Mining Frequency of Drug Side Effects Over a Large Twitter Dataset Using Apache Spark

Despite clinical trials by pharmaceutical companies as well as current FDA reporting systems, there are still drug side effects that have not been caught. To find a larger sample of reports, a possible way is to mine online social media. With its current widespread use, social media such as Twitter has given rise to massive amounts of data, which can be used as reports for drug side effects. To process these large datasets, Apache Spark has become popular for fast, distributed batch processing. In this work, we have improved on previous pipelines in sentimental analysis-based mining, processing, and extracting tweets with drug-caused side effects. We have also added a new ensemble classifier using a combination of sentiment analysis features to increase the accuracy of identifying drug-caused side effects. In addition, the frequency count for the side effects is also provided. Furthermore, we have also implemented the same pipeline in Apache Spark to improve the speed of processing of tweets by 2.5 times, as well as to support the process of large tweet datasets. As the frequency count of drug side effects opens a wide door for further analysis, we present a preliminary study on this issue, including the side effects of simultaneously using two drugs, and the potential danger of using less-common combination of drugs. We believe the pipeline design and the results present in this work would have great implication on studying drug side effects and on big data analysis in general

Expert consensus for respiratory physiotherapy management of mechanically ventilated adults with community-acquired pneumonia: A Delphi study

Rationale and aims: Patients with community‐acquired pneumonia (CAP) are frequently admitted to an intensive care unit. Physiotherapy may be provided to optimize respiratory function; however, there is significant variability in clinical practice and limited research directing best practice for this cohort. This study aimed to determine expert consensus for best physiotherapy practice for invasively ventilated adults with CAP. Method: A modified Delphi technique involved an international expert panel completing three rounds of an online questionnaire. The initial 35‐statement questionnaire, based on a systematic literature review and survey of current clinical practice, covered physiotherapy assessment and treatment of intubated patients with CAP. Quantitative data using Likert scales determined level of agreement, with qualitative data collected through open‐ended responses. Consensus threshold was set a priori at 70%. Items not achieving consensus were modified and new items added based on themes from qualitative data. Quantitative data were analysed descriptively, with thematic analysis used on qualitative data. Results: The panel comprised 29 international clinical and academic experts in critical care physiotherapy. Response rate was more than 95% for each round. Outcome achieved was 38 consensus statements covering assessment and treatment, with 28 statements (74%) providing consensus on recommended clinical practice, two consensus disagreement statements (7%) for what practice is not recommended, and eight statements (21%) indicating which treatments may be beneficial. Conclusion: Expert consensus regarding physiotherapy for intubated adults with CAP patients provides an evidence‐based approach to guide clinical practice. The consensus statements can also be used to guide research evaluating physiotherapy interventions for patients with CAP

Fluoroketone inhibition of Ca(2+)-independent phospholipase A2 through binding pocket association defined by hydrogen/deuterium exchange and molecular dynamics.

The mechanism of inhibition of group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)) by fluoroketone (FK) ligands is examined by a combination of deuterium exchange mass spectrometry (DXMS) and molecular dynamics (MD). Models for iPLA(2) were built by homology with the known structure of patatin and equilibrated by extensive MD simulations. Empty pockets were identified during the simulations and studied for their ability to accommodate FK inhibitors. Ligand docking techniques showed that the potent inhibitor 1,1,1,3-tetrafluoro-7-phenylheptan-2-one (PHFK) forms favorable interactions inside an active-site pocket, where it blocks the entrance of phospholipid substrates. The polar fluoroketone headgroup is stabilized by hydrogen bonds with residues Gly486, Gly487, and Ser519. The nonpolar aliphatic chain and aromatic group are stabilized by hydrophobic contacts with Met544, Val548, Phe549, Leu560, and Ala640. The binding mode is supported by DXMS experiments showing an important decrease of deuteration in the contact regions in the presence of the inhibitor. The discovery of the precise binding mode of FK ligands to the iPLA(2) should greatly improve our ability to design new inhibitors with higher potency and selectivity

Growth hormone as a potential mediator of aerobic exercise-induced reduction in visceral adipose tissue

Obesity remains one of the leading causes of death worldwide and is a well-known risk factor for a myriad of non-communicable diseases including diabetes, cardiovascular disease, and a variety of cancers (Wolf and Colditz, 1998; Frühbeck et al., 2013). While the relationship between obesity and cardiometabolic risk is well-established, the location of adipose tissue, particularly in the abdominal region, is considered a greater predictor of metabolic dysfunction than total fat mass (Kahn et al., 2006). Central obesity, characterized by the excess accumulation of adipose tissue in the abdominal region, is strongly and independently correlated with metabolic syndrome and is assessed clinically through the measurement of waist circumference (Shen et al., 2006). Central adiposity can be further subcategorized into abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) (Snel et al., 2012). While the relationship between SAT and cardiometabolic risk remains equivocal, VAT has been established as a unique pathogenic fat depot. VAT acts as an endocrine organ by secreting adipocytokines and other vasoactive substances (Kanaya et al., 2004) and is associated with cardiometabolic risk independent of body mass index (BMI) or total body adiposity (Fox et al., 2007; Pak et al., 2016). Consequently, it is important to identify new, as well as further develop existing therapies to improve the management of obesity

Cognitive impairment in diabetes mellitus and its management by transcription factor Nrf2-mediated antioxidant defense system

Diabetes mellitus has been an epidemic in the twenty-first century and an approximately 50% risk of diabetes predisposed to cognitive decline leading to dementia in humans. There is an urgent need to understand the pathophysiology and identify molecular targets of cognitive impairment in diabetes mellitus that might lead to improved therapy. Mounting evidence indicates that nuclear factor erythroid 2-related factor 2 (Nrf2) and its regulated downstream antioxidant genes are emerging therapeutic targets. In this chapter, we introduce cognitive dysfunction in diabetes mellitus and its hallmarks, particularly its pathological mechanisms related to oxidative stress in the brain, then justify the role of the transcription factor Nrf2-mediated antioxidant defense system in attenuating cognitive decline in diabetes mellitus. Studies on Nrf2 inducers sourced from natural products (i.e., sulforaphane, astaxanthin, resveratrol, quercetin) that have shown potent cognitive improvement in diabetic models are discussed. These studies have demonstrated that Nrf2 inducers drive the antioxidant and anti-inflammatory responses in the hippocampus region and effectively improve the spatial and memory function in diabetic rats/mice. However, evidence from large and well-designed clinical trials is warranted to support Nrf2 inducers as promising therapeutic agents in the management of cognitive impairment in diabetes mellitus

Development of novel herbal compound formulations targeting neuroinflammation : network pharmacology, molecular docking, and experimental verification

Neuroinfammation plays an important role in the onset and progression of neurodegenerative diseases. Te multicomponent and multitarget approach may provide a practical strategy to address the complex pathological mechanisms of neuroinfammation. Tis study aimed to develop synergistic herbal compound formulas to attenuate neuroinfammation using integrated network pharmacology, molecular docking, and experimental bioassays. Eight phytochemicals with anti-neuroinfammatory potential were selected in the present study. A compound-gene target-signaling pathway network was constructed to illustrate the mechanisms of action of each phytochemical and the interactions among them at the molecular level. Molecular docking was performed to verify the binding afnity of each phytochemical and its key gene targets. An experimental study was conducted to identify synergistic interactions among the eight phytochemicals, and the associated molecular mechanisms were examined by immunoblotting based on the fndings from the network pharmacology analysis. Two paired combinations, andrographolide and 6-shogaol (AN-SG) (IC50 = 2.85 μg/mL), and baicalein-6-shogaol (BA-SG) (IC50 = 3.28 μg/mL), were found to synergistically (combination index <1) inhibit the lipopolysaccharides (LPS)-induced nitric oxide production in microglia N11 cells. Network pharmacology analysis suggested that MAPK14, MAPK8, and NOS3 were the top three relevant gene targets for the three phytochemicals, and molecular docking demonstrated strong binding afnities of the phytochemicals to their coded proteins. Immunoblotting suggested that the AN-SG and BA-SG both showed prominent efects in inhibiting inducible nitric oxide synthase (iNOS) (p < 0.01 and p < 0.05, respectively) and MAPKp-p38 (both p < 0.05) compared with those induced by the LPS stimulation only. Te AN-SG combination exhibited greater inhibitions of the protein expressions of iNOS (p < 0.05 vs. individual components), which may partly explain the mechanisms of the synergy observed.Tis study established a practical approach to developing novel herbal-compound formulations using integrated network pharmacology analysis, molecular docking, and experimental bioassays.Te study provides a scientifc basis and new insight into the two synergistic combinations against neuroinfammation

Chronic treatment of curcumin improves hepatic lipid metabolism and alleviates the renal damage in adenine-induced chronic kidney disease in Sprague-Dawley rats

BACKGROUND: Chronic kidney disease (CKD), including nephrotic syndrome, is a major cause of cardiovascular morbidity and mortality. The literature indicates that CKD is associated with profound lipid disorders due to the dysregulation of lipoprotein metabolism which progresses kidney disease. The objective of this study is to evaluate the protective effects of curcumin on dyslipidaemia associated with adenine-induced chronic kidney disease in rats. METHODS: Male SD rats (n = 29) were divided into 5 groups for 24 days: normal control (n = 5, normal diet), CKD control (n = 6, 0.75% w/w adenine-supplemented diet), CUR 50 (n = 6, 50 mg/kg/day curcumin + 0.75% w/w adenine-supplemented diet), CUR 100 (n = 6, 100 mg/kg/day curcumin + 0.75% w/w adenine-supplemented diet), and CUR 150 (n = 6, 150 mg/kg/day curcumin + 0.75% w/w adenine-supplemented diet). The serum and tissue lipid profile, as well as the kidney function test, were measured using commercial diagnostic kits. RESULTS: The marked rise in total cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, triglycerides and free fatty acids in serum, as well as hepatic cholesterol, triglyceride and free fatty acids of CKD control rats were significantly protected by curcumin co-treatment (at the dose of 50, 100 and 150 mg/kg). Furthermore, curcumin significantly increased the serum high-density lipoprotein (HDL) cholesterol compared to the CKD control rats but did not attenuate the CKD-induced weight retardation. Mathematical computational analysis revealed that curcumin significantly reduced indicators for the risk of atherosclerotic lesions (atherogenic index) and coronary atherogenesis (coronary risk index). In addition, curcumin improved kidney function as shown by the reduction in proteinuria and improvement in creatinine clearance. CONCLUSION: The results provide new scientific evidence for the use of curcumin in CKD-associated dyslipidaemia and substantiates the traditional use of curcumin in preventing kidney damage

Elucidation of the mechanisms and molecular targets of Yiqi Shexue formula for treatment of primary immune thrombocytopenia based on network pharmacology

Yiqi Shexue formula (YQSX) is traditionally used to treat primary immune thrombocytopenia (ITP) in clinical practice of traditional Chinese medicine. However, its mechanisms of action and molecular targets for treatment of ITP are not clear. The active compounds of YQSX were collected and their targets were identified. ITP-related targets were obtained by analyzing the differential expressed genes between ITP patients and healthy individuals. Protein-protein interaction (PPI) data were then obtained and PPI networks of YQSX putative targets and ITP-related targets were visualized and merged to identify the candidate targets for YQSX against ITP. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out. The gene-pathway network was constructed to screen the key target genes. In total, 177 active compounds and 251 targets of YQSX were identified. Two hundred and thirty differential expressed genes with an P value 1 were identified between ITP patient and control groups. One hundred and eighty-three target genes associated with ITP were finally identified. The functional annotations of target genes were found to be related to transcription, cytosol, protein binding, and so on. Twenty-four pathways including cell cycle, estrogen signaling pathway, and MAPK signaling pathway were significantly enriched. MDM2 was the core gene and other several genes including TP53, MAPK1, CDKN1A, MYC, and DDX5 were the key gens in the gene-pathway network of YQSX for treatment of ITP. The results indicated that YQSX's effects against ITP may relate to regulation of immunological function through the specific biological processes and the related pathways. This study demonstrates the application of network pharmacology in evaluating mechanisms of action and molecular targets of complex herbal formulations

Natural product-based bioactive agents in combination attenuate neuroinflammation in a tri-culture model

Introduction: Neuroinflammation is an important pathological event contributing to the onset and progression of neurodegenerative diseases. The hyperactivation of microglia triggers the release of excessive proinflammatory mediators that lead to the leaky blood-brain barrier and impaired neuronal survival. Andrographolide (AN), baicalein (BA) and 6-shogaol (6-SG) possess anti-neuroinflammatory properties through diverse mechanisms of action. The present study aims to investigate the effects of the pair-combinations of these bioactive compounds in attenuating neuroinflammation. Methods: A tri-culture model with microglial N11 cells, microvascular endothelial MVEC(B3) cells, and neuroblastoma N2A cells was established in a transwell system. AN, BA and 6-SG used alone (25 µM) or in pair-wised combinations (12.5 + 12.5 µM) were subjected to the tri-culture system. Upon the stimulation of lipopolysaccharides (LPS) at 1 μg/mL, tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) levels were determined by ELISA assays. Immunofluorescence staining was applied to investigate the nuclear translocation of nuclear factor kappa B p65 (NF-κB p65) on N11 cells, expressions of protein zonula occludens-1 (ZO-1) on MVEC cells and phosphorylated tau (p-tau) on N2A cells, respectively. The endothelial barrier permeability of MVEC cells was assessed by the Evans blue dye, and the resistance from the endothelial barrier was measured by transepithelial/endothelial electrical resistance (TEER) value. Neuronal survival of N2A cells was determined by Alamar blue and MTT assays. Results: Combinations of AN-SG and BA-SG synergistically lowered the TNF and IL-6 levels in LPS-induced N11 cells. Remarkably, the combined anti-neuroinflammatory effects of AN-SG and BA-SG remained significantly greater compared to their individual components at the same concentration level. The molecular mechanism of the attenuated neuroinflammation was likely to be mediated by downregulation of NF-κB p65 translocation (p < 0.0001 vs. LPS stimulation) in N11 cells. In the MVEC cells, both ANSG and BA-SG restored TEER values, ZO-1 expression and reduced permeability. Furthermore, AN-SG and BA-SG significantly improved neuronal survival and reduced expressions of p-tau on N2A cells. Discussion: The AN-SG and BA-SG combinations showed greater antineuroinflammatory potential than those used alone in mono- and tri-cultured N11 cells, thereby further protecting endothelial tight junction and neuronal survival. Taken together, AN-SG and BA-SG may provide improved antineuroinflammatory and neuroprotective activities