Thioredoxin interacting protein,a key molecular switch between oxidative stress and sterile inflammation in cellular response

Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease(NAFLD),retinopathy,critical limb ischemia,and impaired angiogenesis.Sterile inflammation driven by high-fat diet,increased formation of reactive oxygen species,alteration of intracellular calcium level and associated release of inflammatory mediators,are the main common underlying forces in the pathophysiology of NAFLD,ischemic retinopathy,stroke,and aging brain.This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein(TXNIP)to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states.Finally,the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.

Complement activation in obesity, insulin resistance, and type 2 diabetes mellitus

Amplified inflammatory reaction has been observed to be involved in cardiometabolic diseases such as obesity,insulin resistance,diabetes,dyslipidemia,and atherosclerosis.The complement system was originally viewed as a supportive first line of defense against microbial invaders,and research over the past decade has come to appreciate that the functions of the complement system extend beyond the defense and elimination of microbes,involving in such diverse processes as clearance of the immune complexes,complementing T and B cell immune functions,tissue regeneration,and metabolism.The focus of this review is to summarize the role of the activation of complement system and the initiation and progression of metabolic disorders including obesity,insulin resistance and diabetes mellitus.In addition,we briefly describe the interaction of the activation of the complement system with diabetic complications such as diabetic retinopathy,nephropathy and neuropathy,highlighting that targeting complement system therapeutics could be one of possible routes to slow down those aforementioned diabetic complications.

Thrapeutic equivalence in the treatment of hypertension:Can lercanidipine and nifedipine GITS be considered to be interchangeable?

AIM: To undertake a review of the evidence that nifedipine GITS and lercanidipine are therapeutically equivalent in the management of essential hypertension.METHODS: A systematic review of the published literature was prompted by the findings of two meta-analyses which indicated that there was a lower incidence of peripheral(ankle) oedema with lercanidipine. However,neither meta-analysis gave detailed attention to comparative antihypertensive efficacy or cardiovascular protection. Accordingly,a systematic,detailed and critical review was undertaken of individual published papers. The review started with those studies incorporated into the 2 meta-analyses and then all other salient and directly relevant papers identified through the following search criteria: all randomized controlled trials in which the therapeutic profile and antihypertensive effects of lercanidipine were directly compared with those of nifedipine GITS(in hypertensive patients). The searchstrategy was focused on the reports of clinical trials of lercanidipine vs nifedipine GITS,which were identified through a systematic search of PubMed(from 1966 to October 2012),Embase(from 1980 to October 2012) and the Cochrane library(from 1 October 2008 to end October 2013). The search combined terms related to lercanidipine vs nifedipine GITS(including MeSH search using calcium antagonists,calcium channel blockers and dihydropyridines).RESULTS: With regard to blood pressure(BP) control and the consistency of BP control throughout 24-h,there is limited published evidence. However,two studies using 24 h ambulatory blood pressure monitoring clearly identified the dose-dependency of BP lowering with lercanidipine and its variably sustained 24-h efficacy. In contrast,there is evidence of a consistent antihypertensive effect throughout 24 h with nifedipine GITS. The incidence of the most common "side effect",i.e.,peripheral(ankle) oedema can be estimated as follows. For every 100 patients treated with lercanidipine,2.5 will report oedema compared to 6 patients treated with nifedipine GITS. However,98 or 99 patients will continue treatment with nifedipine GITS,compared with 99.5 patients on lercanidipine. Finally,with regard to outcome studies of cardiovascular(CV) morbidity and mortality,there is definitive outcome evidence for nifedipine GITS but there is no evidence that treatment with lercanidipine leads to reductions in CV morbidity and mortality.CONCLUSION: There is no evidence in terms of longterm BP control and CV protection to justify the contention that lercanidipine is therapeutically equivalent to nifedipine GITS.

Salivary cytokines and levels in denture stomatitis: An exploratory case-control study

We aimed to evaluate the microbial and inflammatory characteristics associated with Denture Stomatitis (DS) analyzing: l) Levels of salivary cytokines and cultivable C. albicans;2) DNA-DNA checkerboard on biofilm associated with mucosal tissue-bearing denture surfaces, 3) Serum C-reactive protein (CRP) levels. Thirty-two subjects were enrolled in the study with control (n = 17) and DS types II and III (n = 15) subjects. Samples were collected from unstimulated whole saliva, serum and swabs from denture surfaces. Salivary levels of inflammatory mediators and CRP were measured by multiplex. Samples from denture and mucosal surfaces were analyzed by DNA-DNA checkerboard. Saliva from DS subjects showed increase in IL-8 (p = 0.04) and IL-1β (p = 0.04) with trend for increase in IL-1β, TNFα and IL-6 levels. C. albicans higher counts in DS saliva (p = 0.03) showed association with elevated levels of IL-8 (p = 0.03) and IL-1α (p = 0.01). CRP levels were not different among groups (p = 0.74). DNA-DNA checkerboard analyses indicated typical periodontal pathogens below the detection threshold of 104 organisms on both denture and inflamed mucosal surfaces. The data suggest that DS is associated with elevation of salivary IL1 and IL-8 together with increased C. albicans. There was no evidence of systemic inflammation as measured by serum C-reactive protein levels.

Nascent mRNA damage:depot and disposal

In a recent study published in Cell,Zhou et al.1 have characterized a highly unusual behavior of specialized stress granules(SG),driven by metabolism of UV-damaged pre-mRNA.These cytoplasmic SGs are characterized by an unusual content of intronic sequences and the double-stranded RNA(dsRNA)specific helicase DHX9,both of which are usually found in the nucleus.

Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review

The inflammatory process plays a central role in the development and progression of numerous pathological situations,such as inflammatory bowel disease(IBD),autoimmune and neurodegenerative diseases,metabolic syndrome,and cardiovascular disorders. IBDs involve inflammation of the gastrointestinal area and mainly comprise Crohn's disease(CD) and ulcerative colitis(UC). Both pathological situations usually involve recurring or bloody diarrhea,pain,fatigue and weight loss. There is at present no pharmacological cure for CD or UC. However,surgery may be curative for UC patients. The prescribed treatment aims to ameliorate the symptoms and prevent and/or delay new painful episodes. Flavonoid compounds are a large family of hydroxylated polyphenolic molecules abundant in plants,including vegetables and fruits which are the major dietary sources of these compounds for humans,together with wine and tea. Flavonoids are becoming very popular because they have many health-promoting and disease-preventive effects. Most interest has been directed towards the antioxidant activity of flavonoids,evidencing a remarkable free-radical scavenging capacity. However,accumulating evidence suggests that flavonoids have many other biological properties,including anti-inflammatory,antiviral,anticancer,and neuroprotective activities through different mechanisms of action. The present review analyzes the available data about the different types of flavonoids and their potential effectiveness as adjuvant therapy of IBDs.

Cell-specific mineralocorticoid receptors:future therapeutic targets for stroke?

The mineralocorticoid receptor（MR）,well known to be expressed in renal epithelial cells where it is important in fluid and electrolyte homeostasis,has aldosterone as one of its main agonists.Much research in the last 10–15 years indicates that MRs are also expressed outside of the kidney,including in the brain,vasculature and heart,where they contribute to the pathophysiology of disease（Dinh et al.,2012;]aisser and Farman, 2016）.

Apoptosis-inducing effects of extracts from desert plants in HepG2 human hepatocarcinoma cells

Objective:To investigat the mechanism of antitumor efficacy of Origanum clayi(O.clayi) and Ochradenus baccatus(O.baccatus) extracts by exploring apoptosis-inducing potential.Methods:The aqueous extracts of aerial parts of aforementioned plants were prepared and used for this study.HepG2 cells were treated with varying concentrations(0,2 and 5 mg/mL)of each plant extract for 24 or 48 h.Cell apoptosis was measured by annexin V-fluorescein isothiocyanate binding assay and flow cytometry.The expression levels of various apoptosisrelated genes were determined by semi-quantitative reverse transcription-polymerase chain reaction.Results:O.clayi and O.baccatus extracts exerted apoptotic effects on HepG2 cells for 48 h following treatment.O.clayi extract was found to be a better apoptosis-inducing agent than O.baccatus extract as the former delivered greater efficacy at a lower concentration.Both extracts manifested upregulation of Bax,Bad.cytochrome c.caspase-3,caspase-7.caspase-9 and poly(adenosine diphosphate-ribose) polymerase.Conclusions:The aqueous extracts of O.clayi and O.baccatus are capable of inducing apoptosis in HepG2 cells through modulation of mitochondrial pathway which explains their antitumor activities.These desert plants may serve as useful resources to develop effective remedies for hepatocellular carcinoma and other human malignancies.

Cancer combination therapy with carnosic acid

Carnosic acid(CA)is a natural phenolic diterpene mainly occurring in some species of the Lamiaceae family.Numerous studies described the cytotoxicity of CA towards different types of cancer both in vitro and in vivo.Particularly,the influence of CA in combination with other drugs,vitamins or natural products through affecting various targets has raised interest.Current experimental in vivo data suggested that CA may cooperate with clinically used anticancer drugs promoting their activity against cancer.From this point of view,CA gained importance,because it may alter pharmacodynamic profiles of various agents in the case of their co-administration,and thereby,act in a potentially synergistic manner,which can provide a basis for potential applications of CA in the management of cancer.In the present review,we give an overview of CA as well as CA co-treatment regimens with a special focus on cancer.In this context,the role of CA as an adjuvant treatment alternative is highlighted.

Correlation of docking energies with spectroscopic kinetic assays of potential xanthine oxidase substrates

Here we present a docking model that ranks compounds according to their potential effectiveness as a potential substrate or inhibitor. We utilize xanthine oxidase (XO), a multi-cofactor oxido-reductase which converts hypoxanthine to xanthine and xanthine to uric acid. During the reductive half reaction, electrons flow from the molybdopterin, to each of two Fe/S centers, and finally to FAD. During the oxidative half reaction, electrons are passed from the FAD to O2. Under ideal physiological conditions, this reduction of oxygen generates H2O2 and, under multiple turnover conditions, superoxide in amounts which is regulated by catalase and superoxide dismutase. Utilizing computer modeling predictions of the docking orientations and energies of a group of purine based structures was selected. Correlating computer estimations with steady state kinetic data, a rapid screening process for inhibittor prediction was highlighted. This method allows educated selection of likely inhibitors, thereby decreasing the time and supplies required to complete a traditional kinetic analysis screening. Results demonstrate the functionality and reliability of this method and have proven particularly useful in understanding binding orienttations or poses of each compound.

Protein arginine methyltransferase 6 is a novel substrate of protein arginine methyltransferase 1

BACKGROUND Post-translational modifications play key roles in various biological processes.Protein arginine methyltransferases(PRMTs)transfer the methyl group to specific arginine residues.Both PRMT1 and PRMT6 have emerges as crucial factors in the development and progression of multiple cancer types.We posit that PRMT1 and PRMT6 might interplay directly or in-directly in multiple ways accounting for shared disease phenotypes.AIM To investigate the mechanism of the interaction between PRMT1 and PRMT6.METHODS Gel electrophoresis autoradiography was performed to test the methyltranferase activity of PRMTs and characterize the kinetics parameters of PRMTs.Liquid chromatography-tandem mass spectrometryanalysis was performed to detect the PRMT6 methylation sites.RESULTS In this study we investigated the interaction between PRMT1 and PRMT6,and PRMT6 was shown to be a novel substrate of PRMT1.We identified specific arginine residues of PRMT6 that are methylated by PRMT1,with R106 being the major methylation site.Combined biochemical and cellular data showed that PRMT1 downregulates the enzymatic activity of PRMT6 in histone H3 methylation.CONCLUSION PRMT6 is methylated by PRMT1 and R106 is a major methylation site induced by PRMT1.PRMT1 methylation suppresses the activity of PRMT6.

Basement membrane and blood-brain barrier

The blood-brain barrier (BBB) is a highly complex and dynamic structure, mainly composed of brain microvascular endothelial cells, pericytes, astrocytes and the basement membrane (BM). The vast majority of BBB research focuses on its cellular constituents. Its non- cellular component, the BM, on the other hand, is largely understudied due to its intrinsic complexity and the lack of research tools. In this review, we focus on the role of the BM in BBB integrity. We first briefly introduce the biochemical composition and structure of the BM. Next, the biological functions of major components of the BM in BBB formation and maintenance are discussed. Our goal is to provide a concise overview on how the BM contributes to BBB integrity.

Stem cell treatment improves post stroke neurological outcomes:a comparative study in male and female rats

Background and purpose The therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat controversial.Recent results from our laboratory have demonstrated the potential benefits of human umbilical cord blood-derived mesenchymal stem cells(MSC)in a rodent stroke model.We hypothesised that MSC treatment would effectively promote the recovery of sensory and motor function in both males and females,despite any apparent sex differences in post stroke brain injury.Methods Transient focal cerebral ischaemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery.Following the procedure,male and female rats of the untreated group were euthanised 1 day after reperfusion and their brains were used to estimate the resulting infarct volume and tissue swelling.Additional groups of stroke-induced male and female rats were treated with MSC or vehicle and were subsequently subjected to a battery of standard neurological/neurobehavioral tests(Modified Neurological Severity Score assessment,adhesive tape removal,beam walk and rotarod).The tests were administered at regular intervals(at days 1,3,5,7 and 14)after reperfusion to determine the time course of neurological and functional recovery after stroke.Results The infarct volume and extent of swelling of the ischaemic brain were similar in males and females.Despite similar pathological stroke lesions,the clinical manifestations of stroke were more pronounced in males than females,as indicated by the neurological scores and other tests.MSC treatment significantly improved the recovery of sensory and motor function in both sexes,and it demonstrated efficacy in both moderate stroke(females)and severe stroke(males).Conclusions Despite sex differences in the severity of post stroke outcomes,MSC treatment promoted the recovery of sensory and motor function in male and female rats,suggesting that it may be a promising treatment for stroke.

Detection of PRMT1 inhibitors with stopped flow fluorescence

Protein arginine methyltransferases(PRMTs)are crucial epigenetic regulators in eukaryotic organisms that serve as histone writers for chromatin remodeling.PRMTs also methylate a variety of non-histone protein substrates to modulate their function and activity.The development of potent PRMT inhibitors has become an emerging and imperative research area in the drug discovery field to provide novel therapeutic agents for treating diseases and as tools to investigate the biological functions of PRMTs.PRMT1 is the major type I enzyme that catalyzes the formation of asymmetric dimethyl arginine,and PRMT1 plays important regulatory roles in signal transduction,transcriptional activation,RNA splicing,and DNA repair.Aberrant expression of PRMT1 is found in many types of cancers,pulmonary diseases,cardiovascular disease,diabetes,and renal diseases.PRMT1 is a highly promising target for therapeutic development.We created a stopped flow fluorescence-based assay for PRMT1 inhibitor detection and characterization that has the advantages of being homogeneous,nonradioactive,and mix-and-measure in nature,allowing for continuous measurement of the methylation reaction and its inhibition.To our knowledge,this is the first continuous assay for PRMT1 reaction detection and inhibitor characterization.The approach is not only capable of quantitatively determining the potency(IC50)of PRMT1 inhibitors but can also distinguish cofactor-competitive inhibitors,substrate-competitive inhibitors,and mixed-type inhibitors.

Targeting BMI1 mitigates chemoresistance in ovarian cancer

Resistance to chemotherapy is a prominent clinical problem in high grade serous ovarian cancer(HGSOC).1 An inadequate understanding of adaptive signaling coupled with limited treatment options for a chemoresistant tumor are likely causes for poor outcomes.We previously reported that BMI1,a stem-cell factor is instrumental in regulating chemoresistance.2,3 However,to advance anti-BMI1 therapy from the bench to the bedside,efficacy needs to be tested in patient-derived chemoresistant HGSOC models,which is lacking.