasing amount of metabolites described has not been reflected in a better understanding of their functions and metabolic pathways. Moreover, our knowledge of the biological interactions among metabolites is also incomplete, which limits further studies on the connections between the microbial-entero-brain axis and depression. EXPERT OPINION: This paper summarizes the current knowledge on depression-related metabolites and their involvement in the onset and progression of this disease. More importantly, this paper summarized metabolites from the intestine, and defined them as enterogenic metabolites, to further clarify the function of intestinal metabolites and their biochemical cross-talk, providing theoretical support and new research directions for the prevention and treatment of depression.

Ascorbic acid protects retinal pigment epithelial cells from high glucose by inhibiting the NF-κB signal pathway through MALAT1/IGF2BP3 axis.

BACKGROUND: Diabetic retinopathy (DR) is a common complication of diabetes with nocuous effects on patients' eye health, typically accompanies by excessive inflammation and oxidative stress. Insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3) was engaged with inflammation, whereas its precise role in the DR process was unclear. And enhanced lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and decreased ascorbic acid (AA) were also found in DR. This study was to explore the regulatory role and mechanism of IGF2BP3, MALAT1 and AA in the high glucose (HG)-induced retinal pigment epithelial (RPE) cell injury. METHODS: ARPE-19 cells were treated with HG to establish the in vitro RPE cell injury model. The mRNA and protein levels of the gene were evaluated by qRT-PCR or Western blot. Immunofluorescence detected the translocation condition of the p65 protein. Inflammatory factor levels were detected by ELISA assays. Apoptosis was detected by flow cytometry. The binding interaction of IGF2BP3 and MALAT1 was validated by RIP-qPCR assays. RESULTS: In HG-induced RPE cell injury, IGF2BP3 expression, inflammatory response and apoptosis were enhanced. Next, the IGF2BP3 activated the NF-κB signalling to promote the RPE cell injury development. MALAT1 could directly bind with IGF2BP3 and up-regulate its expression. In addition, AA ameliorated the HG-induced RPE cell injury through the regulation of MALAT1. CONCLUSION: Ascorbic acid ameliorated HG-induced RPE cell injury by repressing the NF-κB signalling pathway via modulating the MALAT1/IGF2BP3 axis.

Multifunctional Lanthanide Metal-Organic Frameworks Based on -NH2 Modified Ligand: Fluorescent Ratio Probe, CrO42- Ions Adsorption, and Photocatalytic Property.

In response to the growing concern for environmental pollution, two lanthanide compounds {[Ln(L)(H2O)]·4H2O}n (where Ln = Tb and Gd, H3L = 1-amino-2,4,6-benzene tricarboxylic acid) were synthesized using a -NH2 modified ligand and systematically characterized. Both compounds exhibit remarkable fluorescence response, adsorption of CrO42- ions, and photocatalytic degradation properties, as well as exceptional acid-base and thermal stability. Remarkably, the pH-dependent 1-Tb exhibits exceptional performance as a fluorescent probe for detecting Fe3+ and CrO42-/Cr2O72- ions in aqueous solutions, while also serving as a ratiometric fluorescent probe for the detection of Cr3+, offering rapid response, high sensitivity, selectivity, and recoverability advantages in application. Moreover, 1-Tb exhibits excellent detection capabilities and displays effective adsorption of CrO42- ions, with a maximum adsorption capacity of 230.71 mg/g. On the other hand, 1-Gd exhibits superior performance compared to 1-Tb in the photocatalytic degradation of antibiotics. The degradation mechanism is further elucidated by conducting experiments with DFT theoretical calculations.

Comparative Evaluation of Metallic and Biodegradable Suture Anchors in Arthroscopic Repair of Anterior Talofibular Ligament Injury: A Short-term Study on Clinical and Functional Outcomes.

BACKGROUND With the development of arthroscopy and suture anchor, the modified BrostrÓ§m technique has made remarkable progress. However, it is unclear which material is most suitable for treating anterior talofibular ligament injury (ATFL). This study evaluated the short-term efficacy of 2 suture anchors (metal vs biodegradable materials) in arthroscopic ATFL repair. MATERIAL AND METHODS From January 2018 to December 2019, 82 patients with ankle disorders (51 men and 31 women) with ATFL injury received arthroscopic repair with suture anchor through the BrostrÓ§m-Gould procedure. The mean age was 38.70±9.35 years (range, 18-54 years). Each patient was followed up. American Orthopedic Foot and Ankle Society score (AOFAS), Karlsson Ankle Functional Score (KAFS), and the Visual Analogue Scale (VAS) were used to evaluate functional status and pain. RESULTS All patients were followed up for 21.21±2.19 months (range, 18-25 months). No complications were found either group. Preoperative clinical and functional scores in both groups had no significant difference (P>0.05). The functional score increased significantly in both groups (P<0.001). At the last follow-up, the mean AOFAS score was 93.00 (90.00, 96.00) in the Biodegradable group and 93.50 (91.00, 96.00) in the Metallic group (P=0.31). The mean KAFS score was 91.50 (85.00, 95.00) in the Biodegradable group and 93.00 (90.00, 95.50) in the Metallic group (P=0.10); the mean VAS score was 1.50 (1.00, 1.80) in the Biodegradable group and 1.30 (0.98, 1.70) in the Metallic group (P=0.22). CONCLUSIONS Arthroscopic repair of ATFL injury with suture anchors can improve the prognosis of CAI. There were no statistically significant differences in clinical and functional outcomes with metal or biodegradable suture anchors at short-term follow-up.

Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction.

BACKGROUND: PI3Kα (Phosphoinositide 3-kinase α) regulates multiple downstream signaling pathways controlling cell survival, growth, and proliferation and is an attractive therapeutic target in cancer and obesity. The clinically-approved PI3Kα inhibitor, BYL719, is in further clinical trials for cancer and overgrowth syndrome. However, the potential impact of PI3Kα inhibition on the heart and following myocardial infarction (MI) is unclear. We aim to determine whether PI3Kα inhibition affects cardiac physiology and post-MI remodeling and to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: Wildtype (WT) 12-wk old male mice receiving BYL719 (daily, p.o.) for 10 days showed reduction in left ventricular longitudinal strain with normal ejection fraction, weight loss, mild cardiac atrophy, body composition alteration, and prolonged QTC interval. RNASeq analysis showed gene expression changes in multiple pathways including extracellular matrix remodeling and signaling complexes. After MI, both p110α and phospho-Akt protein levels were increased in human and mouse hearts. Pharmacological PI3Kα inhibition aggravated cardiac dysfunction and resulted in adverse post-MI remodeling, with increased apoptosis, elevated inflammation, suppressed hypertrophy, decreased coronary blood vessel density, and inhibited Akt/GSK3ß/eNOS signaling. Selective genetic ablation of PI3Kα in endothelial cells was associated with worsened post-MI cardiac function and reduced coronary blood vessel density. In vitro, BYL719 suppressed Akt/eNOS activation, cell viability, proliferation, and angiogenic sprouting in coronary and human umbilical vein endothelial cells. Cardiomyocyte-specific genetic PI3Kα ablation resulted in mild cardiac systolic dysfunction at baseline. After MI, cardiac function markedly deteriorated with increased mortality concordant with greater apoptosis and reduced hypertrophy. In isolated adult mouse cardiomyocytes, BYL719 decreased hypoxia-associated activation of Akt/GSK3ß signaling and cell survival. CONCLUSIONS: PI3Kα is required for cell survival (endothelial cells and cardiomyocytes) hypertrophic response, and angiogenesis to maintain cardiac function after MI. Therefore, PI3Kα inhibition that is used as anti-cancer treatment, can be cardiotoxic, especially after MI.

Influence of the interaction between parental myopia and poor eye habits when reading and writing and poor reading posture on prevalence of myopia in school students in Urumqi, China.

BACKGROUND: To evaluate the prevalence of myopia in school students in Urumqi, China, and explore the influence of the interaction between parental myopia and poor reading and writing habits on myopia to identify the at-risk population and provide evidence to help school students avoid developing myopia. METHODS: A cross-sectional survey was conducted with 6,883 school students aged 7-20 years in Urumqi in December 2019. The Standard Eye Chart and mydriatic optometry were used to determine whether students had myopia. Falconer's method was used to calculate the heritability of parental myopia. Multivariate unconditional logistic regression models were used to analyze the risk factors for myopia and the additive and multiplicative interaction of parental myopia and poor reading and writing habits. RESULTS: After standardizing the age of the 6,883 students, the overall prevalence rate of myopia was 47.50 %. The heritability of parental myopia was 66.57 % for boys, 67.82 % for girls, 65.02 % for the Han group, and 52.71 % for other ethnicities. There were additive interactions between parental myopia and poor reading and writing habits; among them, parental myopia and poor eye habits when reading and writing (the distance between the eyes and book is less than 30 cm when reading and writing, fingers block the sight of one eye while holding the pen, and leaning one's body when reading and writing; habit 1) increased the risk of myopia by 10.99 times (odds ratio [OR] = 10.99, 95 % confidence interval [CI] = 8.33-14.68), parental myopia and poor reading posture (reading while lying down, walking, or in the car; habit 2) increased the risk of myopia by 5.92 times (OR = 5.92, 95 % CI = 4.84-7.27). There was no multiplicative interaction between parental myopia and habit 1 or habit 2 (OR = 0.69, 95 % CI = 0.44-1.08; OR = 0.89, 95 % CI = 0.66-1.21, respectively). CONCLUSION: The prevalence of myopia among students in Urumqi, Xinjiang is relatively high. The risk of developing myopia is affected by parental myopia and poor reading and writing habits. In addition, parental myopia amplifies the harm caused by poor reading and writing habits, thereby increasing the risk of myopia. Students with parents who have myopia should be targeted during myopia prevention efforts.

Hsa_circ_0001806 promotes glycolysis and cell progression in hepatocellular carcinoma through miR-125b/HK2.

OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and a leading cause of cancer death. Circular RNA (circRNA) has been demonstrated to play an important role in regulating tumour development. The current study aims to explore the specific role of hsa_circ_0001806 during HCC progression. METHODS: The expression of hsa_circ_0001806 in HCC tissues and cells was measured through qRT-PCR. Cell proliferation, apoptosis and migration were measured using CCK-8 and Annexin V/PI staining kits, and Transwell assay. Bioinformatics prediction and dual-luciferase reporter assay were adopted to explore the mechanism underlying the cell function of hsa_circ_0001806 in HCC cells. In addition, glycolysis was assessed by measuring the glucose uptake, lactate production and ATP level using a glucose assay kit, fluorometric lactate assay kit and ATP detection assay kit. RESULTS: Hsa_circ_0001806 was up-regulated in HCC tissues and cells and positively associated with the advanced TNM stage, metastasis and poor overall survival. The overexpression of hsa_circ_0001806 promoted HCC cell proliferation, migration and glycolysis and inhibited cell apoptosis, while the silence of hsa_circ_0001806 showed an opposite effect. Furthermore, hsa_circ_0001806 acted as a sponge of miR-125b to up-regulate hexokinase II (HK2) expression. In addition, the inhibition of miR-125b and HK2 overexpression partly reversed the inhibitory effect of hsa_circ_0001806 silencing on HCC cell proliferation, migration and glycolysis. CONCLUSION: The inhibition of hsa_circ_0001806 suppressed HCC cell proliferation, migration and glycolysis through mediating miR-125b/HK2 axis.

Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na+ current, contractility, and Ca2+ release in murine hearts.

BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) is a proto-oncogene with high activity in the heart. BYL719 (BYL) is a PI3Kα-selective small molecule inhibitor and a prospective drug for advanced solid tumors. We investigated whether acute pharmacological inhibition of PI3Kα has pro-arrhythmic effects. METHODS & RESULTS: In isolated wild-type (WT) cardiomyocytes, pharmacological inhibition of PI3Kα (BYL719) increased contractility by 28%, Ca2+ release by 20%, and prolonged action potential (AP) repolarization by 10-15%. These effects of BYL719 were abolished by inhibition of reverse-mode Na+/Ca2+ exchanger (NCX) (KB-R7943) or by inhibition of late Na+ current (INa-L) (ranolazine). BYL719 had no effect on PI3Kα-deficient cardiomyocytes, suggesting BYL719 effects were PI3Kα-dependent and mediated via NCX and INa-L. INa-L was suppressed by activation of PI3Kα, application of exogenous intracellular PIP3, or ranolazine. Investigation of AP and Ca2+ release in whole heart preparations using epicardial optical mapping showed that inhibition of PI3Kα similarly led to prolongation of AP and enhancement of Ca2+ release. In hearts of PI3Kα-deficient mice, ß-adrenergic stimulation in the presence of high Ca2+ concentrations and 12-Hz burst pacing led to delayed afterdepolarizations and ventricular fibrillation. In vivo, administration of BYL719 prolonged QT interval [QTcF (Fridericia) increased by 15%] in WT, but not in PI3Kα-deficient mice. CONCLUSIONS: Pharmacological inhibition of PI3Kα is arrhythmogenic due to activation of INa-L leading to increased sarcoplasmic reticulum Ca2+ load and prolonged QT interval. Therefore, monitoring of cardiac electrical activity in patients receiving PI3K inhibitors may provide further insights into the arrhythmogenic potential of PI3Ka inhibition.

DNA methylation-reprogrammed oxytocin receptor underlies insensitivity to oxytocin in pre-eclamptic placental vasculature.

Pre-eclampsia is associated with inadequate placental blood flow and placental ischaemia. Placental vascular tone is essential for maintaining adequate placental blood flow. Oxytocin is increased in placental system at late pregnancy and onset of labour, and presented strongly concentration-dependent contractions in placental vascular, suggesting that oxytocin could be involved in regulating placental vascular tone and circulation. However, information about the reactivity of oxytocin in pre-eclamptic placental vasculature is limited. This study used a large number of human placentas to reveal the pathophysiological changes and its underlying mechanisms of oxytocin-induced vasoconstrictions in placental vessels under pre-eclamptic condition. Present study found that oxytocin-induced contractions were significantly decreased in human pre-eclamptic placental vasculature, associated with a deactivated transcription of oxytocin receptor gene. The deactivated oxytocin receptor gene transcription was ascribed to a relatively higher DNA methylation status of CpG islands in oxytocin receptor gene promoter. This study was first to reveal that a hyper-methylation of CpG islands in oxytocin receptor gene promoter, leading to a relatively low pattern of oxytocin receptor expression, was responsible for the decreased sensitivity of oxytocin in pre-eclamptic placental vessels.

Prenatal hypoxia plus postnatal high-fat diet exacerbated vascular dysfunction via up-regulated vascular Cav1.2 channels in offspring rats.

BACKGROUND: This study aimed to examine whether and how postnatal high-fat diet had additional impact on promoting vascular dysfunction in the offspring exposed to prenatal hypoxia. METHODS AND RESULTS: Pregnant Sprague-Dawley rats were randomly assigned to hypoxia (10.5% oxygen) or normoxia (21% O2 ) groups from gestation days 5-21. A subset of male offspring was placed on a high-fat diet (HF, 45% fat) from 4-16 weeks of age. Prenatal hypoxia induced a decrease in birth weight. In offspring-fed HF diet, prenatal hypoxia was associated with increased fasting plasma triglyceride, total cholesterol, free fatty acids, and low-density lipoprotein-cholesterol. Compared with the other three groups, prenatal hypoxic offspring with high-fat diet showed a significant increase in blood pressure, phenylephrine-mediated vasoconstrictions, L-type voltage-gated Ca2+ (Cav1.2) channel currents, and elevated mRNA and protein expression of Cav1.2 α1 subunit in mesenteric arteries or myocytes. The large-conductance Ca2+-activated K+ (BK) channels currents and the BK channel units (ß1, not α-subunits) were significantly increased in mesenteric arteries or myocytes in HF offspring independent of prenatal hypoxia factor. CONCLUSION: The results demonstrated that prenatal hypoxia followed by postnatal HF caused vascular dysfunction through ion channel remodelling in myocytes.

[Electrophysiological characteristics of hippocampal postnatal early development mediated by AMPA receptors in rats].

The present study was aimed to investigate the electrophysiological characteristics of hippocampal postnatal early development mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rats. Forty-eight Wistar rats were divided into postnatal 0.5-, 1-, 2- and 3-month groups (n = 12). Spontaneous excitatory postsynaptic currents (sEPSCs) and field excitatory postsynaptic potentials (fEPSPs) mediated by AMPA receptors were recorded to evaluate the changes in the intrinsic membrane properties of hippocampal CA1 pyramidal neurons by using patch-clamp and MED64 planar microelectrode array technique respectively. The results showed that, during the period of postnatal 0.5-3 months, some of the intrinsic membrane properties of hippocampal CA1 pyramidal neurons, such as the membrane capacitance (Cm) and the resting membrane potential (RMP), showed no significant changes, while the membrane input resistance (Rin) and the time constant (τ) of the cells were decreased significantly. The amplitude, frequency and kinetics (both rise and decay times) of sEPSCs were significantly increased during the period of postnatal 0.5-1 month, but they were all decreased during the period of postnatal 1-3 months. In addition, the range of evoked fEPSPs in hippocamal CA1 region was significantly expanded, but the fEPSP amplitudes were decreased significantly during the period of postnatal 0.5-3 months. Furthermore, the evoked fEPSPs could be significantly inhibited by extracellular application of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These results suggest that AMPA receptor may act as a major type of excitatory receptor to regulate synaptic transmission and connections during the early stage of hippocampal postnatal development, which promotes the development and functional maturation of hippocampus in rats.

1,25-Dihydroxyvitamin D3 Deficiency is Involved in the Pathogenesis of Diabetic Retinopathy in the Uygur Population of China.

1,25-Dihydroxyvitamin D3 [1,25(OH)2 D3 ] has recently been shown to have immunomodulatory property. This study aimed to investigate the expression and potential role of 1,25(OH)2 D3 in the pathogenesis of diabetic retinopathy (DR) in the Uygur population. Blood samples were obtained from 22 patients with proliferative DR (PDR), 29 patients with nonproliferative DR (NPDR), and 24 normal controls. ELISA was performed to estimate the serum levels of 1,25(OH)2 D3 . Peripheral blood mononuclear cells (PBMCs) were cultured with or without 1,25(OH)2 D3 in the presence of anti-CD3 and anti-CD28 antibodies to detect the secretion of cytokines and cell proliferation. The FACS cytometric bead array system was used to analyze cytokine levels in the serum and culture supernatants. The Cell Counting Kit was used to determine the rate of cell proliferation. In this study, we found that the patients with PDR showed a decreased serum level of 1,25(OH)2 D3 and increased production of IFN-γ, TNF-α, IL-6, and IL-17A, by anti-CD3 and anti-CD28 antibodies activated PBMCs. Furthermore, 1,25(OH)2 D3 significantly inhibited the proliferation of PBMCs, as well as the secretion of IFN-γ, TNF-α, IL-6, and IL-17A. Overall, our findings suggest a potential protective effect of 1,25(OH)2 D3 in DR, whereas supplementation with 1,25(OH)2 D3 might be an effective strategy for preventing the development of DR. © 2016 IUBMB Life, 68(6):445-451, 2016.

Hydrogen sulfide: an old gas with new cardioprotective effects.

Diabetic cardiovascular complications are reaching epidemic proportions and the risk of HF (heart failure) is increased 2-3-fold by diabetes mellitus. H2S (hydrogen sulfide) is emerging as a new gaseous signalling molecule in the cardiovascular system which possesses multifactorial effects on various intracellular signalling pathways. The proven cardioprotective and vasodilator activities of H2S warrant a detailed investigation into its role in diabetic cardiomyopathy. In the present issue of Clinical Science, Zhou et al. demonstrate an important therapeutic potential of the H2S pathway in diabetic cardiomyopathy.

Immunosuppressants for the prophylaxis of corneal graft rejection after penetrating keratoplasty.

BACKGROUND: Penetrating keratoplasty is a corneal transplantation procedure in which a full-thickness cornea from the host is replaced by a graft from a donor. The use of various immunosuppressants to prevent graft rejection, the most common cause of graft failure in the late postoperative period, is increasing. OBJECTIVES: To assess the effectiveness of immunosuppressants in the prophylaxis of corneal allograft rejection after high- and normal-risk keratoplasty. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to May 2015), EMBASE (January 1980 to May 2015), China National Knowledge Infrastructure (CNKI) (January 1913 to February 2015), VIP database (January 1989 to February 2015), Wanfang Data (www.wanfangdata.com) (January 1990 to February 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the English language databases on 18 May 2015 and the Chinese language databases on 20 February 2015. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) assessing the use of immunosuppressants in the prevention of graft rejection, irrespective of publication language. DATA COLLECTION AND ANALYSIS: We used standard procedures expected by Cochrane. The primary outcome was clear graft survival at 12 months after penetrating keratoplasty. Secondary outcomes included graft rejection, best-corrected visual acuity, and quality of life. We defined 'high-risk keratoplasty' as repeat keratoplasty and other indications of reduced graft survival. MAIN RESULTS: We included six studies conducted in Germany (three studies), Iran, India, and China. Three studies were conducted in people undergoing high-risk keratoplasty and investigated three different comparisons: systemic mycophenolate mofetil (MMF) versus no MMF; systemic MMF versus systemic cyclosporine A (CsA); and topical CsA versus placebo. One study compared topical tacrolimus to topical steroid in people with normal-risk keratoplasty, and two studies compared topical CsA to placebo in people experiencing graft rejection after normal-risk keratoplasty. Overall, we considered the trials to be at unclear or high risk of bias.MMF may not improve clear graft survival (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.84 to 1.33, 1 RCT, 87 participants, low-quality evidence) but may reduce the risk of graft rejection (RR 0.49, 95% CI 0.22 to 1.08, 1 RCT, 87 participants, low-quality evidence) compared to no MMF. Visual acuity was not reported.In 1 study of 52 people comparing systemic MMF and systemic CsA, there were no graft failures in the first year of follow-up. Data from the longest follow-up (three years) suggest that there may be little difference in the effect of these two treatments on clear graft survival (RR 1.10, 95% CI 0.90 to 1.35, low-quality evidence). There was low-quality evidence of an increased risk of graft rejection with systemic MMF compared to systemic CsA, but with wide CIs compatible with increased risk with systemic CsA (RR 1.48, 95% CI 0.56 to 3.93, low-quality evidence). Visual acuity was not reported.One study of 84 people comparing topical CsA to placebo did not report clear graft survival at 1 year, which suggests that all grafts survived to 1 year. This study suggests that the use of topical CsA probably leads to little or no difference in graft rejection (RR 1.00, 95% CI 0.39 to 2.58, moderate-quality evidence). At one year, the mean difference (MD) between the two groups in visual acuity was 0.07 (95% CI -0.01 to 0.15, moderate-quality evidence).Topical CsA probably does not have an effect on clear graft survival in people experiencing graft rejection after normal-risk keratoplasty compared to placebo (RR 1.03, 95% CI 0.96 to 1.10, 2 RCTs, 283 participants, moderate-quality evidence). There were inconsistent findings on graft rejection, with one study reporting a reduced incidence of graft rejection in the CsA group (RR 0.35, 95% CI 0.14 to 0.87, 230 participants) but the other study reporting a higher average number of episodes of graft rejection in people treated with CsA (MD 1.30, 95% CI 0.39 to 2.21, 43 participants). Overall, we judged this to be low-quality evidence due to risk of bias and inconsistency. There was no evidence for a difference in visual acuity between the 2 groups at final follow-up (approximately 18 months, range 2 to 33 months) (MD 0.04, 95% CI -0.10 to 0.18, 1 RCT, 43 participants, low-quality evidence).In 1 study comparing topical tacrolimus to topical steroid, the graft survived in all of the 12 treated participants and 20 control participants at 6 months. Graft rejection was rare (0 out of 12 versus 2 out of 20) (RR 0.32, 95% CI 0.02 to 6.21, low-quality evidence). Visual acuity was not reported.None of the studies reported on quality of life. We identified an unpublished trial of basiliximab (Simulect) (NCT00409656), probably completed in 2005. AUTHORS' CONCLUSIONS: Current evidence on the effect of immunosuppressants in the prevention of graft failure and rejection after high- and normal-risk keratoplasty is largely low quality because the number of trials was limited, and, in general, the trials were small and at risk of bias. Future trials should be large enough to detect important clinical effects, conducted with a view to minimising the risk of bias, and they should measure outcomes important to patients.