Ginger polyphenols attenuate cyclosporine-induced disturbances in kidney function: Potential application in adjuvant transplant therapy

Cyclosporine (CYA), a common immuno-suppressant drug that is used in organ transplants, is associated with nephrotoxic effects. Scientific exploration of natural products of plant origin should be considered; especially, in a world with increasing prevalence of kidney diseases. Effects of ginger polyphenols (GP) in Wistar rats with CYA-induced perturbations in electrolyte balance and kidney function was determined. Fifty Wistar rats were recruited for this study such that graded doses of GP were administered following CYA-induced kidney injury and comparisons were made against control and toxic groups at p?<?0.05. Distilled water, CYA (50?mg/kg p.o. for 10 days) and GP (100, 200 and 400?mg/kg p.o. for 21 days) were administered to the rats at 0.2?ml/100?g. CYA administration induced kidney injury as characterized by significant deleterious alterations in plasma and urine levels of creatinine, urea, Na⁺ and K⁺ electrolyte balance as well as creatinine clearance. Also, there was a significant derangement in feeding pattern and relative kidney weight. Using GSH and SOD as antioxidant indicators, there was significant disturbance of the anti-oxidant system while histopathological results showed evidence of interstitial vacuolations with atrophic glomeruli. These conditions were significantly attenuated (p?<?0.05) following administration of graded doses of GP. It was, therefore, concluded that GP could potentially be a therapeutic choice for patients with CYA-induced kidney injury.     

The clinical course and prognostic factors of severe COVID-19 in Wuhan,China: A retrospective case-control study

With the surge of newly diagnosed and severe cases of coronavirus disease 2019 (COVID-19), the death toll is mounting, this study is aimed to explore the prognostic factors of severe COVID-19. This retrospective study included 122 inpatients diagnosed with COVID-19 from January 13 to February 25, 2020. Univariate and multivariate analysis were used to identity the risk factors, receiver operating characteristics curve (ROC) analysis was used for risk stratification. The baseline neutrophil-to-lymphocyte ratio (NLR) (OR = 1.171, 95%CI = 1.049–1.306, P = .005) and Lactate dehydrogenase (LDH) (OR = 1.007, 95%CI = 1.002–1.011, P = .004) were identified as the independent risk factors for severe COVID-19 conditions, and the NLR-LDH grading system was developed to perform risk stratification. The baseline C-reactive protein (CRP) (OR = 1.019, 95%CI = 1.004–1.306, P = .016) and B-type natriuretic peptide (BNP) (OR = 1.018, 95%CI = 1.004–1.035, P = .007) were identified as the independent predictors for disease progression of severe patients. Accordingly, The NLR-LDH grading system was a useful prognostic tool for the early detection of severe COVID-19. And in the severe patients, CRP and BNP seemed to be helpful for predicting the disease progression or death.     

Synthesis and purification of the aflatoxin B1-lysine adduct

This work reports the chemical synthesis of aflatoxin B₁ (AFB₁)-lysine based on procedures available in the literature, but using lysine without a protection group in the α-amine group. AFB₁-exo-8,9-epoxide was obtained by epoxidation of AFB₁ with chloroperoxybenzoic acid in dichloromethane and phosphate buffer. Purification and identification of the AFB₁-lysine were conducted by liquid chromatography (LC), and its structure was confirmed by LC with mass spectrometer and diode-array detection. The preparation of AFB₁-lysine using lysine without a protection group in the α-amine group was completed in 24?h, being a practical modification of available methods that can be reproduced in analytical laboratories.     

Diesel exhaust particulates affect cell signaling,mucin profiles,and apoptosis in trachea explants of Balb/C mice

Particulate matter from diesel exhaust (DEP) has toxic properties and can activate intracellular signaling pathways and induce metabolic changes. This study was conducted to evaluate the activation of extracellular signal‐regulated kinase (ERK) and c‐Jun N‐terminal kinase (JNK) and to analyze the mucin profile (acid (AB⁺), neutral (PAS⁺), or mixed (AB/PAS⁺) mucus) and vacuolization (V) of tracheal explants after treatment with 50 or 100 μg/mL DEP for 30 or 60 min. Western blot analyses showed small increases in ERK1/2 and JNK phosphorylation after 30 min of 100 μg/mL DEP treatment compared with the control. An increase in JNK phosphorylation was observed after 60 min of treatment with 50 μg/mL DEP compared with the control. We did not observe any change in the level of ERK1/2 phosphorylation after treatment with 50 μg/mL DEP. Other groups of tracheas were subjected to histological sectioning and stained with periodic acid‐Schiff (PAS) reagent and Alcian Blue (AB). The stained tissue sections were then subjected to morphometric analysis. The results obtained were compared using ANOVA. Treatment with 50 μg/mL DEP for 30 min or 60 min showed a significant increase (p < 0.001) in the amount of acid mucus, a reduction in neutral mucus, a significant reduction in mixed mucus, and greater vacuolization. Our results suggest that compounds found in DEPs are able to activate acid mucus production and enhance vacuolization and cell signaling pathways, which can lead to airway diseases. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 1297–1308, 2015.     

Using exposomics to assess cumulative risks and promote health

Under the exposome paradigm all nongenetic factors contributing to disease are considered to be ‘environmental’ including chemicals, drugs, infectious agents, and psychosocial stress. We can consider these collectively as environmental stressors. Exposomics is the comprehensive analysis of exposure to all environmental stressors and should yield a more thorough understanding of chronic disease development. We can operationalize exposomics by studying all the small molecules in the body and their influence on biological pathways that lead to impaired health. Here, we describe methods by which this may be achieved and discuss the application of exposomics to cumulative risk assessment in vulnerable populations. Since the goal of cumulative risk assessment is to analyze, characterize, and quantify the combined risks to health from exposures to multiple agents or stressors, it seems that exposomics is perfectly poised to advance this important area of environmental health science. We should therefore support development of tools for exposomic analysis and begin to engage impacted communities in participatory exposome research. A first step may be to apply exposomics to vulnerable populations already studied by more conventional cumulative risk approaches. We further propose that recent migrants, low socioeconomic groups with high environmental chemical exposures, and pregnant women should be high priority populations for study by exposomics. Moreover, exposomics allows us to study interactions between chronic stress and environmental chemicals that disrupt stress response pathways (i.e., ‘stressogens’). Exploring the impact of early life exposures and maternal stress may be an interesting and accessible topic for investigation by exposomics using biobanked samples. Environ. Mol. Mutagen. 56:715–723, 2015. © 2015 Wiley Periodicals, Inc.     

Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer’s disease

There are currently no disease-modifying treatments for Alzheimer’s disease (AD), and an understanding of preclinical causal biomarkers to help target disease pathogenesis in the earliest phases remains elusive. Here, we investigated whether 19 metabolites previously associated with midlife cognition—a preclinical predictor of AD—translate to later clinical risk, using Mendelian randomization (MR) to tease out AD-specific causal relationships. Summary statistics from the largest genome-wide association studies (GWASs) for AD and metabolites were used to perform bidirectional univariable MR. Bayesian model averaging (BMA) was additionally performed to address high correlation between metabolites and identify metabolite combinations that may be on the AD causal pathway. Univariable MR indicated four extra-large high-density lipoproteins (XL.HDL) on the causal pathway to AD: free cholesterol (XL.HDL.FC: 95% CI = 0.78 to 0.94), total lipids (XL.HDL.L: 95% CI = 0.80 to 0.97), phospholipids (XL.HDL.PL: 95% CI = 0.81 to 0.97), and concentration of XL.HDL particles (95% CI = 0.79 to 0.96), significant at an adjusted P < 0.009. MR–BMA corroborated XL.HDL.FC to be among the top three causal metabolites, in addition to total cholesterol in XL.HDL (XL.HDL.C) and glycoprotein acetyls (GP). Both XL.HDL.C and GP demonstrated suggestive univariable evidence of causality (P < 0.05), and GP successfully replicated within an independent dataset. This study offers insight into the causal relationship between metabolites demonstrating association with midlife cognition and AD. It highlights GP in addition to several XL.HDLs—particularly XL.HDL.FC—as causal candidates warranting further investigation. As AD pathology is thought to develop decades prior to symptom onset, expanding on these findings could inform risk reduction strategies.

More than 50 million people worldwide currently live with dementia, and with an aging world population, this figure is expected to increase to more than 152 million by 2050 (World Alzheimer Report 2018). The most common dementia type is Alzheimer’s disease (AD), characterized by impaired everyday function, severe cognitive decline—particularly working, episodic, and declarative memory (1)—and a range of neuropsychiatric symptoms (2). It represents a major source of global morbidity and mortality and poses significant human and economic costs (3).Disappointingly, AD drug development has proven difficult, with a 99.6% failure rate in the decade of 2002 to 2012, and this rate continues at the same low level today (4). Numerous reasons have been proposed as to why such clinical trials have failed, including incomplete understanding of true causal mechanisms and a failure to intervene early enough in the pathological cascade. It is therefore necessary to discover biomarkers that can identify individuals at high risk of developing AD and at the earliest possible stages of pathology onset. Moreover, it is important for these to be potentially modifiable so as to offer targets for preventative or therapeutic strategies.Metabolomics represents one avenue that may give a deeper insight into AD etiology. Metabolites are small molecules (<1,500 atomic mass units) with a role in metabolism (5). As the products of many biological processes, they sit at the end of the systems biology pathway and therefore represent effective intermediate phenotypes to a given disease because of their proximity to the clinical endpoint (6, 7). Due to 1) their noninvasive nature of measurement, 2) the fact that they are potentially modifiable through diet and lifestyle, and 3) the ability of many to cross the blood brain barrier, blood metabolites are both practical and valuable markers of biological processes and disease states in dementia (8).Markers of lipid metabolism have received particular attention in this context, as the impairment of lipid metabolism has been associated with AD (5, 8–11) and beta-amyloid (Aβ) burden (12, 13). Relevant to early intervention, they have also been associated with cognitive performance and brain function during normal aging (14, 15). Recently, using a large British population-based birth cohort, we investigated associations between 233 blood metabolites and both memory and processing speed at 60 to 64 y of age as well as changes in these cognitive domains from 60 to 64 to 69 y old. Associations with several metabolite classes were observed, including fatty acids (FAs), various compositions of high-density lipoproteins (HDLs), and glycoprotein acetyls (GP) (16).However, it is not yet established whether these metabolites are causally associated with dementia and AD. Using knowledge from these preclinical associations to investigate translatability to later AD risk could hold special utility in informing early treatment intervention, particularly if a causal relationship can be shown. This study therefore aims to expand our observational findings and assess whether 19 blood metabolites previously associated with late midlife cognition causally associate with later clinical AD status. Both univariable and Bayesian multivariable Mendelian randomization (MR) approaches are harnessed to interrogate independent as well as group associations, and a range of sensitivity analyses are performed to further scrutinize results. Identifying candidate blood metabolites, which are detectable preclinically and on the causal pathway to later AD diagnosis, will aid in facilitating further research into early intervention strategies and more targeted therapeutics.     

Triglyceride-Rich Lipoprotein Cholesterol,Small Dense LDL Cholesterol,and Incident Cardiovascular Disease

BackgroundElevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease.ObjectivesThe purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD).MethodsIn a prospective case-cohort study within the Women’s Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein.ResultsThe risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR]_Q4: 3.05 [95% confidence interval (CI): 1.46 to 6.39]; p_trend = 0.002; PAD HR_Q4: 2.58 [95% CI: 1.18 to 5.63]; p_trend = 0.019), whereas sdLDL-C was significantly associated with MI alone (HR_Q4: 3.71 [95% CI: 1.59 to 8.63]; p_trend < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dl).ConclusionsTRL-C strongly associates with future MI and PAD events, whereas sdLDL-C strongly associates with MI alone. These findings signal that the cholesterol content of TRLs and sdLDL influence atherogenesis independently of low-density lipoprotein cholesterol, and high sensitivity C-reactive protein, with potentially different potency across vascular beds. (Women’s Health Study; NCT00000479)     

Serum biomarkers for diagnosis and monitoring viral hepatitis and hepatocellular carcinoma

Introduction: Chronic liver disease due to viral hepatitis continues to be a major global health concern. Timely diagnosis and treatment will prevent cirrhosis, risk of hepatocellular carcinoma (HCC), and requirement for liver transplantation. Numerous serum biomarkers are available for viral hepatitis that are helpful in diagnosis, measuring severity, progression of disease, evaluating the best therapeutic options, and monitoring antiviral treatment response. Determining the clinical use of available diagnostic tests can be challenging for the health care provider.

Areas covered: This review article attempts to summarize the established and emerging serological markers for diagnosis and managing viral hepatitis. The literature search was performed in February 2018 and included MEDLINE and Embase databases for recent relevant literature on biomarkers for viral hepatitis.

Expert Commentary: Despite the discovery of several candidate biomarkers, translating these to clinical practice in viral hepatitis and HCC remains challenging. While limited availability of the new biomarkers in prevalent geographic areas and significant cost remain major obstacles, there have been exciting developments in this field. Understanding the detection limits and sensitivity of these markers and translating them into clinical use is important in management of viral hepatitis and complications of liver disease such as cirrhosis and hepatocellular cancer.     

Recent advances in the molecular diagnosis of mucormycosis

Introduction: Fungal infection burden related to Mucorales has been on the rise with significant associated morbidity and mortality. The major obstacle in the management has been lack of a non-invasive rapid and a reliable diagnostic test. Developing a culture-independent biomarker for the early diagnosis of mucormycosis is a major unmet need in modern mycology. Several approaches have been developed, such as immunohistochemistry (IHC) that can confirm the histopathologic diagnosis of the invasive mold infection, polymerase chain reaction (PCR) on formalin-fixed paraffin-embedded (FFPE) or fresh tissue, body fluids such as bronchoalveolar fluid (BAL), and detection directly from serum/blood. Serologic tests, matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS), metabolomics and metagenomic shotgun sequencing are other evolving technologies.

Area covered: In this review paper, we report the current status of the molecular diagnostics in the diagnosis of mucormycosis: serologic tests, IHC, PCR, protein-based with MALDI-TOF, metabolomics and metagenomic sequencing.

Expert commentary: This review will conclude with an expert commentary on the potential uses/challenges of the currently available tests and the future of molecular diagnostics for mucormycosis.     

Increased concentration of serum periostin is associated with poor outcome of patients with aneurysmal subarachnoid hemorrhage

Objective

To explore the role of serum periostin in patients with aneurysmal subarachnoid hemorrhage (aSAH).

Method

We conducted a retrospective study and 124 aSAH patients treated in Shenzhen People's hospital during March 1st 2015 to December 30th 2016 were included. Baseline information, neurological status and clinical outcome were recorded. Blood samples on admission were collected and enzyme linked immunosorbent assay (ELISA) kits were used to detect the serum level of periostin. Spearman's Correlation Analysis was used to analyze the correlation between periostin and clinical severity. Receiver operating characteristic (ROC) curve was performed to investigate variables’ prognostic value in patients with aSAH.

Results

The average age of patients included was 57.23 years old. Preliminary analysis revealed that serum periostin was significantly correlated with clinical severity. Patients with poor outcome at 12 months had higher level of periostin than patients with good outcome. Multivariate logistic regression analysis showed elevated level of periostin was significantly associated with poor outcome and the AUC was 0.85 for periostin in predicting poor outcome of patient with aSAH.

Conclusion

Elevated serum periostin concentrations are significantly associated with clinical severity and poor outcome of aSAH patients, which indicate serum periostin can be used as a prognostic biomarker in patients with aSAH.