Poloxamer-chitosan-based Naringenin nanoformulation used in brain targeting for the treatment of cerebral ischemia

ObjectiveHere, the aim is to improve the bioavailability of Naringenin (NRG) in brain and to establish the highest remedial benefit from a novel anti-ischemic medicine i.e. NRG.MethodsA novel Naringenin-loaded-nanoemulsion (NE)-(in situ)-gel (i.e. thermoresponsive), was formulated with the help of Poloxamer-407 (20.0% w/v). Chitosan (CS, 0.50% w/v) was used to introduce the mucoadhesive property of NE-(in situ)-gel and finally called as NRG-NE-gel + 0.50%CS. A novel UHPLC-ESI-Q-TOF-MS/MS-method was optimized and used for NRG-NE-gel + 0.50%CS to quantify the Pharmacokinetic-(PK)-parameters in plasma as well as brain and to evaluate the cerebral ischemic parameters after MCAO i.e. locomotor activity, grip strength, antioxidant activity, and quantity the infarction volume in neurons with the safety/toxicity of NRG-NE-gel + 0.50%CS after i.n. administration in the rats.ResultsThe mucoadhesive potency and gelling temperature of NRG-NE-gel + 0.50%CS were observed 6245.38 dynes/cm² and 28.3 ± 1.0 °C, respectively. Poloxamer-407 based free micelles size was observed 98.31 ± 1.17 nm with PDI (0.386 ± 0.021). The pH and viscosity of NRG-NE-gel + 0.50%CS were found to be 6.0 ± 0.20 and 2447 ± 24cp (at 35.0 ± 1.0 °C temperature), respectively. An elution time and m/z NRG were observed 1.78 min and 270.97/150.96 with 1.22 min and m/z of 301.01/150.98 for Quercetin (IS) respectively. Inter and intra %precision and %accuracy was validated 1.01–3.37% and 95.10–99.30% with a linear dynamic range (1.00 to 2000.00 ng/ml). AUC_0-24 of plasma & brain were observed 995.60 ± 24.59 and 5600.99 ± 144.92 (ng min/ml g) in the rats after the intranasal (i.n.) administration of NRG-NE-gel + 0.50%CS. No toxicological response were not found in terms of mortalities, any-change morphologically i.e. in the microstructure of brain as well as nasal mucosa tissues, and also not found any visual signs in terms of inflammatory or necrosis.ConclusionIntranasally administered NRG-NE-gel + 0.50%CS enhanced the bioavailability of Naringenin in the brain. In the cerebral ischemic rats, significantly improved the neurobehavioral activity (locomotor & grip strength) followed by antioxidant activity as well as infarction volume. Finally, the toxicity studies carried out and established the safe nature of optimized-NRG-NE-gel + 0.50%CS.     

A comparative ex vivo permeation evaluation of a novel 5-Fluorocuracil nanoemulsion-gel by topically applied in the different excised rat,goat, and cow skin

Aim of the study5-Fluorouracil (5-FU) can’t be given orally because of very low bioavailability and produces serious adverse effects. Therefore, the main objective of this research is to develop, evaluate, and comparative effects by different nanoformulations of topical application on chemoprevention of skin cancer in different types of skin.Material and methodsCastor oil (oil), Transcutol HP (surfactant), and Polyethylene glycol (PEG)–400 (co-surfactant) have taken on the basis of nonionic property and highest nanoemulsion (NE)-region. Aqueous micro titration method with ultra-sonication method (based on high energy) was used for the preparation of 5-FU-NE. Optimized-5-FU-NE was stable thermodynamically, and their characterizations was performed on the basis of globule size, zeta potential, refractive index, and viscosity. Optimized-NE has been converted into 5-FU-NE-Gel with the help of Carbopol® 934 and also performed their permeation studies in the different skins (cow, goat, and rat, ex vivo) using Logan transdermal diffusion cell (DHC-6T). Optimized-5-FU-NE and 5-FU-NE-Gel were evaluated cytotoxic studies (in vitro) on the melanoma cell lines.ResultsThe permeation of 5-FU from 5-FU-NE-Gel nanoformulation for rat skin model was 1.56 times higher than the 5-FU-NE and 12.51 times higher than the 5-FU-S for the cow and goat skin model. The values of steady state flux and permeability coefficient for 5-FU-NE-Gel of rat skin were higher i.e. 12.0244 ± 1.12 µgcm⁻²h⁻¹ and 1.2024 ± 0.073 × 10⁻² µg cm⁻²h⁻¹, respectively. Optimized-5-FU-NE and 5-FU-NE-Gel nanoformulation were found to be physically stable. SK-MEL-5 cancer cells have showed the results based on cytotoxicity studies (in vitro) that 5-FU as Optimized-5-FU-NE-Gel is much more efficacious than 5-FU-NE followed by free 5-FU. Localization of 5-FU from 5-FU-NE-Gel was higher with higher permeation in rat skin.Conclusion5-FU-NE-Gel is found to be for the better to treatment of cutaneous malignancies. It can be developed 5-FU-NE-Gel could be a promising vehicle for the skin cancer chemoprevention.     

Pharmacological intervention of biosynthesized Nigella sativa silver nanoparticles against hexavalent chromium induced toxicity in male albino mice

Hexavalent chromium, toxic heavy metal, among the top-rated environmental contaminants, is declared a potent endocrine disruptor in humans and animals. The present study was planned to find harmful effects on the reproductive system caused by Cr (VI) and the ameliorative effect of Nigella sativa and Nigella sativa-mediated AgNP on male mice (Mus musculus). In the present study, known infertility medicine, clomiphene citrate is also used as a positive control. The main objective of the present study was to assess the ameliorative potential of oral administration of a dose of 50 mg/kg BW clomiphene citrate (control), AgNP via chemical synthesis, Nigella sativa seed extract, and Nigella sativa-mediated AgNP against the Cr (VI) at the dose of 1.5 mg/kg BW from K₂Cr₂O₇ orally induced toxicity over eight weeks on the reproductive performance of male albino mice. Nigella sativa mediated AgNPs were characterized by UV, SEM, FTIR, and XRD. The histological analysis, smear study, antioxidant capacity test, and hormone analysis were conducted by blood samples of albino mice. Cr exposed groups showed a significant decrease in sperm head breadth (5.29 ± 0.54 µ) and length (19.54 ± 1.18 µ), middle piece length, tail length, LH (1.65 ± 0.15 ng/mL), testosterone (2.63 ± 0.29 ng/mL), SOD (61.40 ± 2.48 mmol/mL), CAT (87.40 ± 6.01 mmol/mL), GSH (1.54 ± 0.09 µmol/mL), and no of spermatogonia (1.22 ± 0.25), and spermatocytes (2.33 ± 0.943). However, FSH level (160.00 ± 4.98 ng/mL), seminiferous tubule CSA (1094.69 ± 49.76 mm²), size of spermatogonia (41.30 ± 1.24 µ), and spermatocytes (26.07 ± 1.34 µ) were significantly increased. Administration of Nigella sativa and Nigella sativa-mediated AgNPs reduced the toxicity.     

Impact of iterative reconstructions on image quality and detectability of focal liver lesions in low-energy monochromatic images

PurposeTo assess the impact of iterative reconstructions on image quality and detectability of focal liver lesions in low-energy monochromatic images from a Fast kV-Switching Dual Energy CT (KVSCT) platform.MethodsAcquisitions on an image-quality phantom were performed using a KVSCT for three dose levels (CTDI_vol:12.72/10.76/8.79 mGy). Raw data were reconstructed for five energy levels (40/50/60/70/80 keV) using Filtered Back Projection (FBP) and four levels of ASIR (ASIR30/ASIR50/ASIR70/ASIR100). Noise power spectrum (NPS) and task-based transfer function (TTF) were measured before computing a Detectability index (d′) to model the detection task of liver metastasis (LM) and hepatocellular carcinoma (HCC) as function of keV.ResultsFrom 40 to 70 keV, noise-magnitude was reduced on average by −68% ± 1% with FBP; −61% ± 3% with ASIR50 and −52% ± 6% with ASIR100. The mean spatial frequency of the NPS decreased when the energy level decreased and the iterative level increased. TTF values at 50% decreased as the energy level increased and as the percentage of ASIR increased. The detectability of both lesions increased with increasing dose level and percentage of ASIR. For the LM, d′ peaked at 70 keV for all reconstruction types, except for ASIR70 at 12.72 mGy and ASIR100, where d' peaked at 50 keV. For HCC, d’ peaked at 60 keV for FBP and ASIR30 but peaked at 50 keV for ASIR50, ASIR70 and ASIR100.ConclusionsUsing percentage of ASIR above 50% at low-energy monochromatic images could limit the increase of noise-magnitude, benefit from spatial resolution improvement and hence enhance detectability of subtle low contrast focal liver lesions such as HCC.     

Nordic Walking Improves Cardiometabolic Parameters,Fitness Performance,and Quality of Life in Older Adults With Type 2 Diabetes

ObjectiveTo assess the effect of Nordic walking (NW) on cardiometabolic health, physical performance, and well-being in sedentary older adults with type 2 diabetes (T2D).MethodsFifteen subjects with T2D (female, 5; male, 10; age, 65 ± 6.2 years [mean ± standard deviation]; body mass index, 27.3 ± 4.9 kg/m² [mean ± standard deviation]) were enrolled in a 6-month NW training program. The fasting glucose and glycosylated hemoglobin levels, lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), systolic blood pressure (SBP), and diastolic blood pressures were measured before and after the intervention. Participants’ quality of life (Short-Form Health Survey) and physical fitness (6-minute walking test) were also evaluated.ResultsCompared with baseline, NW significantly improved the fasting glucose level (103.5 ± 18.5 vs 168.7 ± 37.7 mg/dL, P = .01), SBP (121.8 ± 12.2 vs 133 ± 14.4 mm Hg, P = .02), physical fitness (759.88 ± 69 vs 615.5 ± 62.6 m, P < .001), and both mental health (54.5 ± 4.4 vs 45.7 ± 5.6, P < .01) and physical health (49.8 ± 4.7 vs 40.3 ± 5.9, P < .01). The levels of glycosylated hemoglobin (6.15% ± 0.8% vs 6.4% ± 1%, P = .46), total cholesterol (162.2 ± 31.2 vs 175.5 ± 28.8 mg/dL, P = .13), low-density lipoprotein cholesterol (95.2 ± 24.2 vs 106.3 ± 32.3 mg/dL, P = .43), and triglycerides (135.5 ± 60.8 vs 127.6 ± 57.4 mg/dL, P = 0.26) improved without reaching significance.ConclusionNW training improved the glycemic levels, SBP, physical fitness, and perception of quality of life in older adults with T2D. NW represents a suitable complementary strategy to improve the global health status in this population.     

Pomegranate peels waste hydrolyzate optimization by Response Surface Methodology for Bioethanol production

Unwanted agricultural waste is largely comprised of lignocellulosic substrate which could be transformed into sugars. The production of bioethanol from garbage manifested an agreeable proposal towards waste management as well as energy causation. The goal of this work is to optimize parameters for generation of bioethanol through fermentation by different yeast strains while Saccharomyces cerevisiae used as standard strain. The low cost fermentable sugars from pomegranate peels waste (PPW) were obtained by hydrolysis with HNO₃ (1 to 5%). The optimum levels of hydrolysis time and temperature were elucidated via RSM (CCD) ranging from 30 to 60 min and 50 to 100 °C respectively. The result shows that optimum values (g/L) for reducing sugars was 61.45 ± 0.01 while for total carbohydrates was 236 ± 0.01. These values were found when PPW was hydrolyzed with 3% HNO₃, at 75 °C for one hour. The hydrolyzates obtained from the dilute HNO₃ pretreated PPW yielded a maximum of 0.43 ± 0.04, 0.41 ± 0.03 g ethanol per g of reducing sugars by both Metchnikowia sp. Y31 and M. cibodasensis Y34 at day 7 of ethanologenic experiment. The current study exhibited that by fermentation of dilute HNO₃ hydrolyzates of PPW could develop copious amount of ethanol by optimized conditions.     

The clinical application of 68Ga-PSMA PET/CT and regulating mechanism of PSMA expression in patients with brain metastases of lung cancer

Brain metastases (BMs) of lung cancer are common malignant intracranial tumours associated with severe neurological symptoms and an abysmal prognosis. Prostate-specific membrane antigen (PSMA) has been reported to express significantly in a variety of solid tumours. However, the clinical applications of ⁶⁸Ga-PSMA PET/CT and the mechanism of PSMA expression in patients with BMs of lung cancer have rarely been reported. Experiments with ⁶⁸Ga-PSMA PET/CT and immunohistochemical staining were conducted to evaluate the expression of PSMA from seven patients with BMs of lung cancer who accepted surgical treatment in Fudan University Shanghai Cancer Center between October 2020 and October 2021. The mechanism of PSMA expression in BMs of lung cancer was explored by using single-cell RNA sequencing. The median maximum standardized uptake value (SUVmax) in BMs was higher than that in primary lung cancer (8.6 ± 2.8 vs. 3.6 ± 1.3, P < 0.01). The mean SUVmax in BMs was 1.76-fold higher than that in the liver, which indicated the potential of PSMA radioligand therapy (PSMA-RLT) for BMs. BMs showed intense PSMA staining, while normal lung tissue had no PSMA staining and there was only faint primary lung cancer staining by immunohistochemistry (IHC). Single-cell RNA sequencing (scRNA-seq) analysis found that PSMA was mainly expressed in oligodendrocytes of BMs, whereas it was expressed at lower levels in solid cells of lung cancer. PSMA expression in oligodendrocytes might be regulated by the factors ATF3 and NR4A1, which were associated with ER stress.     

Phenotype Prevalence and Health-Related Quality of Life of Lebanese Women With Polycystic Ovary Syndrome

ObjectivePolycystic ovary syndrome (PCOS) is one of the most common endocrine disorders. Our study aimed to assess, for the first time, the phenotype prevalence and the health-related quality of life of Lebanese women with PCOS.MethodsThis was a cross-sectional study conducted on 322 Lebanese women with PCOS, using a questionnaire containing sociodemographic data, comorbidities, disease-related clinical questions, and the validated PCOS questionnaire (PCOSQ). The quality of life mean scores and phenotypes were compared and correlated among the different sociodemographic data, comorbidities, and disease-related questions.ResultsPhenotype A (67%) was the most common phenotype. High waist circumference and higher Body Mass Index (BMI) were reported mostly in classic phenotypes in comparison with nonclassic (P < .05). The mean total score of all PCOSQ domains was 3.61 ± 1.60. The mean score for each domain (from the greatest to the least serious concern) was menstrual problems (3.31 ± 1.26), emotion (3.33 ± 1.22), weight (3.41 ± 2.12), body hair (3.86 ± 1.79), and infertility (4.15 ± 1.61). Age was negatively correlated only to weight domain score (r = ?0.17, P = .002). BMI was associated only with emotion and weight domain scores (P = .017 and P < .001, respectively). A bigger impairment in nearly all subscales of the PCOSQ in patients presenting with abdominal obesity, glucose intolerance, and increased blood pressure was noted (P < .05).ConclusionMost Lebanese women with PCOS present phenotype A and have a serious impairment in their health-related quality of life, particularly in the menstrual and emotional domains. This highlights the need for community and individual support.     

Differences in Clinical Manifestations and Tumor Features Between Metastatic Pheochromocytoma/Paraganglioma Patients With and Without Germline SDHB Mutation

ObjectiveTo compare metastatic pheochromocytoma/paraganglioma (MPP) patients with germline SDHB mutations (SDHB MPP) and without SDHB mutations (non-SDHB MPP) in terms of baseline clinical manifestations, tumor characteristics, and outcomes.MethodsClinical data were retrospectively reviewed in 101 MPP patients, including 34 SDHB MPP patients and 61 non-SDHB MPP patients.ResultsSDHB MPP patients presented at a younger age at onset, diagnosis, or metastasis (25 ± 16 vs 36 ± 14, 28 ± 17 vs 38 ± 15, and 31 ± 17 vs 44 ± 14 years old, respectively, P < .01 for all) than non-SDHB patients. Compared with their non-SDHB counterparts, SDHB patients were more likely to have paragangliomas (83% vs 47%, P < .05), synchronous metastases (44% vs 23%, P < .05), bone metastases (80% vs 48%, P < .01), and a shorter progression-free survival (3 years vs 5 years, P < .01). The Ki-67 index was higher in SDHB tumors (P < .05). The 5- and 10-year survival rates were 79% and 74%, respectively, in all patients. Seventeen patients died from MPP, and the time from metastasis to death in patients who had received systemic therapy was significantly longer than in those who had not (3.1 ± 1.5 vs 1.4 ± 0.7 years, P < .01).ConclusionCompared with MPP patients without SDHB mutations, MPP patients with SDHB mutations were younger at onset, diagnosis, or metastasis; had a higher incidence of synchronous metastases, higher ratio of paraganglioma, and higher Ki-67 index; had a shorter postoperative progression-free survival; and were more likely to develop bone metastasis or sole liver metastasis. Our results suggest that patients with SDHB mutations should be identified early and monitored regularly to achieve optimal clinical outcomes.     

Combined immobilized lipases for effective biodiesel production from spent coffee grounds

This work describes the enzymatic transesterification of the oil extracted from SCGs for synthesis of biodiesel as a promising alternative to diesel fuels based on petroleum. Biocatalysts from various sources were tested for biodiesel synthesis using coffee oil among which CaCO₃- immobilized Staphylococcus aureus and Bacillus stearothermophilus showed the highest conversion yields (61 ± 2.64% and 64.3 ± 1.53%, respectively) in 4 h. In further optimizing reaction parameters, methanol to oil molar ratio, biocatalyst quantity, water content, as well as incubation time and temperature markedly improved oil-to-biodiesel conversion up to 99.33 ± 0.57 % in a solvent free reaction after 12 h at 55 °C. A mixture of inexpensive CaCO₃-immobilized bacterial lipases at a 1:1 ratio was the best environment-friendly catalyst for biofuel synthesis as well as the ideal trade-off between conversion and cost. Obtained coffee biodiesel remained stable beyond 40 days at ambient storage conditions and its chemical characteristics were comparable to those of other known biodiesels according to the European requirements (EN14214). Collectively, SCGs, after oil extraction, could be an ideal substrate for the production of an environment-friendly biodiesel by using appropriate mixture of CaCO₃-immobilized lipases.     

Clinical Effects of Sodium-Glucose Transporter Type 2 Inhibitors in Patients With Partial Lipodystrophy

ObjectiveSevere insulin resistance syndromes, such as lipodystrophy, lead to diabetes, which is challenging to control. This study explored the safety and efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in a series of 12 patients with severe insulin resistance due to partial lipodystrophy.MethodsA retrospective chart review of the safety (N = 22) and efficacy (N = 12) of SGLT2is in patients with partial lipodystrophy was conducted at our institution. The efficacy outcomes included hemoglobin A1C level, insulin dose, fasting plasma glucose level, C-peptide level, lipid profile, 24-hour urinary glucose excretion, estimated glomerular filtration rate, and blood pressure before and after 12 months of SGLT2i treatment.ResultsThe hemoglobin A1C level decreased after SGLT2i treatment (at baseline: 9.2% ± 2.0% [77.0 ± 21.9 mmol/mol]; after 12 months: 8.4% ± 1.8% [68.0 ± 19.7 mmol/mol]; P = .028). Significant reductions were also noted in systolic (P = .011) and diastolic blood pressure (P = .013). There was a trend toward a decreased C-peptide level (P = .071). The fasting plasma glucose level, lipid level, and estimated glomerular filtration rate remained unchanged. The adverse effects included extremity pain, hypoglycemia, diabetic ketoacidosis (in a patient who was nonadherent to insulin), pancreatitis (in a patient with prior pancreatitis), and fungal infections.ConclusionSGLT2is reduced the hemoglobin A1C level in patients with partial lipodystrophy, with a similar safety profile compared with that in patients with type 2 diabetes. After individual consideration of the risks and benefits of SGLT2is, these may be considered a part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings.     

Halonatronomonas betaini gen. nov., sp. nov., a haloalkaliphilic isolate from soda lake capable of betaine degradation and proposal of Halarsenatibacteraceae fam. nov. and Halothermotrichaceae fam. nov. within the order Halanaerobiales

A search for the organisms responsible for anaerobic betaine degradation in soda lakes resulted in isolation of a novel bacterial strain, designated Z-7014^T. The cells were Gram-stain-negative, non-endospore-forming rods. Growth occurred at 8–52 °C (optimum 40–45 °C), pH 7.1–10.1 (optimum pH 8.1–8.8) and 1.0–3.5 M Na⁺ (optimum 1.8 M), i.e. it can be regarded as a haloalkaliphile. The strain utilized a limited range of substrates, mostly peptonaceous but not amino acids, and was able to degrade betaine. Growth on betaine occurred only in the presence of peptonaceous substances which could not be replaced by vitamins. The G + C content of the genomic DNA of strain Z-7014^T was 36.1 mol%. The major cellular fatty acids (>5% of the total) were C_16:0 DMA, C_{18: 0} DMA, C_16:1ω8, C_16:0, C_18:1 DMA, C_16:1 DMA, C_18:1ω9, and C_18:0. Phylogenetic analysis of the 16S rRNA gene sequence revealed that strain Z-7014^T formed a distinct evolutionary lineage in the order Halanaerobiales with the highest similarity to Halarsenitibacter silvermanii SLAS-1^T (83.6%), Halothermothrix orenii H168^T (85.6%), and Halocella cellulosilytica DSM 7362^T (85.6%). AAI and POCP values between strain Z-7014^T and type strains of the order Halanaerobiales were 51.7–57.8%, and 33.8–58.3%, respectively. Based on polyphasic results including phylogenomic data, the novel strain could be distinguished from other genera, which suggests that strain Z-7014^T represents a novel species of a new genus, for which the name Halonatronomonas betaini gen. nov., sp. nov. is proposed. The type strain is Z-7014^T (=KCTC 25237^T = VKM B-3506^T). On the basis of phylogenomic data, it is also proposed to evolve two novel families Halarsenitibacteraceae fam. nov. and Halothermotrichaceae fam. nov. within the current order Halanaerobiales.     

COVID-19 May Increase the Risk of Insulin Resistance in Adult Patients Without Diabetes: A 6-Month Prospective Study

ObjectiveDuring the coronavirus disease 2019 (COVID-19) pandemic, exploring insulin resistance and beta-cell activity is important for understanding COVID-19‒associated new-onset diabetes. We assessed insulin sensitivity and fasting insulin secretion in patients with COVID-19 without diabetes on admission and at 3 and 6 months after discharge.MethodsThis 6-month prospective study assessed data from the records of 64 patients without diabetes diagnosed with COVID-19 at Wenzhou Central Hospital, China. Each patient was followed up at 3 and 6 months after discharge. Repeated measures analysis of variance was used to investigate differences in multiple measurements of the same variable at different times. Linear regression analysis was performed to analyze the contributor for changes in the triglyceride-glucose (TyG) index.ResultsFasting C-peptide levels in patients at baseline were lower than the normal range. Compared with the baseline results, patients had significantly elevated fasting C-peptide levels (0.35 ± 0.24 vs 2.36 ± 0.98 vs 2.52 ± 1.11 μg/L; P < .001), homeostasis model assessment for beta-cell function (0.42, interquartile range [IQR] 0.36-0.62 vs 2.54, IQR 1.95-3.42 vs 2.90, IQR 2.02-4.23; P < .001), and TyG indices (8.57 ± 0.47 vs 8.73 ± 0.60 vs 8.82 ± 0.62; P = .006) and decreased fasting glucose levels (5.84 ± 1.21 vs 4.95 ± 0.76 vs 5.40 ± 0.68 mmol/L; P = .003) at the 3- and 6-month follow-up. Male gender, age, interferon-alfa treatment during hospitalization, and changes in total cholesterol and high-density lipoprotein levels were significantly associated with changes in the TyG index.ConclusionOur study provided the first evidence that COVID-19 may increase the risk of insulin resistance in patients without diabetes.     

A new isoflavonol and other constituents from Cameroonian propolis and evaluation of their anti-inflammatory,antifungal and antioxidant potential

Propolis is rich in diverse bioactive compounds. Propolis samples were collected from three localities of Cameroon and used in the study. Column chromatography separation of propolis MeOH:DCM (50:50) extracts yielded a new isoflavonol, 2-hydroxy-8-prenylbiochanin A (1) alongside 2′,3′-dihydroxypropyltetraeicosanoate (2) and triacontyl p-coumarate (3) isolated from propolis for first time together with seven compounds: β-amyrine (4), oleanolic acid (5), β-amyrine acetate (6), lupeol (7), betulinic acid (8), lupeol acetate (9) and lupenone (10). These compounds were tested for their inhibitory effect on oxidative burst where intracellular reactive oxygen species (ROS) were produced from zymosan stimulated human whole blood phagocytes and on production of nitric oxide (NO) from lipopolysaccharide (LPS) stimulated J774.2 mouse macrophages. The cytotoxicity of these compounds was evaluated on NIH-3 T3 normal mouse fibroblast cells, antiradical potential on 2,2-diphenyl-1-picrylhydrazylhydrazyl (DPPH·) as well as their anti-yeast potential on four selected candida species. Compound 1 showed higher NO inhibition (IC₅₀ = 23.3 ± 0.3 µg/mL) than standard compound L-NMMA (IC₅₀ = 24.2 ± 0.8 µg/mL). Higher ROS inhibition was shown by compounds 6 (IC₅₀ = 4.3 ± 0.3 µg/mL) and 9 (IC₅₀ = 1.1 ± 0.1 µg/mL) than Ibuprofen (IC₅₀ = 11.2 ± 1.9 µg/mL). Furthermore, compound 1 displayed moderate level of cytotoxicity on NIH-3 T3 cells, with IC₅₀ = 5.8 ± 0.3 µg/mL compared to the cyclohexamide IC₅₀ = 0.13 ± 0.02 µg/mL. Compound 3 showed lower antifungal activity on Candida krusei and Candida glabrata, MIC of 125 μg/mL on each strain compared to 50 μg/mL for fuconazole. The extracts showed low antifungal activities ranging from 250 to 500 μg/mL on C. albicans, C. krusei and C. glabrata and the values of MIC on Candida parapsilosis were 500 μg/mL and above. DPPH* scavenging activity was exhibited by compounds 1 (IC₅₀ = 15.653 ± 0.335 μg/mL) and 3 (IC₅₀ = 89.077 ± 24.875 μg/mL) compared to Vitamin C (IC₅₀ = 3.343 ± 0.271 μg/mL) while extracts showed moderate antiradical activities with IC₅₀ values ranging from 309.31 ± 2.465 to 635.52 ± 11.05 µg/mL. These results indicate that compounds 1, 6 and 9 are potent anti-inflammatory drug candidates while 1 and 3 could be potent antioxidant drugs.     

Anemia in Patients With Diabetes and Prediabetes With Normal Kidney Function: Prevalence and Clinical Outcomes

ObjectiveAnemia is a known complication of diabetes mellitus (DM); however, its prevalence and prognostic relevance in patients with DM and pre-DM with normal kidney function have not been well defined. This study assessed the prevalence of anemia in patients with DM and pre-DM and evaluated its association with clinical outcomes during a 4-year follow-up period.MethodsThis retrospective analysis included patients with DM and pre-DM referred to the Meir Medical Center Endocrine Institute in 2015. Patients with an estimated glomerular filtration rate (eGFR) of <60 mL/min or any other recognized cause of anemia were excluded. The risk of developing microvascular or macrovascular complications or of death during the 4-year follow-up period was determined.ResultsA total of 622 patients (408 with DM and 214 with pre-DM) were included. The mean age of the patients was 64 ± 10.6 years, and 70% were women. The baseline hemoglobin A1C level was 7.1% ± 1.7% (54 mmol/mol), and the eGFR was 86.1 ± 15.3 mL/min. At the time of inclusion, 77 patients (19%) with DM and 23 (11%) with pre-DM had anemia (hemoglobin level 11.9 ± 0.8 and 11.8 ± 0.8 g/dL, respectively), compared with normal hemoglobin levels of 13.8 ± 0.9 and 13.7± 0.9 g/dL, respectively, in the others. A multivariable analysis demonstrated an inverse correlation between baseline hemoglobin (as a continuous variable) and mortality (P = .035), microvascular complications (P = .003), and eGFR decline (P < .001) but not between baseline hemoglobin and macrovascular complications (P = .567).ConclusionThis study found a significant prevalence of anemia unrelated to renal failure, both in patients with DM and pre-DM. Anemia in these patients is associated with the development of microvascular complications, eGFR decline, and mortality. These results underscore the need for intensive lifestyle and pharmacologic interventions in these patients.     

Increased Prolactin is an Adaptive Response to Protect Against Metabolic Disorders in Obesity

ObjectiveProlactin (PRL) is a polypeptide hormone named for its crucial role in lactation. Recently, PRL has been recognized as a metabolic hormone that regulates energy metabolism. The current study aimed to investigate the relationship between circulating PRL and metabolic alterations in overweight/obese patients and the effect of weight loss through bariatric surgery on circulating PRL.MethodsA total of 448 overweight/obese patients aged between 18 and 40 years and 120 age- and sex-matched healthy controls with normal weight were enrolled. Among all participants, 156 obese patients underwent bariatric surgery.ResultsCirculating PRL levels were significantly increased in the overweight (15.27 ± 9.58 μg/L) and obese (17.75 ± 9.15 μg/L) groups compared with the normal weight (13.57 ± 9.03 μg/L) group. Multiple regression analyses demonstrated that the adipose tissue insulin resistance (adipo-IR) level was an independent predictor for PRL (β = −0.451, P < .01). Despite comparable anthropometric parameters, the overweight/obese patients with a higher PRL tertile had decreased levels of triglycerides, nonesterified fatty acids, homeostasis model assessment of insulin resistance, and adipo-IR compared with the patients in the moderate and lower PRL tertiles. Serum PRL levels were significantly decreased following the alleviation of metabolic parameters after bariatric surgery (from 17.12 ± 8.27 to 13.00 ± 5.78 μg/L, P < .05), and the decrease in PRL levels was significantly greater in the lower adipo-IR group than in the higher adipo-IR group (P < .01).ConclusionAn increased serum PRL level might be an adaptive response for protecting against metabolic disorders in obesity.     

Punica granatum waste to ethanol valorisation employing optimized levels of saccharification and fermentation

Pomegranate peels (PPW) as municipal waste is inexpensive biomass that could be a renewable source of sugars particularly rich in hemicellulosic contents. The subsequent conversion of available sugars in PPW can provide prospective strategy for cost-effective bioenergy production. In this study, an experimental setup based on CCD was implemented with the aim of bioconversion of biomass into bioethanol. The factors considered were Hydrochloric acid concentration (X₁), the hydrolysis temperature (X₂) and time (X₃) for optimization with dilute Hydrochloric acid (HCl) saccharification. The present study investigates the optimised level of bioethanol synthesis from acid pre-treated PPW explained by RSM. Subsequently, three yeasts viz. Saccharomyces cerevisiae K7, Metschnikowia sp. Y31 and M. cibodasensis Y34 were utilized for fermentation of acid hydrolysed and detoxified feed stocks. Optimum values of reducing sugars 48.02 ± 0.02 (gL^?1) and total carbohydrates 205.88 ± 0.13 (gL^?1) were found when PPW was hydrolyzed with 1% HCl concentration at 100?C of temperature for 30 min. Later on, fermentation of PPWH after detoxification with 2.5% activated charcoal. The significant ethanol (g ethanol/g of reducing sugars) yields after fermentation with Metschnikowia sp. Y31 and M. cibodasensis Y34 found to be 0.40 ± 0.03 on day 5 and 0.41 ± 0.02 on last day of experiment correspondingly. Saccharomyces cerevisiae K7 also produce maximum ethanol 0.40 ± 0.00 on last day of incubation utilizing the PPWH. The bioconversion of commonly available PPW into bioethanol as emphasize in this study could be a hopeful expectation and also cost-effective to meet today energy crisis.     

Xanthone C-glycosides isomers purified from Dryopteris ramosa (Hope) C. Chr. with bactericidal and cytotoxic prospects

Xanthones C-glycosides are plants secondary metabolites with diverse biological activities. Among the C-glycoside xanthones, the mangiferin (MF) is of widespread occurrence in plants while isomangiferin (IsoMF) is not very common. For the present study mangiferin (MF) and isomangiferin (IsoMF) were isolated from Dryopteris ramosa. The antibacterial potential of MF and IsoMF was evaluated by using agar well diffusion method while cytotoxic properties of MF and IsoMF were assessed by brine shrimp lethality test (BSLT). The antibacterial potential of MF and IsoMF increases in dose dependent manner. The minimum inhibitory concentration (MIC) indicated strong antibacterial potential of MF against Salmonella setubal (125 µg/mL) and Bacillus subtilis (125 µg/mL) while MF showed weak antibacterial potential against Escherichia coli (500 µg/mL). On the other hand the IsoMF showed better antibacterial potential against all the tested strain including Escherichia coli (MIC = 250 µg/mL). The MF and IsoMF showed poor cytotoxicity towards Brine shrimp nauplii as indicated by their LD₅₀ (969.77 ± 0.67 and 768.92 ± 0.81 µg/mL respectively). The present study has highlighted the antibacterial potential of MF and IsoMF. Further evaluation of these two isomeric compounds may prove to be the future remedies for various bacterial infections and other human ailments.     

Embryo Quality May Be Associated With Serum Inhibin B Levels but Not With Serum or Follicular Fluid Levels of Other Components of the Activin–Follistatin–Inhibin Axis

ObjectiveWe investigated the potential associations of embryo quality with serum and/or follicular fluid (FF) concentrations of the molecules of the activin–follistatin–inhibin (AFI) axis and antimüllerian hormone and aimed to identify molecules that could predict a positive assisted reproductive technology (ART) outcome.MethodsIn this cross-sectional study, we measured AFI hormone and antimüllerian hormone levels in the serum and FF of follicles (n = 101) obtained from healthy oocyte donors who underwent an assisted reproductive technology course (n = 32). After egg retrieval, embryos were characterized as good or bad quality according to the European Society of Human Reproduction and Embryology criteria. Women were divided into 3 groups (<50%; 50%-66.7%; and >66.7%) according to the percentage of good quality embryos obtained.ResultsThere was no difference between good and bad quality embryos in any of the molecules measured in FF. Moreover, there was no difference in the parameters measured in the serum among women according to the percentage of good quality embryos (ie, suitable for transfer or freezing) except for inhibin B, which tended to increase along with a good quality embryo rate (55.6 ± 7.9 vs 95.3 ± 14.3 vs 113.9 ± 36.9; P = .045).ConclusionsAmong the molecules of the AFI axis, only serum but not FF inhibin B levels were marginally associated with good quality embryo rates.     

Hemodynamic monitoring by intracardiac impedance measured by cardiac resynchronization defibrillators: Evaluation in a controlled clinical setting (BIO.Detect HF II study)

BackgroundIn patients with cardiac resynchronization therapy defibrillators (CRT-Ds), intracardiac impedance measured by dedicated CRT-D software may be used to monitor hemodynamic changes. We investigated the relationship of hemodynamic parameters assessed by intracardiac impedance and by echocardiography in a controlled clinical setting.MethodsThe study enrolled 68 patients (mean age, 66 ± 9 years; 74% males) at 12 investigational sites. The patients had an indication for CRT-D implantation, New York Heart Association class II/III symptoms, left ventricular ejection fraction 15%–35%, and a QRS duration ≥150 ms. Two months after a CRT-D implantation, hemodynamic changes were provoked by overdrive pacing. Intracardiac impedance was recorded at rest and at four pacing rates ranging from 10 to 40 beats/min above the resting rate. In parallel, echocardiography measurements were performed. We hypothesized that a mean intra-individual correlation coefficient (r_mean) between stroke impedance (difference between end-systolic and end-diastolic intracardiac impedance) measured by CRT-D and the aortic velocity time integral (i.e., stroke volume) determined by echocardiography would be significantly larger than 0.65.ResultsThe hypothesis was evaluated in 40 patients with complete data sets. The r_mean was 0.797, with a lower confidence interval bound of 0.709. The study hypothesis was met (p = 0.007). A stepwise reduction of stroke impedance and stroke volume was observed with increasing heart rate.ConclusionsIntracardiac impedance measured by implanted CRT-Ds correlated well with the aortic velocity time integral (stroke volume) determined by echocardiography. The impedance measurements bear potential and are readily available technically, not requiring implantation of additional material beyond standard CRT-D system.