ResearchPad - pharmacology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[The effect of monetary incentive on survey response for vulnerable children and youths: A randomized controlled trial]]> https://www.researchpad.co/article/elastic_article_13807 In surveys non-responders may introduce bias and lower the validity of the studies. Ways to increase response rates are therefore important. The purpose of the study was to investigate if an unconditional monetary incentive can increase the response rate for vulnerable children and youths in a postal questionnaire survey.MethodsThe study was designed as a randomized controlled trial. The study population consisted of 262 children and youth who participated in an established intervention study aimed at creating networks for different groups of vulnerable children and youths. The mean age of the participants was 16.7 years (range 11–28) and 67.9% were female. The questionnaire was adapted to three different age groups and covered different aspects of the participants’ life situation, including the dimensions from the Strengths and Difficulties Questionnaire (SDQ). In the follow-up survey, participants were randomly allocated to two groups that either received a €15 voucher for a supermarket together with the questionnaire or only received the questionnaire. We used Poisson regression to estimate the differences in response rate (Rate Ratio RR) between the intervention group and the control group.ResultsThe response rate was 75.5% in the intervention group and 42.9% in the control group. The response rate in the intervention group was significantly higher than in the control group when adjusting for age and gender (Rate Ratio, RR 1.73; 95% CI 1.38–2.17). We did not find any significant differences in scales scores between the two groups for the five scales of the SDQ. In stratified analyses, we found the effect of the incentive to be higher for males (RR 2.81; 95% CI 1.61–4.91) than for females (1.43; 95% CI 1.12–1.84).ConclusionsMonetary incentives can increase the response rate for vulnerable children and youths in surveys.Trial registrationThe trial was retrospectively registered at ClinicalTrials.gov Identifier: NCT01741675. ]]> <![CDATA[Mapping Pharmacological Network of Multi-Targeting Litchi Ingredients in Cancer Therapeutics]]> https://www.researchpad.co/article/elastic_article_13026 Considerable pharmacological studies have demonstrated that the extracts and ingredients from different parts (seeds, peels, pulps, and flowers) of Litchi exhibited anticancer effects by affecting the proliferation, apoptosis, autophagy, metastasis, chemotherapy and radiotherapy sensitivity, stemness, metabolism, angiogenesis, and immunity via multiple targeting. However, there is no systematical analysis on the interaction network of “multiple ingredients-multiple targets-multiple pathways” anticancer effects of Litchi. In this study, we summarized the confirmed anticancer ingredients and molecular targets of Litchi based on published articles and applied network pharmacology approach to explore the complex mechanisms underlying these effects from a perspective of system biology. The top ingredients, top targets, and top pathways of each anticancer function were identified using network pharmacology approach. Further intersecting analyses showed that Epigallocatechin gallate (EGCG), Gallic acid, Kaempferol, Luteolin, and Betulinic acid were the top ingredients which might be the key ingredients exerting anticancer function of Litchi, while BAX, BCL2, CASP3, and AKT1 were the top targets which might be the main targets underling the anticancer mechanisms of these top ingredients. These results provided references for further understanding and exploration of Litchi as therapeutics in cancer as well as the application of “Component Formula” based on Litchi’s effective ingredients.

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<![CDATA[Characterization of Amphetamine, Methylphenidate, Nicotine, and Atomoxetine on Measures of Attention, Impulsive Action, and Motivation in the Rat: Implications for Translational Research]]> https://www.researchpad.co/article/elastic_article_12990 Amphetamine (AMP), methylphenidate (MPH), and atomoxetine (ATX) are approved treatments for ADHD, and together with nicotine (NIC), represent pharmacological agents widely studied on cognitive domains including attention and impulsive action in humans. These agents thus represent opportunities for clinical observation to be reinvestigated in the preclinical setting, i.e., reverse translation. The present study investigated each drug in male, Long Evans rats trained to perform either (1) the five-choice serial reaction time task (5-CSRTT), (2) Go/NoGo task, or (3) a progressive ratio (PR) task, for the purpose of studying each drug on attention, impulsive action and motivation. Specific challenges were adopted in the 5-CSRTT designed to tax attention and impulsivity, i.e., high frequency of stimulus presentation (sITI), variable reduction in stimulus duration (sSD), and extended delay to stimulus presentation (10-s ITI). Initially, performance of a large (> 80) cohort of rats in each task variant was conducted to examine performance stability over repeated challenge sessions, and to identify subgroups of “high” and “low” attentive rats (sITI and sSD schedules), and “high” and “low” impulsives (10-s ITI). Using an adaptive sequential study design, the effects of AMP, MPH, ATX, and NIC were examined and contrasting profiles noted across the tests. Both AMP (0.03–0.3 mg/kg) and MPH (1–6 mg/kg) improved attentional performance in the sITI but not sSD or 10-s ITI condition, NIC (0.05–0.2 mg/kg) improved accuracy across all conditions. ATX (0.1–1 mg/kg) detrimentally affected performance in the sITI and sSD condition, notably in “high” performers. In tests of impulsive action, ATX reduced premature responses notably in the 10-s ITI condition, and also reduced false alarms in Go/NoGo. Both AMP and NIC increased premature responses in all task variants, although AMP reduced false alarms highlighting differences between these two measures of impulsive action. The effect of MPH was mixed and appeared baseline dependent. ATX reduced break point for food reinforcement suggesting a detrimental effect on motivation for primary reward. Taken together these studies highlight differences between AMP, MPH, and ATX which may translate to their clinical profiles. NIC had the most reliable effect on attentional accuracy, whereas ATX was reliably effective against all tests of impulsive action.

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<![CDATA[Predictive Nephrotoxicity Profiling of a Novel Antifungal Small Molecule in Comparison to Amphotericin B and Voriconazole]]> https://www.researchpad.co/article/elastic_article_12985 Candida albicans is the major fungal species associated with superficial mucosal infections such as oral candidiasis as well as systemic mycoses with high morbidity and mortality. On top of the rising drug resistance, currently available antifungal agents have significant adverse effects. Nephrotoxicity is the major treatment complication associated with antifungal agents.Recently, we discovered a novel antifungal small molecule SM21 with promising antifungal activity. The present study aimed to comparatively evaluate the in vivo and in vitro nephrotoxicity of SM21 comparing with Amphotericin B and voriconazole.Experimental ApproachNephrotoxicity of SM21 and its analogue were comparatively evaluated with Amphotericin B (AmB) and voriconazole. Immortalized human kidney proximal tubule epithelial cells (HK-2) were used for in vitro analysis of nephrotoxicity using cytotoxicity assays and qPCR gene expression analysis (Kim-1/HAVcr-1, CASP3). Sprague Dawley (SD) rat model was used to evaluate the nephrotoxicity in vivo using classical (SCr and BUN) and next-generation kidney injury urinary biomarkers (Kim-1, CLU, ALB, NGAL, β2M, and Cys C) alongside histopathological and immunohistochemical standards.Key ResultsAmB treatment showed a stronger cytotoxic impact on HK-2 viability and gene expression of cell death markers (Kim-1/HAVcr-1, CASP3) compared with SM21 and SM21 analogue in vitro (P < 0.01). In vivo data further demonstrated that SM21 did not significantly increase classical as well as novel nephrotoxic biomarkers, and minimal renal tubular necrosis and abnormalities were observed (15 mg kg−1 BW/day).Conclusions and ImplicationsSM21 had a significantly better safety profile in terms of nephrotoxicity with no major tubular epithelial abnormalities observed in kidney cells and no augmentation of kidney injury biomarkers compared to AmB. Kim-1 and CLU were the most sensitive biomarkers for detection of AmB-induced kidney damage. Future clinical trials should consider inclusion of these novel biomarkers as early indicators of acute kidney injury in antifungal-induced nephrotoxicity. ]]> <![CDATA[Proline-Rich Antimicrobial Peptides in Medicinal Maggots of <i>Lucilia sericata</i> Interact With Bacterial DnaK But Do Not Inhibit Protein Synthesis]]> https://www.researchpad.co/article/elastic_article_12973 In the search for new antibiotics to combat multidrug-resistant microbes, insects offer a rich source of novel anti-infectives, including a remarkably diverse array of antimicrobial peptides (AMPs) with broad activity against a wide range of species. Larvae of the common green bottle fly Lucilia sericata are used for maggot debridement therapy, and their effectiveness in part reflects the large panel of AMPs they secrete into the wound. To investigate the activity of these peptides in more detail, we selected two structurally different proline rich peptides (Lser-PRP2 and Lser-PRP3) in addition to the α-helical peptide Lser-stomoxyn. We investigated the mechanism of anti-Escherichia coli action of the PRPs in vitro and found that neither of them interfered with protein synthesis but both were able to bind the bacterial chaperone DnaK and are therefore likely to inhibit protein folding. However, unlike Lser-stomoxyn that permeabilized the bacterial membrane by 1% at the low concentration (0.25 µM) neither of the PRPs alone was able to permeabilize E. coli membrane. In the presence of this Lser-stomoxyn concentration significant increase in anti-E. coli activity of Lser-PRP2 was observed, indicating that this peptide needs specific membrane permeabilizing agents to exert its antibacterial activity. We then examined the AMPs-treated bacterial surface and observed detrimental structural changes in the bacterial cell envelope in response to combined AMPs. The functional analysis of insect AMPs will help select optimal combinations for targeted antimicrobial therapy.

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<![CDATA[hERG K<sup>+</sup> Channels Promote Survival of Irradiated Leukemia Cells]]> https://www.researchpad.co/article/elastic_article_12959 Many tumor cells express highly elevated activities of voltage-gated K+ channels in the plasma membrane which are indispensable for tumor growth. To test for K+ channel function during DNA damage response, we subjected human chronic myeloid leukemia (CML) cells to sub-lethal doses of ionizing radiation (0–8 Gy, 6 MV photons) and determined K+ channel activity, K+ channel-dependent Ca2+ signaling, cell cycle progression, DNA repair, and clonogenic survival by whole-cell patch clamp recording, fura-2 Ca2+ imaging, Western blotting, flow cytometry, immunofluorescence microscopy, and pre-plating colony formation assay, respectively. As a result, the human erythroid CML cell line K562 and primary human CML cells functionally expressed hERG1. Irradiation stimulated in both cell types an increase in the activity of hERG1 K+ channels which became apparent 1–2 h post-irradiation. This increase in K+ channel activity was paralleled by an accumulation in S phase of cell cycle followed by a G2/M cell cycle arrest as analyzed between 8 and 72 h post-irradiation. Attenuating the K+ channel function by applying the hERG1 channel inhibitor E4031 modulated Ca2+ signaling, impaired inhibition of the mitosis promoting subunit cdc2, overrode cell cycle arrest, and decreased clonogenic survival of the irradiated cells but did not affect repair of DNA double strand breaks suggesting a critical role of the hERG1 K+ channels for the Ca2+ signaling and the cell cycle control during DNA damage response.

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<![CDATA[Berberine Facilitates Extinction of Drug-Associated Behavior and Inhibits Reinstatement of Drug Seeking]]> https://www.researchpad.co/article/elastic_article_12956 A high rate of relapse is a major clinical problem among drug-addicted individuals. Persistent traces of drug-associated reward memories contribute to intense craving and often trigger relapse. A number of interventions on drug-associated memories have shown significant benefits in relapse prevention. Among them are pre- or post-extinction pharmacological manipulations that facilitate the extinction of drug-associated behavior. Berberine, a bioactive isoquinoline alkaloid, has been recently reported to provide therapeutic benefits for a number of central nervous system (CNS) disorders, including morphine addiction. The present study aimed to investigate whether berberine could serve as a post-extinction pharmacological intervention agent to reduce risks of reinstatement of drug seeking. We found that an intragastric administration of berberine at doses of 25 and 50 mg/kg during the critical time window significantly facilitated the extinction of morphine-reward related behavior in free access and confined conditioned place preference (CPP) extinction paradigms, and subsequently, it prevented reinstatement and spontaneous recovery of morphine-induced CPP in mice. Intriguingly, the berberine treatment with or without extinction training altered expression of plasticity-related proteins such as brain-derived neurotrophic factor (BDNF), AMPA receptors (GluA1 and GluA2) in the nucleus accumbens (NAc). Moreover, the post-extinction berberine treatment significantly reduced reinstatement of cocaine-induced CPP and operant intravenous self-administration (IVSA) memories in rats. Altogether, our findings suggest that extinction training combined with the post-extinction berberine treatment can facilitate extinction of drug-associated behavior making it an attractive therapeutic candidate in relapse prevention.

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<![CDATA[Protective Actions of Acidic Hydrolysates of Polysaccharide Extracted From <i>Mactra veneriformis</i> Against Chemical-Induced Acute Liver Damage]]> https://www.researchpad.co/article/elastic_article_12937 The present study aimed to explore the hepatoprotective effects of acidic hydrolysates of polysaccharide extracted from the marine clam M. veneriformis (Ah-MVPS) against ethanol- and CCl4-induced liver damage. Moreover, we also seek to probe the mechanism associated with the liver protection effect of Ah-MVPS. A series of animal and cell experiments were executed to detect suitable serological and histological indicators in hepatic tissues. Ah-MVPS can significantly reduce liver damage by means of an increase in hepatocyte superoxidase dismutase and inhibition of leakages of alanine aminotransferase and aspartate transaminase, as well as through alleviation of malondialdehyde excalation. Ah-MVPS inhibited steatosis and water-like hepatic deterioration in histological examination. They can suppress membrane destruction in boundaries and the collapse of reticular scaffolds of injured mouse hepatocytes and can substantially reduce the inflammatory extent of liver tissue aroused by excessive intake of ethanol or CCl4. In cell assays, Ah-MVPS markedly elevated the viability of L-02 cells exposed to an intoxication of ethanol or H2O2. The beneficial effect of Ah-MVPS might arise, at least in part, because of the amelioration of peroxidation or oxidative stress. Taken together, our findings reveal that Ah-MVPS have potential for development as protective agents to attenuate acute liver injuries.

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<![CDATA[Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation]]> https://www.researchpad.co/article/elastic_article_12925 Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.

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<![CDATA[Icariside II, a PDE5 Inhibitor, Suppresses Oxygen-Glucose Deprivation/Reperfusion-Induced Primary Hippocampal Neuronal Death Through Activating the PKG/CREB/BDNF/TrkB Signaling Pathway]]> https://www.researchpad.co/article/elastic_article_12918 Ischemic stroke remains the leading cause of death and adult disability. Cerebral ischemic/reperfusion (I/R) injury is caused by ischemic stroke thereafter aggravates overwhelming neuronal apoptosis and even the death of neurons. Of note, hippocampus is more susceptive to cerebral I/R injury than the other brain region. This study was designed to explore the effects and mechanism of icariside II (ICS II), a pharmacologically active compound exists in herbal Epimedii with previous study-proved as a phosphodiesterase 5 (PDE5) inhibitor, on the oxygen glucose deprivation/reoxygenation (OGD/R)-induced primary hippocampal neurons injury.MethodsEffects of ICS II on primary hippocampal neuronal impairment and apoptosis induced by OGD/R were examined by MTT, lactate dehydrogenase (LDH) release, TUNEL staining, and flow cytometry, respectively. Activation of memory-related signaling pathways was measured using Western blot analysis. The direct interaction between ICS II and PDE5 was further evaluated by molecular docking.ResultsICS II (12.5, 25, 50 μM) markedly abrogated OGD/R-induced hippocampal neuronal death as suggested by the increase in neurons viability and the decrease in cellular LDH release. Furthermore, ICS II not only effectively decreased the protein expression and activity of PDE5, restored the 3′5′-cyclic guanosine monophosphate (cGMP) level and its downstream target protein kinase G (PKG) activity but also increased the phosphorylation of cAMP response element binding protein (CREB) level, expressions of brain derived neurotrophic factor (BDNF), and tyrosine protein kinase B (TrkB). Mechanistically, the inhibitory effects of ICS II were abrogated by Rp-8-Br-cGMP (a PKG inhibitor) or ANA-12 (a TrkB inhibitor), which further confirmed that the favorable effects of ICS II were attributed to its activation of the PKG/CREB/BDNF signaling pathways. Intriguingly, ICS II might effectively bind and inhibited PDE5 activity as demonstrated by relatively high binding scores (−6.52 kcal/mol).ConclusionsICS II significantly rescues OGD/R-induced hippocampal neuronal injury. The mechanism is, at least partly, due to inhibition of PDE5 and activation of PKG/CREB/BDNF/TrkB signaling pathway. Hence it is thought that ICS II might be a potential naturally PDE5 inhibitor to combat cerebral I/R injury. ]]> <![CDATA[The Impact of Plasma Protein Binding Characteristics and Unbound Concentration of Voriconazole on Its Adverse Drug Reactions]]> https://www.researchpad.co/article/elastic_article_12912 This study investigated voriconazole (VRC) unbound plasma concentration and its relationship with adverse drug reactions (ADRs) in patients with malignant hematologic disease. Plasma samples were collected from patients or spiked in vitro. A time-saving rapid equilibrium dialysis assay was used for the separation of unbound and bound VRC, following a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis method for drug concentration detection. Liver function and treatment details were collected from the electronic medical records of patients. Protein concentration was determined according to instructions. VRC plasma protein binding rate (PPB) in patient is significantly higher [69.5 ± 6.2%] than that in in-vitro samples, influenced by total drug concentration (Ct), plasma protein concentration, and protein type. The α1-acid glycogen (AAG) has the highest affinity with VRC. Relationship between total PPB of VRC with PPB of individual protein is not a simple addition, but a compressive combination. Unbound drug concentration (Cu) of VRC shows significant relationships with Ct, protein concentration, AST level, metabolism type of CYP2C19 and co-administration of high PPB medicines. Unbound plasma concentration of VRC shows a more sensitive relationship with ADRs than Ct.

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<![CDATA[Quercetin Combined With Human Umbilical Cord Mesenchymal Stem Cells Regulated Tumour Necrosis Factor-α/Interferon-γ-Stimulated Peripheral Blood Mononuclear Cells <i>via</i> Activation of Toll-Like Receptor 3 Signalling]]> https://www.researchpad.co/article/elastic_article_12908 The beneficial effect of quercetin in rheumatic diseases is unclear. Studies have already confirmed that human umbilical cord mesenchymal stem cells (hUCMSCs) alleviate some symptoms of rheumatoid arthritis (RA) by their immunosuppressive capacities. This study explored whether there are additive effects of quercetin and hUCMSCs on peripheral blood mononuclear cells (PBMCs) under simulated rheumatic conditions. hUCMSCs were pretreated with quercetin (10 μM) before coculture with TNF-α/IFN-γ-stimulated PBMCs at a ratio of 1:1 for 3 days. PBMC proliferation was inhibited, and the proportion of Th17 cells was shifted. These effects may be related to the effect of quercetin on functional molecules in hUCMSCs, including nitric oxide (NO), indoleamine 2,3-dioxygenase (IDO), interleukin 6 (IL-6) and Toll-like receptor-3 (TLR-3) and the Akt/IκB pathways. These results suggest that quercetin effectively promoted the immunoregulatory effect of hUCMSCs by inhibiting the Akt/IκB pathway, activating the Toll-like receptor-3 pathway, and regulating downstream cytokines.

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<![CDATA[Cannabidiol (CBD) and Δ<sup>9</sup>-tetrahydrocannabinol (THC) for chronic insomnia disorder (‘CANSLEEP’ trial): protocol for a randomised, placebo-controlled, double-blinded, proof-of-concept trial]]> https://www.researchpad.co/article/elastic_article_12560 Insomnia is a highly prevalent and costly condition that is associated with increased health risks and healthcare utilisation. Anecdotally, cannabis use is frequently reported by consumers to promote sleep. However, there is limited research on the effects of cannabis on sleep and daytime function in people with insomnia disorder using objective measures. This proof-of-concept study will evaluate the effects of a single dose of an oral cannabis-based medicine on sleep and daytime function in participants with chronic insomnia disorder.Methods and analysisA randomised, crossover, placebo-controlled, single-dose study design will be used to test the safety and efficacy of an oral oil solution (‘ETC120’) containing 10 mg Δ9-tetrahydrocannabinol (THC) and 200 mg cannabidiol (CBD) in 20 participants diagnosed with chronic insomnia disorder. Participants aged 35–60 years will be recruited over an 18-month period commencing August 2019. Each participant will receive both the active drug and matched placebo, in a counterbalanced order, during two overnight study assessment visits, with at least a 1-week washout period between each visit. The primary outcomes are total sleep time and wake after sleep onset assessed via polysomnography. In addition, 256-channel high-density electroencephalography and source modelling using structural brain MRI will be used to comprehensively examine brain activation during sleep and wake periods on ETC120 versus placebo. Next-day cognitive function, alertness and simulated driving performance will also be investigated.Ethics and disseminationEthics approval was received from Bellberry Human Research Ethics Committee (2018-04-284). The findings will be disseminated in a peer-reviewed open-access journal and at academic conferences.Trial registration numberANZCTRN12619000714189. ]]> <![CDATA[Placental transfer of Letermovir &amp; Maribavir in the <i>ex vivo</i> human cotyledon perfusion model. New perspectives for <i>in utero</i> treatment of congenital cytomegalovirus infection]]> https://www.researchpad.co/article/elastic_article_11236 Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment.MethodsThe objective was to investigate the placental transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)).ResultsFor LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively.ConclusionsDrugs’ concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules. ]]> <![CDATA[Cytotoxicity of snake venom enzymatic toxins: phospholipase A<sub>2</sub> and <span style="font-variant: all-small-caps">l</span>-amino acid oxidase]]> https://www.researchpad.co/article/elastic_article_9179 The phospholipase A2 (PLA2) and l-amino acid oxidase (LAAO) are two major enzymes found in the venoms from most snake species. These enzymes have been structurally and functionally characterised for their pharmacological activities. Both PLA2 and LAAO from different venoms demonstrate considerable cytotoxic effects on cancer cells via induction of apoptosis, cell cycle arrest and suppression of proliferation. These enzymes produce more pronounced cytotoxic effects in cancer cells than normal cells, thus they can be potential sources as chemotherapeutic agents. It is proposed that PLA2 and LAAO contribute to an elevated oxidative stress due to their catalytic actions, for instance, the ability of PLA2 to produce reactive oxygen species during lipolysis and formation of H2O2 from LAAO catalytic activity which consequently lead to cell death. Nonetheless, the cell-death signalling pathways associated with exposure to these enzymatic toxins are not fully elucidated yet. Here in this review, we will discuss the cytotoxic effects of PLA2 and LAAO in relationship to their catalytic mechanisms and the underlying mechanisms of cytotoxic actions.

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<![CDATA[Small molecules that target the ubiquitin system]]> https://www.researchpad.co/article/elastic_article_9166 Eukaryotic life depends upon the interplay between vast networks of signaling pathways composed of upwards of 109–1010 proteins per cell. The integrity and normal operation of the cell requires that these proteins act in a precise spatial and temporal manner. The ubiquitin system is absolutely central to this process and perturbation of its function contributes directly to the onset and progression of a wide variety of diseases, including cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infectious diseases, and muscle dystrophies. Whilst the individual components and the overall architecture of the ubiquitin system have been delineated in some detail, how ubiquitination might be successfully targeted, or harnessed, to develop novel therapeutic approaches to the treatment of disease, currently remains relatively poorly understood. In this review, we will provide an overview of the current status of selected small molecule ubiquitin system inhibitors. We will further discuss the unique challenges of targeting this ubiquitous and highly complex machinery, and explore and highlight potential ways in which these challenges might be met.

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<![CDATA[Non-invasive monitoring of pharmacodynamics during the skin wound healing process using multimodal optical microscopy]]> https://www.researchpad.co/article/elastic_article_9076 Impaired diabetic wound healing is one of the serious complications associated with diabetes. In patients with diabetes, this impairment is characterized by several physiological abnormalities such as metabolic changes, reduced collagen production, and diminished angiogenesis. We designed and developed a multimodal optical imaging system that can longitudinally monitor formation of new blood vessels, metabolic changes, and collagen deposition in a non-invasive, label-free manner.Research design and methodsThe closure of a skin wound in (db/db) mice, which presents delayed wound healing pathologically similar to conditions in human type 2 diabetes mellitus, was non-invasively followed using the custom-built multimodal microscope. In this microscope, optical coherence tomography angiography was used for studying neovascularization, fluorescence lifetime imaging microscopy for nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) assessment, fluorescence intensity changes of NAD(P)H and flavin adenine dinucleotide (FAD) cofactors for evaluating metabolic changes, and second harmonic generation microscopy for analyzing collagen deposition and organization. The animals were separated into four groups: control, placebo, low concentration (LC), and high concentration (HC) treatment. Images of the wound and surrounding areas were acquired at different time points during a 28-day period.ResultsVarious physiological changes measured using the optical imaging modalities at different phases of wound healing were compared. A statistically significant improvement in the functional relationship between angiogenesis, metabolism, and structural integrity was observed in the HC group.ConclusionsThis study demonstrated the capability of multimodal optical imaging to non-invasively monitor various physiological aspects of the wound healing process, and thus become a promising tool in the development of better diagnostic, treatment, and monitoring strategies for diabetic wound care. ]]> <![CDATA[Substantial improvement of tetraene macrolide production in <i>Streptomyces diastatochromogenes</i> by cumulative drug resistance mutations]]> https://www.researchpad.co/article/elastic_article_7861 Tetraene macrolides remain one of the most reliable fungicidal agents as resistance of fungal pathogens to these antibiotics is relatively rare. The modes of action and biosynthesis of polyene macrolides had been the focus of research over the past few years. However, few studies have been carried out on the overproduction of polyene macrolides. In the present study, cumulative drug-resistance mutation was used to obtain a quintuple mutant G5-59 with huge tetraene macrolide overproduction from the starting strain Streptomyces diastatochromogenes 1628. Through DNA sequence analysis, the mutation points in the genes of rsmG, rpsL and rpoB were identified. Additionally, the growth characteristic and expression level of tetrRI gene (belonging to the large ATP binding regulator of LuxR family) involved in the biosynthesis of tetraene macrolides were analyzed. As examined with 5L fermentor, the quintuple mutant G5-59 grew very well and the maximum productivity of tetramycin A, tetramycin P and tetrin B was as high as 1735, 2811 and 1500 mg/L, which was 8.7-, 16- and 25-fold higher than that of the wild-type strain 1628, respectively. The quintuple mutant G5-59 could be useful for further improvement of tetraene macrolides production at industrial level.

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<![CDATA[Methamphetamine administration increases hepatic CYP1A2 but not CYP3A activity in female guinea pigs]]> https://www.researchpad.co/article/elastic_article_7848 Methamphetamine use has increased over the past decade and the first use of methamphetamine is most often when women are of reproductive age. Methamphetamine accumulates in the liver; however, little is known about the effect of methamphetamine use on hepatic drug metabolism. Methamphetamine was administered on 3 occassions to female Dunkin Hartley guinea pigs of reproductive age, mimicking recreational drug use. Low doses of test drugs caffeine and midazolam were administered after the third dose of methamphetamine to assess the functional activity of cytochrome P450 1A2 and 3A, respectively. Real-time quantitative polymerase chain reaction was used to quantify the mRNA expression of factors involved in glucocorticoid signalling, inflammation, oxidative stress and drug transporters. This study showed that methamphetamine administration decreased hepatic CYP1A2 mRNA expression, but increased CYP1A2 enzyme activity. Methamphetamine had no effect on CYP3A enzyme activity. In addition, we found that methamphetamine may also result in changes in glucocorticoid bioavailability, as we found a decrease in 11β-hydroxysteroid dehydrogenase 1 mRNA expression, which converts inactive cortisone into active cortisol. This study has shown that methamphetamine administration has the potential to alter drug metabolism via the CYP1A2 metabolic pathway in female guinea pigs. This may have clinical implications for drug dosing in female methamphetamine users of reproductive age.

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<![CDATA[Pooling individual participant data from randomized controlled trials: Exploring potential loss of information]]> https://www.researchpad.co/article/elastic_article_7838 Pooling individual participant data to enable pooled analyses is often complicated by diversity in variables across available datasets. Therefore, recoding original variables is often necessary to build a pooled dataset. We aimed to quantify how much information is lost in this process and to what extent this jeopardizes validity of analyses results.MethodsData were derived from a platform that was developed to pool data from three randomized controlled trials on the effect of treatment of cardiovascular risk factors on cognitive decline or dementia. We quantified loss of information using the R-squared of linear regression models with pooled variables as a function of their original variable(s). In case the R-squared was below 0.8, we additionally explored the potential impact of loss of information for future analyses. We did this second step by comparing whether the Beta coefficient of the predictor differed more than 10% when adding original or recoded variables as a confounder in a linear regression model. In a simulation we randomly sampled numbers, recoded those < = 1000 to 0 and those >1000 to 1 and varied the range of the continuous variable, the ratio of recoded zeroes to recoded ones, or both, and again extracted the R-squared from linear models to quantify information loss.ResultsThe R-squared was below 0.8 for 8 out of 91 recoded variables. In 4 cases this had a substantial impact on the regression models, particularly when a continuous variable was recoded into a discrete variable. Our simulation showed that the least information is lost when the ratio of recoded zeroes to ones is 1:1.ConclusionsLarge, pooled datasets provide great opportunities, justifying the efforts for data harmonization. Still, caution is warranted when using recoded variables which variance is explained limitedly by their original variables as this may jeopardize the validity of study results. ]]>