Tolerance to decentration of biaspheric intraocular lenses with refractive phase-ring extended depth of focus and diffractive trifocal designs.

PURPOSE: This study aimed to investigate the in vitro tolerance to decentration of biaspheric intraocular lens (IOLs) with refractive phase-ring extended depth-of-focus (EDOF) and diffractive trifocal designs. METHODS: This experimental study was carried out at the Department of Optics and Optometry and Vision Science, University of Valencia, Spain. The modulation transfer function (MTF) of the ETLIO130C EDOF and the TFLIO130C trifocal IOLs (AST Products Inc., Billerica, MA, USA) were determined at different levels of decentration for a given wavelength and pupil diameter using the PMTF optical bench (Lambda-X Ophthalmics, Nivelles, Belgium). The modulation transfer function (MTF) curves, the through-focus MTF curves, and the Strehl ratios were measured at 3-mm pupil aperture for 0.25-, 0.50- and 0.75-mm decentration. RESULTS: The optical design of the trifocal TFLIO130C IOL is robust to small decentrations, with virtually no change in MTF response for 0.25 mm decentration. For greater decentration levels, the MTF response is slightly reduced with increasing decentration. The ETLIO130C EDOF design is robust to decentration, as the MTF response is only minimally affected when increasing the decentration up to 0.75 mm. CONCLUSIONS: MTF responses are slightly reduced with greater levels of decentration, but the range of focus provided by both trifocal and EDOF designs are preserved. The effects for average levels of decentration reported in the literature are minimum for both IOL designs.

Transport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines.

Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington's Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occluded, and cytosol-facing conformations. Notably, tetrabenazine induces a substantial rearrangement of TM2 and TM7, extending beyond the typical rocker-switch movement. These functionally dynamic snapshots, complemented by biochemical analysis, unveil the essential components responsible for ligand recognition, elucidate the proton-driven exchange cycle, and provide a framework to design improved pharmaceutics targeting VMAT2.

Association between systemic iron status and ß-cell function and insulin sensitivity in patients with newly diagnosed type 2 diabetes.

Objective: Abnormal iron metabolism is related to the risk of diabetes, but the underlying mechanism of this association remains uncertain. This study was conducted to evaluate the contributions of systemic iron status to ß-cell function and insulin sensitivity of patients with newly diagnosed T2DM. Methods: A total of 162 patients with newly diagnosed T2DM and 162 healthy controls were enrolled in the study. Basic characteristics, biochemical indicators, and iron metabolism biomarkers, including serum iron (SI), ferritin (SF), transferrin (Trf), and transferrin saturation (TS), were collected. All patients underwent a 75 g oral glucose tolerance test. A series of parameters for assessing ß-cell function and insulin sensitivity were calculated. The multivariate stepwise linear regression model was used to investigate the contributions of iron metabolism to ß-cell function and insulin sensitivity. Results: Compared with healthy controls, patients with newly diagnosed T2DM had significantly higher levels of SF. Among the diabetic patients, the SI and TS levels were higher, and the percentage of Trf levels below normal values was lower in men than in women. In all diabetic patients, SF was the independent risk factor associated with impaired ß-cell function. Further stratification analysis showed that Trf was an independent protective factor for ß-cell function in male patients, while SF was an independent risk factor for impaired ß-cell function in female patients. However, systemic iron status did not affect insulin sensitivity. Conclusion: Elevated SF levels and decreased Trf levels had a profound effect on impaired ß-cell function in Chinese patients with newly diagnosed T2DM.

An Effective Treatment of Perimenopausal Syndrome by Combining Two Traditional Prescriptions of Chinese Botanical Drugs.

Ethnopharmacological relevance: Two types of traditional Chinese formulas of botanical drugs are prescribed for treating perimenopausal syndrome (PMS), a disorder in middle-aged women during their transition to menopause. One is for treating PMS as kidney deficiency (KD) due to senescence and declining reproductive functions, and the other is for treating it as liver qi stagnation (LQS) in association with stress and anxiety. Despite the time-tested prescriptions, an objective attestation to the effectiveness of the traditional Chinese treatment of PMS is still to be established and the associated molecular mechanism is still to be investigated. Materials and methods: A model for PMS was generated from perimenopausal rats with chronic restraint stress (CRS). The effectiveness of traditional Chinese formulas of botanical drugs and a combination of two of the formulas was evaluated based on 1H NMR plasma metabolomic, as well as behavioral and physiological, indicators. To investigate whether the formulas contained ligands that could compensate for the declining level of estrogen, the primary cause of PMS, the ligand-based NMR technique of saturation transfer difference (STD) was employed to detect possible interacting molecules to estrogen receptors in the decoction. Results: Each prescription of the classical Chinese formula moderately attenuated the metabolomic state of the disease model. The best treatment strategy however was to combine two traditional Chinese formulas, each for a different etiology, to adjust the metabolomic state of the disease model to that of rats at a much younger age. In addition, this attenuation of the metabolomics of the disease model was by neither upregulating the estrogen level nor supplementing an estrogenic compound. Conclusion: Treatment of PMS with a traditional Chinese formula of botanical drugs targeting one of the two causes separately could ameliorate the disorder moderately. However, the best outcome was to treat the two causes simultaneously with a decoction that combined ingredients from two traditional prescriptions. The data also implicated a new paradigm for phytotherapy of PMS as the prescribed decoctions contained no interacting compound to modulate the activity of estrogen receptors, in contrast to the treatment strategy of hormone replacement therapy.

Circulating microRNA-194 levels in Chinese patients with diabetic kidney disease: a case-control study.

OBJECTIVE: MicroRNAs (miRNAs) regulate gene expression and are involved in diabetic kidney disease (DKD) pathogenesis. We investigated circulating miRNA-194 levels as a biomarker of DKD prevalence and incidence, and the relationship between miRNA-194 and CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP). METHODS: We recruited 136 type-2 diabetes mellitus (T2DM) patients at the First People's Hospital of Lianyungang and 127 healthy individuals. Circulating miRNA-194 and CHOP levels were measured using quantitative reverse transcription qRT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Anthropometric and biochemistry measurements were also made. RESULTS: T2DM patients showed higher circulating miRNA-194 (p = 0.029) and lower circulating CHOP (p < 0.001) levels than controls. Circulating miRNA-194 levels were significantly higher in T2DM patients with a microalbumin/creatinine ratio (UmALB/Cr) ⩾ 300 mg/g (p < 0.001). In addition, there were significant intergroup differences in the circulating CHOP concentrations (p = 0.005). Bivariate analysis revealed that circulating miR-194 levels were negatively correlated with alpha-fetoprotein and CHOP levels (r = -0.222, -0.301; p = 0.018, 0.001, respectively), but positively correlated with fasting glucose, UmALB/Cr, Cr, Cystatin C, quantitative insulin check index (QUICKI) (r = 0.193, 0.446, 0.260, 0.339, and 0.250, respectively; p = 0.036, <0.001, 0.005, <0.001, and 0.006, respectively), particularly UmALB/Cr and Cystatin C (p < 0.001). Logistic regression analysis after adjusting for covariates associated with UmALB/Cr identified duration of T2DM, systolic blood pressure, Cr, estimated glomerular filtration rate, and waist circumference as independent factors associated with T2DM patients with UmALB/Cr > 300 (p = 0.030, 0.013, <0.001, <0.001, and 0.031, respectively). CONCLUSION: Circulating miRNA-194 levels could be a novel biomarker for DKD.

Levels of circulating GRP78 and CHOP in endoplasmic reticulum stress pathways in Chinese type 2 diabetic kidney disease patients.

ABSTRACT: The current study aimed to investigate circulating glucose-regulated protein 78 (GRP78) as well as CCAAT/enhancer-binding protein homologous protein (CHOP) concentrations in Chinese type 2 diabetes mellitus (T2DM) patients, especially those with microalbuminuria. We recruited 67 patients with T2DM and 63 control subjects. We determined circulating GRP78 and CHOP concentrations by ELISA, collected anthropometric data, and measured biochemical parameters in a clinical laboratory. Compared with control groups, patients with T2DM showed decreased circulating levels of GRP78 (0.21 [0.16-0.24] vs 0.16 [0.16-0.19] ng/mL, P < .01) and CHOP ([0.29 ±â€Š0.02] vs [0.27 ±â€Š0.03]ng/mL, P < .01). Reduction in circulating GRP78 and CHOP levels was more pronounced in patients with more severe categories of albuminuria. Amounts of circulating GRP78 correlated directly with serum fasting c-peptide, cystatin-c (Cys-c), creatinine (Cr), blood urea nitrogen (BUN), and uric acid, and inversely with glomerular filtration rates. Circulating CHOP level was positively correlated with age, Cr, BUN, Cys-c, and urinary microalbumin/creatinine (UmALB/Cr). Circulating GRP78 was predicted independently by Cr, BUN, serum uric acid, estimated glomerular filtration rate, and Cys-c, while CHOP depended on age, Cr, BUN, estimated glomerular filtration rate, UmALB/Cr, and Cys-c. After controlling for confounding factors, circulating GRP78 and CHOP expression were significantly associated with diabetic kidney disease (binary logistic regression, P < .01). Patients with T2DM showed increased circulating GRP78 and CHOP concentrations. Receiver operating characteristic areas under the curve for predicting diabetic kidney disease based on GRP78 and CHOP were 0.686 (95% CI: 0.558-0.813) and 0.670 (0.524-0.816), respectively.

Effects of dapagliflozin on cardiovascular outcomes in type 2 diabetes: Study protocol of a randomized controlled trial.

BACKGROUND: Dapagliflozin, a novel inhibitor of renal sodium-glucose cotransporter 2, allows an insulin-independent approach to improve type 2 diabetes hyperglycemia. This current research is a double blinded, randomized, and prospective trial to determine the effect of dapagliflozin on cardiovascular outcomes in type 2 diabetes. METHODS: This randomized controlled, double-blinded, single center trial is carried out according to the principles of Declaration of Helsinki. This present study was approved in institutional review committee of the Lianyungang Hospital affiliated to Xuzhou Medical University (LW-20200901001). All the patients received the informed consent. Diabetic patients were randomized equally to receive 28-week treatment with dapagliflozin or matching placebo. The major outcome of our current study was the change in the level of hemoglobin A1c (HbA1c) from the baseline to week 28. Secondary outcome measures contained the levels of fasting blood glucose, the mean change in seated systolic and diastolic blood pressure, body weight, and the mean change in calculated average daily insulin dose in patients treated with insulin at baseline, the other laboratory variables, and self-reported adverse events. The P < .05 was regarded as statistically significant. RESULTS: We assumed that the dapagliflozin administration in patients with type 2 diabetes would reduce HbA1c, body weight, systolic blood pressure, and achieve the goal of glycemic control, without adversely impacting cardiovascular risk. TRIAL REGISTRATION: This study protocol was registered in Research Registry (researchregistry5987).

Predictive values of obesity categories for cardiovascular disease risk factors in Chinese adult population.

OBJECTIVE: Whether obesity categories can be used to predict cardiovascular disease (CVD) in Chinese adults remains unclear. This aim of this study was to examine the predictive values of obesity categories for CVD risk factors in Chinese adults. METHODS: This study comprised a sample size of 3480 men and 6364 women aged ≥25 years (age range 25-89 years), from the medical health check-up center of Lianyungang First People's Hospital. The following CVD risk factor outcomes were used: hypertension, diabetes, dyslipidemia, insulin resistance, and metabolic syndrome (Mets). Framingham risk scores were used to evaluate the CVD. Four categories of obesity were used, based on body mass index (BMI) and waist circumference: no risk, increased risk, high risk, and very high risk. Predictive abilities were determined by calculating the odds ratios (OR) of CVD risk. RESULTS: A graded linear relationship between obesity categories and CVD risk was observed across the categories, except for dyslipidemia. The people in the very high-risk category had the highest OR of having more unfavorable CVD risk factors compared with those in the lower risk category. For example, the OR of diabetes increased with the increase in risk category (OR, 1.13, 1.36, and 1.83, respectively, for increased, high, and very high risk categories in men and OR, 1.52, 1.80, and 2.78, respectively, for increased, high, and very high risk category in women). CONCLUSIONS: These findings suggest that obesity categories provide clinical insights into identifying multiple CVD risk factors in Chinese adults.

Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance.

The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome contains Nod-like receptors, a subclass of pattern recognition receptors, suggesting that this complex has a prominent role in host defenses. Various structurally diverse stimulators activate the NLRP3 inflammasome through different signaling pathways. We previously reported that ugonin U (UgU), a natural flavonoid isolated from Helminthostachys zeylanica (L) Hook, directly stimulates phospholipase C (PLC) and triggers superoxide release in human neutrophils. In the present study, we showed that UgU induced NLRP3 inflammasome assembly and subsequent caspase-1 and interleukin (IL)-1ß processing in lipopolysaccharide-primed human monocytes. Moreover, UgU elicited mitochondrial superoxide generation in a dose-dependent manner, and a specific scavenger of mitochondrial reactive oxygen species (ROS) diminished UgU-induced IL-1ß and caspase-1 activation. UgU induced Ca2+ mobilization, which was inhibited by treatment with inhibitors of PLC or inositol triphosphate receptor (IP3R). Blocking Ca2+ mobilization, PLC, or IP3R diminished UgU-induced IL-1ß release, caspase-1 activation, and mitochondrial ROS generation. These data demonstrated that UgU activated the NLPR3 inflammasome activation through Ca2+ mobilization and the production of mitochondrial ROS. We also demonstrated that UgU-dependent NLRP3 inflammasome activation enhanced the bactericidal function of human monocytes. The ability of UgU to stimulate human neutrophils and monocytes, both of which are professional phagocytes, and its capacity to activate the NLRP3 inflammasome, which is a promising molecular target for developing anti-infective medicine, indicate that UgU treatment should be considered as a possible novel therapy for treating infectious diseases.