Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats

Glucose is the most common substrate for energy metabolism. Despite the varying demands for glucose, the body needs to regulate its internal environment and maintain a constant and stable condition. Glucose homeostasis requires harmonized interaction between several tissues, achieving equilibrium between glucose output and uptake. In this thesis we aimed to investigate factors modulating glucose homeostasis in a rat model of type 2 diabetes, the Goto-Kakizaki (GK) rat. In addition, we investigated sex differences in hepatic carbohydrate and lipid metabolism in healthy rats. In Paper I, three-week but not three-day treatment with a Southeast Asian herb, Gynostemma pentaphyllum (GP), significantly reduced plasma glucose (PG) levels in GK rats. An intra-peritoneal glucose tolerance test (IPGTT) was significantly improved in GP-treated compared to placebo-treated group. In the GP treated rats, the glucose response in an intra-peritoneal pyruvate tolerance test was significantly lower, indicating decreased gluconeogenesis, and hepatic glucose output (HGO) was reduced. GP-treatment significantly reduced hepatic glycogen content, but not glycogen synthase activity. The study provides evidence that the GP extract exerted anti-diabetic effect in GK rats, reducing PG levels and HGO, suggesting that GP improves the hepatic insulin sensitivity by suppressing gluconeogenesis. In Paper II, shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increased glucose uptake in L6 myotubes, but did not phosphorylate Akt. Furthermore we found no evidence for the involvement of AMP activated protein kinase (AMPK) in shikonin induced glucose uptake. Shikonin increased the intracellular levels of calcium in these cells and stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myotubes. In GK rats treated with shikonin once daily for 4 days, PG levels were significantly decreased. In an insulin sensitivity test, the absolute PG levels were significantly lower in the shikonin-treated rats. These findings suggest that shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium. In Paper III, GK and control Wistar rats were injected daily for up to 4 weeks with either a non-hematopoietic erythropoietin analog ARA290 or with placebo. PG levels in GK but not Wistar rats were significantly lower in ARA290-treated compared to placebo. After 2 and 4 weeks, the IPGTT was significantly improved in ARA290 treated GK rats. In insulin and pyruvate tolerance tests, glucose responses were similar in ARA290 and placebo groups. In isolated GK rat islets, glucose-stimulated insulin release was two-fold higher and islet intracellular calcium concentrations in response to several secretagogues were significantly higher in ARA290-treated than in placebo-treated GK rats. These findings indicate that treatment with ARA290 significantly improved glucose tolerance in diabetic GK rats, most likely due to improvement of insulin release. In Paper IV, sex differences in hepatic carbohydrate and lipid metabolism were characterized in healthy rats. No sex-differences were observed regarding hepatic triglyceride content, fatty acid oxidation rates or insulin sensitivity. Male rats had higher ratios of insulin to glucagon levels, increased hepatic glycogen content, a lower degree of AMPK phosphorylation, a higher rate of glucose production and higher expression levels of gluconeogenic genes, as compared to female rats. A sex-dependent response to mild starvation was observed with males being more sensitive. In conclusion, sex-differences reflect a higher capacity of the healthy male rat liver to respond to increased energy demands. Key words: glucose homeostasis, type 2 diabetes, GK rats, L6 myotubes, hepatic glucose output, insulin sensitivity, sex differences

β-Adrenergic Inhibition of Contractility in L6 Skeletal Muscle Cells

The β-adrenoceptors (β-ARs) control many cellular processes. Here, we show that β-ARs inhibit calcium depletion-induced cell contractility and subsequent cell detachment of L6 skeletal muscle cells. The mechanism underlying the cell detachment inhibition was studied by using a quantitative cell detachment assay. We demonstrate that cell detachment induced by depletion of extracellular calcium is due to myosin- and ROCK-dependent contractility. The β-AR inhibition of L6 skeletal muscle cell detachment was shown to be mediated by the β2-AR and increased cAMP but was surprisingly not dependent on the classical downstream effectors PKA or Epac, nor was it dependent on PKG, PI3K or PKC. However, inhibition of potassium channels blocks the β2-AR mediated effects. Furthermore, activation of potassium channels fully mimicked the results of β2-AR activation. In conclusion, we present a novel finding that β2-AR signaling inhibits contractility and thus cell detachment in L6 skeletal muscle cells by a cAMP and potassium channel dependent mechanism

Carnosine:can understanding its actions on energy metabolism and protein homeostasis inform its therapeutic potential?

The dipeptide carnosine (β-alanyl-L-histidine) has contrasting but beneficial effects on cellular activity. It delays cellular senescence and rejuvenates cultured senescent mammalian cells. However, it also inhibits the growth of cultured tumour cells. Based on studies in several organisms, we speculate that carnosine exerts these apparently opposing actions by affecting energy metabolism and/or protein homeostasis (proteostasis). Specific effects on energy metabolism include the dipeptide's influence on cellular ATP concentrations. Carnosine's ability to reduce the formation of altered proteins (typically adducts of methylglyoxal) and enhance proteolysis of aberrant polypeptides is indicative of its influence on proteostasis. Furthermore these dual actions might provide a rationale for the use of carnosine in the treatment or prevention of diverse age-related conditions where energy metabolism or proteostasis are compromised. These include cancer, Alzheimer's disease, Parkinson's disease and the complications of type-2 diabetes (nephropathy, cataracts, stroke and pain), which might all benefit from knowledge of carnosine's mode of action on human cells. © 2013 Hipkiss et al.; licensee Chemistry Central Ltd

Sand Drift Potential by Wind in Shileh Plain of Sistan

Introduction: Wind erosion is one of the most important factors in desert environments. Prevailing winds can shift sand dunes and affect their accumulation and morphology. Also, wind regime determines the direction of sand dune mobility in different ways. Therefore, the wind regime, frequency, direction and velocity are supposed to be the most important factors to form the morphology of sand dunes. Wind energy and changes in different directions (wind regime) have large impacts on the morphology, maintenance and transformation of wind features. Having a global knowledge of the magnitude of aeolian processes, we can assess the powerful impact of sand dune mobility on residential areas and infrastructures. The most important factors including the frequency, magnitude and directional mobility of aeolian processes have a very important effect on the entrainment and form of sand dunes. Materials and Methods: To understand and identify the wind erosion regions, wind regime is a useful way since there is a strong correlation between wind regimes and sand dune morphology and structure. Sand rose and wind rose are assumed to be easy, fast and most accurate methods for the identification of wind erosion. Wind regimes processes have been studied by many researchers who believed that investigating wind regimes and sand dune mobility gives a measure of drift potential. Drift potential is a measure of the sand-moving capability by wind; derived from reduction of surface-wind data through a weighting equation. To predict drift potential, wind velocity and direction data from meteorological synoptic stations were used. Regarding the estimation of sand transport rate by wind, many formulas exist such as Bagnold, Kawamura, and Lattau. Also, many software applications have been suggested. However, among these formulas, Fryberger’s is the best and has been widely used since 1979. Results and Discussion: The aim of this study was to analyze wind velocities and directions from 1992 to 2003 in order to predict the volume of sand transportation and its direction using sand-rose and wind-rose softwares. As described earlier, in this research, the drift potential (DP) is estimated for all possible wind speed categories, summed up for all categories of each direction sector using Fryberger’s Equation. The sand drift potential in Shileh was estimated about 3439 vector units with a resultant drift direction along the Southeast, which places it in the high class of wind erosive power based on the Fryberger and Dean (1979) classification method. The sand drift potential values show that the resultant drift direction is from the Northwest towards the Southeast. It was also found that the most powerful winds (the prevailing winds) blow in the summer and the spring seasons, respectively. In contrast, the percentage of calm winds increases during autumn and winter times. The sand transport discharge was predicted to be 20.422 t m-1 year-1 using Lattau and Lattau Equation. With regard to the monthly sand rose, it was seen that the resultant drift potential was low in December and January and high in June and July. The prevailing wind direction ranged from North to Northwest in all seasons. The winds with the highest velocities were observed in the summer, while the winds with lower velocities were observed during the winter. Wind velocities higher than 11 m s-1 had the largest frequencies in the summer and the lowest frequencies in the winter. Wind unidirectional index (UDI) is estimated to be 0.95, implying that the index provides a suitable condition for the creation of transverse (barchanoid) dunes. Conclusion: The Sistan plain is one of the windiest places in the world that is exposed to wind erosion and dust storms. The result of this study is very important due to the construction of an international roadway that connects Chabahar port to Sistan plain and continues towards the Afghanistan border. Therefore, the practical result of this research could be used to protect this highway from sand dune migration. The residential areas and the infrastructure can be damaged by the migration of sand dunes since the sand dunes can move both spatially and temporally. For example, we can even notify the highway passengers about the rate of monthly and seasonal migration of sand dunes so that they avoid travelling during high-storm seasons. The results of this study are also important regarding wind-break design to protect the infrastructure such as highways and agricultural fields. Therefore, sand encroachment hazards affect man-made infrastructures due to wind speed and direction. Sand drift potential is a serious hazard to settlements and other lands as well. This problem is accelerated by the extreme arid conditions (such as the case of Shileh) that may occur in different months of summer. Keywords: Resultant Drift Direction, Sand Drift Potential, Sand Dune, Wind Erosion, Wind Regim

Predicting Municipal Solid Waste Generation through Time Series Method (ARMA Technique) and System Dynamics Modeling (Vensim Software)

Background and Objective: Predicting municipal solid waste generation has an important role in solid waste management. The aim of this study was to predict municipal solid waste generation in Isfahan through time series method and system dynamics modeling. Materials and Methods: Verified data of solid waste generation was collected from Waste Management Organization and population information was collected from the National Statistics Center, Iran for the period 1996-2011. Next, the effect of   factors on solid waste generation such as population, urbanization, gross domestic product was investigated. Moreover, the relationship between each of these factors was identified using generalized estimating equation  model. Finally, the quantity of the solid waste generated in Isfahan city was predicted using system dynamics modeling by Vensim software and time series method by ARMA technique. Results: It was found that population and gross domestic product have a significant relationship with the amount of solid waste with P value 0.026 and 0 respectively. The annual average of municipal solid waste generation would be 1501.4 ton/day in 2021 estimated by the time series method and 1436 ton/day estimated by the system dynamics modeling. In addition, average annual growth rate achieved was 3.44%. Conclusion: According to the results obtained, population and gross domestic product have a significant effect on MSW generation. Municipal solid waste generation will increase in future. Increasing solid waste is not the same in different areas and methods. The prediction of the time series method by ARMA technique gives precise results compared with other methods

Phoretic uropodine mites (Acari: Mesostigmata) associated with the red palm weevil, Rhynchophorus ferrugineus (Coleoptera: Curculionidae) in Iran

During an investigation on phoretic mite associates of the red palm weevil, Rhynchophorus ferrugineus, in Sistan and Balouchestan Province of Iran, two uropodine species were collected and identified as Centrouropoda almerodai (Uropodidae) and Uroobovella marginata (Dinychidae). This is the first record of the genus Centrouropoda from Iran and the first record of phoretic mites associated with this weevil from the country

Umbilical Cord Bilirubin Level as a Predictive Indicator of Neonatal ‎Jaundice

BACKGROUND AND OBJECTIVE: Neonatal jaundice is a major problem among infants in the first weeks of life. Research on several indicators of severe neonatal jaundice including alpha-fetoprotein  and umbilical cord bilirubin level has indicated contradictory results. Therefore, the aim of the present study was to evaluate the significance of umbilical cord bilirubin level as a predictive indicator of severe neonatal jaundice. METHODS: This prospective, cross-sectional study was performed on 102 healthy infants, born to healthy mothers at Babol Clinic Hospital, Babol, Iran. After birth, 2 cc blood samples were obtained from the umbilical cord and the bilirubin level was measured in the hospital laboratory. The infants were followed-up after hospital discharge in terms of jaundice presentations. In case jaundice was diagnosed in infants, they were compared in treated and untreated groups. FINDINGS: Clinical jaundice was not detected in 54 cases (52.94%). Overall, 48 neonates (47.05%) suffered from clinical jaundice and 10 cases (8.9%) presented with severe jaundice, requiring treatment based on the criteria proposed by the American Academy of Pediatrics (AAP). The mean umbilical cord bilirubin level was 1.82±0.42 mg/dl in the untreated group and 2.36±0.56 mg/dl in the treated group (P=0.000). The area under the ROC curve for umbilical cord bilirubin level was 0.722 in the treated group, based on the AAP criteria. The cut-off point of 2 mg/dl showed 80% sensitivity and 73% specificity in predicting severe jaundice (requiring treatment), based on the AAP criteria. CONCLUSION: As the results indicated, measurement of umbilical cord bilirubin level and determination of a suitable cut-off point could be valuable in predicting severe jaundice in newborns

Efficient sonocatalytic degradation of orange II dye and real textile wastewater using peroxymonosulfate activated with a novel heterogeneous TiO2–FeZn bimetallic nanocatalyst

TiO2–FeZn nanocatalyst combined with sonolysis were used to activate peroxymonosulfate (PMS) as a highly efficient advanced oxidation process (US/TiO2–FeZn/PMS) for the decoloration of orange II dye (OII) and real textile wastewater. The characterization of the as-synthesized NPs was performed by SEM, FTIR, EDX and XRD analyses. Optimal experimental conditions of operational parameters were obtained: pH = 3, 15 mg/L initial OII concentration, 0.2 g/L PMS, 0.7 g/L nanocatalyst dosing, and 300 W ultrasonic power. The decolorization was observed to increase with increasing the dose of nanocatalyst and the ultrasonic power, and with decreasing pH (under acidic conditions). Under optimal experimental conditions, decolorization and COD removal of textile wastewater were 99.9 and 74.6, respectively, at 40 min. The TiO2–FeZn/PMS/US as a novel process exhibited a higher removal of OII (95) than TiO2 NPs/PMS/US process (54). The OII removal efficiency by the different processes decreased in the following order: TiO2–FeZn/US/PMS > TiO2–FeZn/PMS > TiO2–FeZn/US > TiO2 /US/PMS > US/PMS > TiO2–FeZn > PMS > US. The recyclability study revealed that the process could be reused up to three consecutive cycles. The current US/nanocatalyst/PMS system was concluded to be an efficient, reusable and stable nanocatalyst for the oxidation of textile dyes. © 2023, Iranian Chemical Society