LCMS-Metabolomic Profiling and Genome Mining of Delftia lacustris DSM 21246 Revealed Lipophilic Delftibactin Metallophores.

Bacteria have evolved various strategies to combat heavy metal stress, including the secretion of small molecules, known as metallophores. These molecules hold a potential role in the mitigation of toxic metal contamination from the environment (bioremediation). Herein, we employed combined comparative metabolomic and genomic analyses to study the metallophores excreted by Delftia lacustris DSM 21246. LCMS-metabolomic analysis of this bacterium cultured under iron limitation led to a suite of lipophilic metallophores exclusively secreted in response to iron starvation. Additionally, we conducted genome sequencing of the DSM 21246 strain using nanopore sequencing technology and employed antiSMASH to mine the genome, leading to the identification of a biosynthetic gene cluster (BGC) matching the known BGC responsible for delftibactin A production. The isolated suite of amphiphilic metallophores, termed delftibactins C-F (1-4), was characterized using various chromatographic, spectroscopic, and bioinformatic techniques. The planar structure of these compounds was elucidated through 1D and 2D NMR analyses, as well as LCMS/MS-based fragmentation studies. Notably, their structures differed from previously known delftibactins due to the presence of a lipid tail. Marfey's and bioinformatic analyses were employed to determine the absolute configuration of the peptide scaffold. Delftibactin A, a previously identified metallophore, has exhibited a gold biomineralizing property; compound 1 was tested for and also demonstrated this property.

Green synthesized silver nanoparticles using the plant-based reducing agent Matricaria chamomilla induce cell death in colorectal cancer cells.

OBJECTIVE: There is a need to treat cancer cells with safe and natural nanoparticles to avoid the side effects of chemotherapeutic agents. Chamomile is considered a safe, natural plant with anticancer activity. We synthesize simple, inexpensive, and eco-friendly silver nanoparticles (SNs) using Chamomile (CHM) to tune their anticancer properties. MATERIALS AND METHODS: SN-CHM was synthesized by reducing 1 mM silver nitrate aqueous solution in 100 mL with the aqueous ethanolic flower extract of CHM (18 mg/mL, w/v). The reaction proceeded overnight at 600 rpm and 28°C. SN-CHM was characterized for their % yield, average diameter, charge, morphology, and silver release. Moreover, SN-CHM was investigated for its antioxidant and anticancer activities at 200 µg/mL and 5 mg/ mL, respectively. RESULTS: A 59.12% yield and a uniform SN-CHM size of 115 ± 3.1 nm with a ζ-potential of -27.67 ± (-3.92) mv were observed. The UV-visible absorption showed shifts from 379.5 to 383.5 nm for CHM and SN-CHM, respectively. Moreover, Ag+ was ultimately released from SN-CHM after 5 h. Fourier Transform Infrared Spectroscopy (FT-IR) showed characteristic absorption peaks of CHM and produced SN-CHM. Furthermore, SN-CHM showed moderate antioxidant activity. SN-CHM inhibited the % viability of SW620 and HT-29 cell lines at 20 µM. SN-CHM may also greatly upregulate the apoptotic gene BAX while considerably downregulating the anti-apoptotic genes BCL2 and BCL-Xl. CONCLUSIONS: CHM can be a safe soft drink, especially when conjugated with Ag ions as anticancer NPs. SN-CHM is considered potent anticancer activity against SW620, and HT-29 cell lines.

Comparative metabolomic profiling of Cupriavidus necator B-4383 revealed production of cupriachelin siderophores, one with activity against Cryptococcus neoformans.

Cupriavidus necator H16 is known to be a rich source of linear lipopeptide siderophores when grown under iron-depleted conditions; prior literature termed these compounds cupriachelins. These small molecules bear ß-hydroxyaspartate moieties that contribute to a photoreduction of iron when bound as ferric cupriachelin. Here, we present structural assignment of cupriachelins from C. necator B-4383 grown under iron limitation. The characterization of B-4383 cupriachelins is based on MS/MS fragmentation analysis, which was confirmed by 1D- and 2D-NMR for the most abundant analog (1). The cupriachelin congeners distinguish these two strains with differences in the preferred lipid tail; however, our rigorous metabolomic investigation also revealed minor analogs with changes in the peptide core, hinting at a potential mechanism by which these siderophores may reduce biologically unavailable ferric iron (4-6). Antifungal screening of the C. necator B-4383 supernatant extract and the isolated cupriachelin analog (1) revealed inhibitory activity against Cryptococcus neoformans, with IC50 values of 16.6 and 3.2 µg/mL, respectively. This antifungal activity could be explained by the critical role of the iron acquisition pathway in the growth and pathogenesis of the C. neoformans fungal pathogen.

Metabolism of natural and synthetic bioactive compounds in Cunninghamella fungi and their applications in drug discovery.

Investigation of xenobiotic metabolism is a key step for drug discovery. Since the in vivo investigations may be associated with harmful effects attributed to production of toxic metabolites, it is deemed necessary to predict their structure especially at the preliminary clinical studies. Furthermore, the application of microorganisms that are capable of metabolizing drugs mimic human metabolism and consequently may predict possible metabolites. The genus Cunninghamella has been proven to be a potential candidate, which mimics xenobiotic metabolism occurring inside the human body, including phase I and II metabolic reactions. Moreover, biotransformation with Cunninghamella showed chemical diversity, where a lot of products were detected in relation to the initial substrates after being modified by oxidation, hydroxylation, and conjugation reactions. Some of these products are more bioactive than the parent compounds. The current review presents a comprehensive literature overview regarding the Cunninghamella organisms as biocatalysts, which simulate mammalian metabolism of natural secondary and synthetic compounds.

Litoarbolide A: an undescribed sesquiterpenoid from the Red Sea soft coral Litophyton arboreum with an in vitro anti-malarial activity evaluation.

Soft corals distributed across the Red Sea coasts are a rich source of diverse and bioactive natural products. Chemical probing of the Red Sea soft coral Litophyton arboreum led to isolation and structural characterization of an undescribed sesquiterpenoid, litoarbolide A (1), along with 14 previously reported metabolites (2-15). The chemical structures of the isolates were assigned based on NMR as well as high resolution electrospray ionization mass spectrometry (HR-ESI-MS) data. Litoarbolide A is supposed to be the biosynthetic precursor to other sesquiterpenoids, which formed via further post-translational modifications. Furthermore, these metabolites were evaluated for anti-malarial activity, where only the acyclic sesquiterpenoid of a sec-germacrane nucleus (7) showed an activity against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum with IC50 at 3.7 and 2.2 mg/mL, respectively. Moreover, the isolated metabolites were all non-toxic to the Vero cell line. These findings support the consideration of L. arboreum in further natural anti-malarial studies.

Ridge Regression Method and Bayesian Estimators under Composite LINEX Loss Function to Estimate the Shape Parameter in Lomax Distribution.

In this paper, the Ridge Regression method is employed to estimate the shape parameter of the Lomax distribution (LD). In addition to that, the approaches of both classical and Bayesian are considered with several loss functions as a squared error (SELF), Linear Exponential (LLF), and Composite Linear Exponential (CLLF). As far as Bayesian estimators are concerned, informative and noninformative priors are used to estimate the shape parameter. To examine the performance of the Ridge Regression method, we compared it with classical estimators which included Maximum Likelihood, Ordinary Least Squares, Uniformly Minimum Variance Unbiased Estimator, and Median Method as well as Bayesian estimators. Monte Carlo simulation compares these estimators with respect to the Mean Square Error criteria (MSE's). The result of the simulation mentioned that the Ridge Regression method is promising and can be used in a real environment. where it revealed better performance the than Ordinary Least Squares method for estimating shape parameter.

A new comprehensive approach for regional drought monitoring.

The Standardized Precipitation Index (SPI) is a vital component of meteorological drought. Several researchers have been using SPI in their studies to develop new methodologies for drought assessment, monitoring, and forecasting. However, it is challenging for SPI to provide quick and comprehensive information about precipitation deficits and drought probability in a homogenous environment. This study proposes a Regional Intensive Continuous Drought Probability Monitoring System (RICDPMS) for obtaining quick and comprehensive information regarding the drought probability and the temporal evolution of the droughts at the regional level. The RICDPMS is based on Monte Carlo Feature Selection (MCFS), steady-state probabilities, and copulas functions. The MCFS is used for selecting more important stations for the analysis. The main purpose of employing MCFS in certain stations is to minimize the time and resources. The use of MCSF makes RICDPMS efficient for drought monitoring in the selected region. Further, the steady-state probabilities are used to calculate regional precipitation thresholds for selected drought intensities, and bivariate copulas are used for modeling complicated dependence structures as persisting between precipitation at varying time intervals. The RICDPMS is validated on the data collected from six meteorological locations (stations) of the northern area of Pakistan. It is observed that the RICDPMS can monitor the regional drought and provide a better quantitative way to analyze deficits with varying drought intensities in the region. Further, the RICDPMS may be used for drought monitoring and mitigation policies.

Bayesian Estimation of Different Scale Parameters Using a LINEX Loss Function.

The LINEX loss function, which climbs exponentially with one-half of zero and virtually linearly on either side of zero, is employed to analyze parameter analysis and prediction problems. It can be used to solve both underestimation and overestimation issues. This paper explained the Bayesian estimation of mean, Gamma distribution, and Poisson process. First, an improved estimator for µ 2 is provided (which employs a variation coefficient). Under the LINEX loss function, a better estimator for the square root of the median is also derived, and an enhanced estimation for the average mean in such a negatively exponential function. Second, giving a gamma distribution as a prior and a likelihood function as posterior yields a gamma distribution. The LINEX method can be used to estimate an estimator λ B L ^ using posterior distribution. After obtaining λ B L ^ , the hazard function h B L ^ and D B L ^ the function of survival estimators are used. Third, the challenge of sequentially predicting the intensity variable of a uniform Poisson process with a linear exponentially (LINEX) loss function and a constant cost of production time is investigated using a Bayesian model. The APO rule is offered as an approximation pointwise optimal rule. LINEX is the loss function used. A variety of prior distributions have already been studied, and Bayesian estimation methods have been evaluated against squared error loss function estimation methods. Finally, compare the results of Maximum Likelihood Estimation (MLE) and LINEX estimation to determine which technique is appropriate for such information by identifying the lowest Mean Square Error (MSE). The displaced estimation method under the LINEX loss function was also examined in this research, and an improved estimation was proposed.

Application of the LINEX Loss Function with a Fundamental Derivation of Liu Estimator.

For a variety of well-known approaches, optimum predictors and estimators are determined in relation to the asymmetrical LINEX loss function. The applications of an iteratively practicable lowest mean squared error estimation of the regression disturbance variation with the LINEX loss function are discussed in this research. This loss is a symmetrical generalisation of the quadratic loss function. Whenever the LINEX loss function is applied, we additionally look at the risk performance of the feasible virtually unbiased generalised Liu estimator and practicable generalised Liu estimator. Whenever the variation σ 2 is specified, we get all acceptable linear estimation in the class of linear estimation techniques, and when σ 2 is undetermined, we get all acceptable linear estimation in the class of linear estimation techniques. During position transformations, the proposed Liu estimators are stable. The estimators' biases and hazards are calculated and evaluated. We utilize an asymmetrical loss function, the LINEX loss function, to calculate the actual hazards of several error variation estimators. The employment of δ P (σ), which is easy to use and maximin, is recommended in the conclusions.

Author Correction: Assessment of the cardioprotective effect of liraglutide on methotrexate induced cardiac dysfunction through suppression of inflammation and enhancement of angiogenesis in rats.

Correction to: European Review for Medical and Pharmacological Sciences 2021; 25 (19): 6013-6024-DOI: 10.26355/eurrev_202110_26879-PMID: 34661261, published online on 15 October 2021. After publication, the authors applied to add some corrections to the paper. They wanted to change the second affiliation of one co-author Dr. Eman Said. The second affiliation will be "Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Saudi Arabia", instead of "College of Pharmacy, Qassim University, Al-Qassim, Saudi Arabia". There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause.  https://www.europeanreview.org/article/26879.

Sarcoroseolides A-D, four undescribed cembranoids from the Red Sea soft coral Sarcophyton roseum.

Four undescribed cembranoids, sarcoroseolides A-D (1-4) along with nine reported related cembranoids (5-13) were isolated from the soft coral Sarcophyton roseum. The chemical structures of sarcoroseolides A-D were elucidated by extensive 1 D and 2 D NMR as well as HR-ESIMS spectroscopic data. Moreover, the geometric and absolute configurations were assigned by the modified Mosher's method and/or NOESY experiments. The extract and the isolated metabolites were evaluated for their potential anti-inflammatory and cytotoxic activities.

Licochalcone L, an undescribed retrochalcone from Glycyrrhiza inflata roots.

Glycyrrhiza inflata Batalin is among the three glycyrrhizin producing Glycyrrhiza species and can be distinguished from other species with regard to its retrochalcone contents. Seven retrochalcones, echinatin and licochalcones A, C, D, E, K, and L were isolated and characterized from the chloroform extract of G. inflata roots. Among the isolates, licochalcone L was found to be previously undescribed. Structure elucidation of these specialised metabolites was achieved through NMR and mass spectroscopic data analyses.

Assessment of the cardioprotective effect of liraglutide on methotrexate induced cardiac dysfunction through suppression of inflammation and enhancement of angiogenesis in rats.

OBJECTIVE: Methotrexate (MTX) is one of the most commonly used anti-cancer drugs for various types of neoplasms. It is associated with multiple cytotoxic effects including nephrotoxicity, hepatotoxicity and cardiotoxicity. Liraglutide (LIR) is a potent anti-diabetic drug and also has antioxidant and anti-inflammatory properties. In this study, we tried to investigate the protective effect of LIR on MTX induced cardiotoxicity and to identify the molecular mechanisms for this protection. MATERIALS AND METHODS:  Rats were divided into 4 groups, including control group, LIR group, MTX group and LIR + MTX group. ECG was measured then blood samples were taken, and hearts were excised for biochemical and histological investigations. RESULTS: MTX group exhibited a mild non-significant irregular bradycardia, an increase of CK-MB besides a decrease of total antioxidant capacity. MTX administration also resulted in downregulation of vascular endothelial growth factor (VEGF), while caused upregulation of interleukin 1 beta (IL-1B) and interleukin 6 (IL-6) in comparison to the control group. Also, MTX group showed histological abnormalities besides negative VEGF and positive iNOS as detected by immunohistochemical staining compared to the control group. LIR administration could reverse these results. CONCLUSIONS: LIR prevented MTX induced cardiotoxicity through its antioxidant and anti-inflammatory properties.

Cervical cancer screening uptake in Sub-Saharan Africa: a systematic review and meta-analysis.

OBJECTIVES: The objective of this study is to estimate the pooled uptake of cervical cancer screening and identify its predictors in Sub-Saharan Africa. STUDY DESIGN: Systematic review and meta-analysis. METHODS: We searched PubMed, EMBASE, CINAHL, African Journals OnLine, Web of Science and Scopus electronic databases from January 2000 to 2019. All observational studies published in the English language that reported cervical cancer uptake and/or predictors in Sub-Saharan Africa were initially screened. We assessed methodological quality using the Newcastle-Ottawa Scale. An inverse variance-weighted random-effects model meta-analysis was performed to estimate the pooled uptake and odds ratio (OR) of predictors with a 95% confidence interval (CI). The I2 test statistic was used to check between-study heterogeneity, and the Egger's regression statistical test was used to check publication bias. RESULTS: We initially screened 3537 citations and subsequently 29 studies were selected for this review, which included a total of 36,374 women. The uptake of cervical cancer screening in Sub-Saharan Africa was 12.87% (95% CI: 10.20, 15.54; I2 = 98.5%). A meta-analysis of seven studies showed that knowledge about cervical cancer increased screening uptake by nearly five times (OR: 4.81; 95% CI: 3.06, 7.54). Other predictors of cervical screening uptake include educational level, age, Human Immune deficiency Virus (HIV) status, contraceptive use, perceived susceptibility and awareness about screening locations. CONCLUSIONS: Cervical screening uptake is low in Sub-Saharan Africa as a result of several factors. Health outreach and promotion programmes to target these identified predictors are required.

Communication Aspects of Visible Light Positioning (VLP) Systems Using a Quadrature Angular Diversity Aperture (QADA) Receiver.

Visible light positioning (VLP) is a promising indoor localization system in which light emitting diode (LED) luminaires are used as positioning beacons. Data communication is an essential aspect of any VLP system, as each luminaire must transmit information about its own location to the receiver. The quadrature angular diversity aperture (QADA) is a new receiver designed specifically for VLP systems using angle-of-arrival estimation. Previous QADA research has focused only on positioning and assumed error-free communication. In this paper, we investigate, via simulations and experiment, the actual communication characteristics of a VLP system that uses a QADA receiver. We calculate the signal-to-noise ratio and bit-error-rates for a range of scenarios and demonstrate the impact of the dimensions of the receiver. We show that reliable communication is assured in typical operating scenarios, proving that communication will not be a limiting factor when using QADA in VLP systems.

Iron Pathophysiology in Stroke.

Ischemic and hemorrhagic stroke are the common types of stroke that lead to brain injury neurological deficits and mortality. All forms of stroke remain a serious health issue, and there is little successful development of drugs for treating stroke. Incomplete understanding of stroke pathophysiology is considered the main barrier that limits this research progress. Besides mitochondria and free radical-producing enzymes, labile iron is an important contributor to oxidative stress. Although iron regulation and metabolism in cerebral stroke are not fully understood, much progress has been achieved in recent years. For example, hepcidin has recently been recognized as the principal regulator of systemic iron homeostasis and a bridge between inflammation and iron regulation. This review discusses recent research progress in iron pathophysiology following cerebral stroke, focusing molecular regulation of iron metabolism and potential treatment targets.

Ethnic differences in sedentary behaviour in 6-8-year-old children during school terms and school holidays: a mixed methods study.

BACKGROUND: Sedentary behaviour (SB) in childhood is a major public health concern. Little is known about ethnic differences in SB during school and holiday weeks among White British (WB) and South Asian (SA) children, which this study aims to address through investigating inclinometer measured SB and exploring reasons for child engagement in SB. METHODS: A mixed methods study, comprising of a quantitative investigation with 160, 6-8 years old children and a qualitative study with a subsample of 18 children, six parents and eight teachers was undertaken. Children of WB and SA ethnicity in three schools were invited to wear inclinometers for seven school terms (summer/winter/spring) and seven holidays (winter/spring) days during July 2016-May 2017. Total SB, SB accumulated in bouts > 30 min and breaks in SB were explored using multivariate linear mixed effects models which adjusted for wear time, sex, deprivation, overweight status, season, term, weekday and school. Nine focus groups and two interviews were carried out using the Theoretical Domains Framework to explore SB perceptions among parents, teachers and children. Data were analysed using the Framework Approach. RESULTS: 104/160 children provided 836 valid days of data. Children spent on average eight hours of SB/day during term time and holidays, equating to 60% of their awake time, and had on average 111 SB breaks /day. SA children had 25 fewer SB breaks/ day when compared to WB (p < 0.001). Perceived reasons for engagement in SB included: boredom, enjoyment of screen activities (by children), parenting practices, curriculum pressures (by teachers), the need to sit down and learn, and child's preference for screen activities (by parents). CONCLUSIONS: Children spent 60% of their awake time being sedentary, regardless of ethnicity or school term. There were no significant ethnic differences for any of the SB outcomes except for breaks in SB. Interventions aimed at reducing SB should consider involving parents and teachers and should focus on increasing breaks in SB, especially for SA children, who are at a higher risk of cardio metabolic ill health.

Vitamin D attenuates gentamicin-induced acute renal damage via prevention of oxidative stress and DNA damage.

BACKGROUND: Despite being one of the most nephrotoxic drugs, gentamicin (GM) remains a mainstay as a first-choice agent in a vast variety of clinical situations owing to its superlative efficiency as a broad-spectrum antibiotic in treating several life-threatening bacterial infections. This urgently calls for the need for in-depth analysis of the mechanisms governing GM-induced nephrotoxicity and entails the necessity of presenting novel protective agents capable of ameliorating those renal deleterious effects. The reactive oxygen species and redox-sensitive transcription factors in GM-induced nephrotoxicity have recently called attention. PURPOSE: This study has been designed to shed light on the possible mechanisms of GM-induced nephrotoxicity and to provide a consensus set of histopathological, immunohistochemical, genetic and biochemical parameters elucidating the protective role of vitamin D against this nephrotoxicity. METHODS: Twenty-four adult male albino rats were equally divided into four groups: group I (control group), group II (GM), group III (GM + vitamin D) and group IV (vitamin D only). Kidney function tests, histopathological examination, gene expression of nuclear factor 2, nuclear factor kappa beta (NF-κB) and western blot of NF-κB p65, assessment of glutathione peroxidase and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase by ELISA, as well as immunohistochemical evaluation of inducible nitric oxide, malondialdehyde, 8-hydroxy 2 deoxyguanine and vitamin D receptor, have been carried out. RESULTS: The kidney function deterioration, tissue oxidative stress development and the histopathological changes induced by GM were significantly attenuated by vitamin D administration. CONCLUSION: Vitamin D attenuates GM nephrotoxicity through its antioxidant properties and prevention of DNA damage.

Effect of Caffeine on Serum Tumour Necrosis Factor Alpha and Lactate Dehydrogenase in Wistar Rats Exposed to Cerebral Ischaemia-reperfusion Injury.

Caffeine is known to confer neuro-protection via A1 and A2A adenosine receptor antagonism in which adenosine neuro-modulates excitotoxic release of glutamate. Currently, it is unclear whether caffeine modulates inflammation in ischaemic stroke model. The present study examined effects of caffeine following ischaemia-reperfusion injury on neuro-inflammatory tumour necrosis alpha (TNF-α), lactate dehydrogenase (LDH), as well as effect of caffeine against brain ischaemic damage on histology. Thirty three adult male Wistar rats (180-300 g) were used in this study. They were randomly divided into four groups (n=5 each): Group I (Control) that received neither the operation nor any treatment; Group II (Sham/Water) received a pseudo-ischaemic-reperfusion and 1ml water for injection; Group III (BCCO/Water) that received complete bilateral common carotid occlusion (BCCO) and 1ml water for injection; Group IV (BCCO/Caffeine) that received complete BCCO and caffeine solution intraperitoneally at a dose of 50% LD50 value (144mg/kg); and thirteen rats were used for LD50 assessment. Sensory and motor functions significantly (p<0.05) decreased in the rat following ischaemia-reperfusion injury when compared to pre-injury state on Garcia neurological score. Caffeine reduced brain ischaemic injury and significantly reduced (p<0.05) TNF-α activity. While no significant effects (p>0.05) of caffeine was observed on LDH activity. This study has shown neuro-protective roles of caffeine against ischaemia-reperfusion damage to brain tissue, inflammatory TNF-α activity, but not on LDH activity.