Natural products from plants targeting key enzymes for the future development of antidiabetic agents.

Covering: 2000 to January 2023Diabetes is a metabolic disease of serious concern nowadays, with a negative economic impact. In 2021, the International Diabetes Federation estimated that more than 537 million adults live with diabetes, causing over 6.7 million deaths in that year. Intensive scientific research on medicinal plants in the last 100 years reveals that herbal drugs have been an essential source of products for developing antidiabetic agents acting on different physiological targets. This review summarizes recent research from 2000 to 2022 on plant natural compounds affecting selected crucial enzymes (dipeptidyl peptidase IV, diacylglycerol acyltransferase, fructose 1,6-biphosphatase, glucokinase, and fructokinase) involved in glucose homeostasis. Enzyme-aimed treatments usually induce reversible inhibition, irreversible by covalent changes of the objective enzymes, or bind non-covalently but so tightly that their inhibition is irreversible. Depending on the binding site, these inhibitors could be orthosteric or allosteric; in any case, the desired pharmacological action is achieved. One crucial advantage of targeting enzymes in drug discovery is that the required assays are usually simple, using biochemical experiments capable of analyzing enzyme activity.

Methods for interpolating missing data in aerobiological databases.

Missing data is a common problem in scientific research. The availability of extensive environmental time series is usually laborious and difficult, and sometimes unexpected failures are not detected until samples are processed. Consequently, environmental databases frequently have some gaps with missing data in it. Applying an interpolation method before starting the data analysis can be a good solution in order to complete this missing information. Nevertheless, there are several different approaches whose accuracy should be considered and compared. In this study, data from 6 aerobiological sampling stations were used as an example of environmental data series to assess the accuracy of different interpolation methods. For that, observed daily pollen/spore concentration data series were randomly removed, interpolated by using different methods and then, compared with the observed data to measure the errors produced. Different periods, gap sizes, interpolation methods and bioaerosols were considered in order to check their influence in the interpolation accuracy. The moving mean interpolation method obtained the highest success rate as average. By using this method, a success rate of the 70% was obtained when the risk classes used in the alert systems of the pollen information platforms were taken into account. In general, errors were mostly greater when there were high oscillations in the concentrations of biotic particles during consecutive days. That is the reason why the pre-peak and peak periods showed the highest interpolation errors. The errors were also higher when gaps longer than 5 days were considered. So, for completing long periods of missing data, it would be advisable to test other methodological approaches. A new Variation Index based on the behaviour of the pollen/spore season (measurement of the variability of the concentrations every 2 consecutive days) was elaborated, which allows to estimate the potential error before the interpolation is applied.

Lack of short-term increase in serum mediators of fibrogenesis and in non-invasive markers of liver fibrosis in HIV/hepatitis C virus-coinfected patients starting maraviroc-based antiretroviral therapy.

The aim of this study was to analyze serum changes in mediators of fibrogenesis and in non-invasive markers of liver fibrosis among HIV/HCV-coinfected patients starting maraviroc (MVC)-based antiretroviral therapy. Patients included in this prospective pilot study met the following criteria: (1) HIV-infection, (2) detectable serum HCV-RNA, and ((3) started MVC. Transforming growth factor-ß1 (TGF-beta1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were measured in serum samples at baseline and 6 months after starting MVC. AST-to-platelet ratio index (APRI) was assessed at the same time points. Twenty-four patients were analyzed. Median (IQR) serum levels at baseline and after 6 months on MVC of TGF-beta1 were 27,295 (20,562-36,844) and 33,753 (18,973-46,130) pg/mL (p=0.116), of MMP-2 were 216 (186-274) and 241 (194-306) ng/mL (p=0.247), and of TIMP-1 were 237 (170-284) and 216 (171-271) ng/mL (p=0.415). APRI levels were 0.99 (0.53-3.46) at baseline and 0.83 (0.48-2.34) at 6 months (p=0.16). Serum mediators of liver fibrogenesis and fibrosis do not change significantly in HIV/HCV-coinfected patients in the short-term after starting MVC. As TGF-beta1 levels have been shown to increase over time in HCV infection and liver fibrosis worsens rapidly in HIV/HCV coinfection, these parameters seem to evolve in a different way in MVC-treated patients.

Predictive factors for mortality and intensive care unit admission in patients with emphysematous pyelonephritis: 5-year experience in a tertiary care hospital.

INTRODUCTION AND OBJECTIVES: Emphysematous pyelonephritis is a life-threatening infection of the kidney and surrounding tissues associated with a high mortality rate. The aim of this study was to determine predictive factors for mortality and intensive care unit admission in patients with emphysematous pyelonephritis, and to propose a therapeutic algorithm based on current literature and our experience. METHODS: A retrospective study was done including patients with emphysematous pyelonephritis in a single center in the north of Mexico from 2011 to 2016. Demographic, clinical, microbiological and biochemical parameters, therapeutic management, and outcomes were assessed. Factors associated with admission to intensive care unit and mortality were determined. Comparison was assessed using X2 test for categorical variables, and T-test for numerical variables. Univariate and multivariate logistic regression analyses were performed. Statistical significance was set at P < .05. RESULTS: A total of 63 patients were included, of which 55 (87.3%) were females, with a mean age of 55.5 ±â€¯12.2 years. The most common comorbidities were diabetes and hypertension. Escherichia coli was the most common isolated microorganism (51.7%) and extended-spectrum beta-lactamase-producing agents were reported in 31.7%. Conservative therapy was provided to 38.7%, double J stent 42.9%, open/percutaneous drainage 12.7%, and nephrectomy 25.3%. Overall mortality and intensive care admission were 20.6% and 36.5%, respectively. In the multivariate analysis, hemodynamic instability (P = .005), qSOFA ≥ 2 (P = .003), hypoalbuminemia (P = .02), and early nephrectomy (P = .002) were associated with intensive care admission. Huang scale 4 (P = .006) and early nephrectomy (P = .001) were associated to mortality. CONCLUSIONS: Emphysematous pyelonephritis is a life-threatening disease and evidence of management is based in small case series due to the low incidence of this condition. Hemodynamic instability, hypoalbuminemia, qSOFA ≥ 2, Huang scale ≥3, and early nephrectomy are associated with poor prognosis.

The structural properties of GaN/AlN core-shell nanocolumn heterostructures.

The growth and structural properties of GaN/AlN core-shell nanowire heterostructures have been studied using a combination of resonant x-ray diffraction, Raman spectroscopy and high resolution transmission electron microscopy experiments. For a GaN core of 20 nm diameter on average surrounded by a homogeneous AlN shell, the built-in strain in GaN is found to agree with theoretical calculations performed using a valence force field model. It is then concluded that for an AlN thickness up to at least 12 nm both core and shell are in elastic equilibrium. However, in the case of an inhomogeneous growth of the AlN shell caused by the presence of steps on the sides of the GaN core, plastic relaxation is found to occur. Consistent with the presence of dislocations at the GaN/AlN interface, it is proposed that this plastic relaxation, especially efficient for AlN shell thickness above 3 nm, is promoted by the shear strain induced by the AlN inhomogeneity.

Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera.

Formation of a novel structure, the aggresome, has been proposed to represent a general cellular response to the presence of misfolded proteins (Johnston, J.A., C.L. Ward, and R.R. Kopito. 1998. J. Cell Biol. 143:1883-1898; Wigley, W.C., R.P. Fabunmi, M.G. Lee, C.R. Marino, S. Muallem, G.N. DeMartino, and P.J. Thomas. 1999. J. Cell Biol. 145:481-490). To test the generality of this finding and characterize aspects of aggresome composition and its formation, we investigated the effects of overexpressing a cytosolic protein chimera (GFP-250) in cells. Overexpression of GFP-250 caused formation of aggresomes and was paralleled by the redistribution of the intermediate filament protein vimentin as well as by the recruitment of the proteasome, and the Hsp70 and the chaperonin systems of chaperones. Interestingly, GFP-250 within the aggresome appeared not to be ubiquitinated. In vivo time-lapse analysis of aggresome dynamics showed that small aggregates form within the periphery of the cell and travel on microtubules to the MTOC region where they remain as distinct but closely apposed particulate structures. Overexpression of p50/dynamitin, which causes the dissociation of the dynactin complex, significantly inhibited the formation of aggresomes, suggesting that the minus-end-directed motor activities of cytoplasmic dynein are required for aggresome formation. Perinuclear aggresomes interfered with correct Golgi localization and disrupted the normal astral distribution of microtubules. However, ER-to-Golgi protein transport occurred normally in aggresome containing cells. Our results suggest that aggresomes can be formed by soluble, nonubiquitinated proteins as well as by integral transmembrane ubiquitinated ones, supporting the hypothesis that aggresome formation might be a general cellular response to the presence of misfolded proteins.

The membrane transport factor TAP/p115 cycles between the Golgi and earlier secretory compartments and contains distinct domains required for its localization and function.

The mammalian protein TAP/p115 and its yeast homologue Uso1p have an essential role in membrane traffic (Nakajima et al., 1991; Waters et al., 1992; Sztul et al., 1993; Rabouille et al.; 1995). To inquire into the site and mechanism of TAP/p115 action, we aimed to localize it and to identify domains required for its function. We show that in interphase cells, TAP/p115 localizes predominantly to the Golgi and to peripheral structures that represent vesicular tubular clusters (VTCs) involved in ER to Golgi transport. Using BFA/ nocodazole treatments we confirm that TAP/p115 is present on ER to Golgi transport intermediates. TAP/ p115 redistributes to peripheral structures containing ERGIC-53 during a 15 degreesC treatment, suggesting that it is a cycling protein. Within the Golgi, TAP/p115 is associated with pleiomorphic structures on the cis side of the cis-Golgi cisterna and the cis-most cisterna, but is not detected in more distal compartments of the Golgi. TAP/p115 binds the cis-Golgi protein GM130, and the COOH-terminal acidic domain of TAP/p115 is required for this interaction. TAP/p115 interaction with GM130 occurs only in the Golgi and is not required for TAP/p115 association with peripheral VTCs. To examine whether interaction with GM130 is required to recruit TAP/p115 to the Golgi, TAP/p115 mutants lacking the acidic domain were expressed and localized in transfected cells. Mutants lacking the GM130-binding domain showed normal Golgi localization, indicating that TAP/p115 is recruited to the Golgi independently of its ability to bind GM130. Such mutants were also able to associate with peripheral VTCs. Interestingly, TAP/p115 mutants containing the GM130-binding domain but lacking portions of the NH2-terminal region were restricted from the Golgi and localized to the ER. The COOH-terminal domain required for GM130 binding and the NH2-terminal region required for Golgi localization appear functionally relevant since expression of TAP/p115 mutants lacking either of these domains leads to loss of normal Golgi morphology.

The structural properties of GaN insertions in GaN/AlN nanocolumn heterostructures.

The strain state of 1 and 2.5 nm thick GaN insertions in GaN/AlN nanocolumn heterostructures has been studied by means of a combination of high resolution transmission electron microscopy, Raman spectroscopy and theoretical modeling. It is found that 2.5 nm thick GaN insertions are partially relaxed, which has been attributed to the presence of dislocations in the external AlN capping layer, in close relationship with the morphology of GaN insertions and with the AlN capping mechanism. The observed plastic relaxation in AlN is consistent with the small critical thickness expected for GaN/AlN radial heterostructures.

Etiology of Fournier gangrene as a prognostic factor in mortality: Analysis of 121 cases. / Etiología de la gangrena de Fournier como factor pronóstico de mortalidad: análisis de 121 casos.

OBJECTIVE: Evaluate the origin of Fournier gangrene (FG) as a prognostic factor of morbidity and mortality. MATERIAL AND METHODS: Patients who came to our clinic with a diagnosis of FG from 2010 to 2017 were included retrospectively. Patients were categorized depending on the origin of the infection. Three severity factors were determined in each group: days of hospital stay, the FG severity index, and mortality. Logistic regression test was performed to analyze the data. RESULTS: Of the 130 patients evaluated, the origin was established in 121 based on the clinical history and radiological and surgical findings. Thirty-five patients had an intestinal origin with a mortality of 20.68%, 46 patients had a testicular origin with a mortality of 2.22%, 12 patients had a urinary origin with a mortality of 0%, and 28 patients with a cutaneous origin with a mortality of 16.6%. The testicular origin was the most frequent (38%) in addition to presenting a lower hospital stay, a lower FG severity index, and a lower mortality than those with an intestinal origin (P=.022). CONCLUSIONS: The origin of the infection has a significant prognostic value in the mortality of the patient.

Increasing resolution of airborne pollen forecasting at a discrete sampled area in the southwest Mediterranean Basin.

Daily fluctuations of the airborne pollen concentrations produce variations on symptomatology in allergic population. Such fluctuations are influenced by local vegetal coverage, flowering phenology, geography and climatology. Since 1991, airborne pollen of Malaga province (southern Spain) has been monitored in 7 different locations. Malaga station has been kept operational uninterruptedly throughout the studied period, while the rest of the stations only worked in periods of 2-4 years. Weekly, its pollen information is updated online to inform the population in order to prevent allergic diseases. Increasing the spatial resolution of pollen information would be very useful for allergic population living at unsampled locations. Due to the impossibility of keeping operational a high number of pollen stations covering the whole province of Malaga, the aim of this study is to create spatial models to extrapolate and forecast the pollen concentrations to Malaga province by using the concentrations registered at the capital as unique input. To do so, the relationships obtained between the airborne pollen concentrations detected at Malaga city and those detected at the other stations have been used to elaborate models for the main pollen types registered at the province. These models were spatially interpolated all over the province by using co-kriging techniques and the Compensated Thermicity Index as covariable. As result of this work, pollen distribution of the 8 most prevalent taxa has been depicted all over the whole Malaga province and an allergy alert system has been set up to extrapolate pollen information from Malaga to the whole province.