University of North Texas System

Reactive species produced in the cell during normal cellular metabolism can chemically react with cellular biomolecules such as nucleic acids, proteins, and lipids, thereby causing their oxidative modifications leading to alterations in their compositions and potential damage to their cellular activities. Fortunately, cells have evolved several antioxidant defense mechanisms (as metabolites, vitamins, and enzymes) to neutralize or mitigate the harmful effect of reactive species and/or their byproducts. Any perturbation in the balance in the level of antioxidants and the reactive species results in a physiological condition called “oxidative stress.” A catalase is one of the crucial antioxidant enzymes that mitigates oxidative stress to a considerable extent by destroying cellular hydrogen peroxide to produce water and oxygen. Deficiency or malfunction of catalase is postulated to be related to the pathogenesis of many age-associated degenerative diseases like diabetes mellitus, hypertension, anemia, vitiligo, Alzheimer’s disease, Parkinson’s disease, bipolar disorder, cancer, and schizophrenia. Therefore, efforts are being undertaken in many laboratories to explore its use as a potential drug for the treatment of such diseases. This paper describes the direct and indirect involvement of deficiency and/or modification of catalase in the pathogenesis of some important diseases such as diabetes mellitus, Alzheimer’s disease, Parkinson’s disease, vitiligo, and acatalasemia. Details on the efforts exploring the potential treatment of these diseases using a catalase as a protein therapeutic agent have also been described.

The blood-brain barrier (BBB) has been a great hurdle for brain drug delivery. The BBB in healthy brain is a diffusion barrier essential for protecting normal brain function by impeding most compounds from transiting from the blood to the brain; only small molecules can cross the BBB. Under certain pathological conditions of diseases such as stroke, diabetes, seizures, multiple sclerosis, Parkinson's disease and Alzheimer disease, the BBB is disrupted. The objective of this review is to provide a broad overview on current strategies for brain drug delivery and related subjects from the past five years. It is hoped that this review could inspire readers to discover possible approaches to deliver drugs into the brain. After an initial overview of the BBB structure and function in both healthy and pathological conditions, this review re-visits, according to recent publications, some questions that are controversial, such as whether nanoparticles by themselves could cross the BBB and whether drugs are specifically transferred to the brain by actively targeted nanoparticles. Current non-nanoparticle strategies are also reviewed, such as delivery of drugs through the permeable BBB under pathological conditions and using non-invasive techniques to enhance brain drug uptake. Finally, one particular area that is often neglected in brain drug delivery is the influence of aging on the BBB, which is captured in this review based on the limited studies in the literature.

Chronic overnutrition creates chronic hyperglycemia that can gradually induce insulin resistance and insulin secretion impairment. These disorders, if not intervened, will eventually be followed by appearance of frank diabetes. The mechanisms of this chronic pathogenic process are complex but have been suggested to involve production of reactive oxygen species (ROS) and oxidative stress. In this review, I highlight evidence that reductive stress imposed by overflux of NADH through the mitochondrial electron transport chain is the source of oxidative stress, which is based on establishments that more NADH recycling by mitochondrial complex I leads to more electron leakage and thus more ROS production. The elevated levels of both NADH and ROS can inhibit and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH), respectively, resulting in blockage of the glycolytic pathway and accumulation of glycerol 3-phospate and its prior metabolites along the pathway. This accumulation then initiates all those alternative glucose metabolic pathways such as the polyol pathway and the advanced glycation pathways that otherwise are minor and insignificant under euglycemic conditions. Importantly, all these alternative pathways lead to ROS production, thus aggravating cellular oxidative stress. Therefore, reductive stress followed by oxidative stress comprises a major mechanism of hyperglycemia-induced metabolic syndrome.

Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).

BACKGROUND: Microbiologically contaminated drinking water is a cause of community-acquired infection, and guidelines for prevention of such infections have been established. Microbes in hospital water can also cause nosocomial infection, yet guidelines for preventing such infections do not exist. The purpose of this review is to assess the magnitude of the problem caused by waterborne nosocomial infections and to plea for immediate action for their prevention. METHODS: We conducted a MEDLINE search of the literature published between January 1, 1966, and December 31, 2001. STUDY SELECTION AND DATA EXTRACTION: Investigations in which microorganisms (other than Legionella species) caused waterborne nosocomial infections and public health agency recommendations for drinking water. RESULTS: Forty-three outbreaks of waterborne nosocomial infections have been reported, and an estimated 1400 deaths occur each year in the United States as a result of waterborne nosocomial pneumonias caused by Pseudomonas aeruginosa alone. Despite the availability of effective control measures, no clear guidelines exist for the prevention of these infections. By contrast, guidelines for the prevention of community-acquired waterborne infections are now routinely used. Hospitals caring for patients at high risk for infection do not enforce the standards of water quality recommended by US and United Kingdom public health agencies for the patients' community counterparts. CONCLUSION: Because of the seriousness of these nosocomial waterborne infections and the availability, low cost, and proven effectiveness of sterile water, we recommend that hospitalized patients at high risk for infection avoid exposure to hospital water and use sterile water instead.

Abstract In diabetes mellitus, the polyol pathway is highly active and consumes approximately 30% glucose in the body. This pathway contains 2 reactions catalyzed by aldose reductase (AR) and sorbitol dehydrogenase, respectively. AR reduces glucose to sorbitol at the expense of NADPH , while sorbitol dehydrogenase converts sorbitol to fructose at the expense of NAD + , leading to NADH production. Consumption of NADPH , accumulation of sorbitol, and generation of fructose and NADH have all been implicated in the pathogenesis of diabetes and its complications. In this review, the roles of this pathway in NADH / NAD + redox imbalance stress and oxidative stress in diabetes are highlighted. A potential intervention using nicotinamide riboside to restore redox balance as an approach to fighting diabetes is also discussed.

AbstractMesoporous silica nanoparticles (MSNs) have been widely explored as drug delivery vehicles in cell and animal studies. To move this nanoparticle platform into the clinic, however, further work needs to be done to predict and assess potential adverse reactions and side-effects to optimize for their efficacious and safe use in patients. Toxicity may be dependent on a number of characteristics, including the size, shape, surface chemistry, and charge of MSNs. Thus, altering various physical and chemical properties of MSNs, while controlling for others, should reveal important parameters necessary for biocompatibility. In this work, reports on biocompatibility of MSNs in recent years have been reviewed and the effects of size, shape, surface chemistry, and porosity highlighted. Advances in triggered release of the drug from MSN delivery systems are also discussed. This article brings together current research on MSN biocompatibility and emphasizes the need for standardized characterization of MSNs, predictive cell studies, and harmonization of animal studies by investigators in the field, to move these sophisticated nanodevices from bench to bedside.Keywords: biocompatibilitymesoporous silicananoparticles Additional informationFundingThe authors thank the University of North Texas System of College of Pharmacy for their support.

and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.

The concept of allostery has evolved in the past century. In this Editorial, we briefly overview the history of allostery, from the pre-allostery nomenclature era starting with the Bohr effect (1904) to the birth of allostery by Monod and Jacob (1961). We describe the evolution of the allostery concept, from a conformational change in a two-state model (1965, 1966) to dynamic allostery in the ensemble model (1999); from multi-subunit (1965) proteins to all proteins (2004). We highlight the current available methods to study allostery and their applications in studies of conformational mechanisms, disease, and allosteric drug discovery. We outline the challenges and future directions that we foresee. Altogether, this Editorial narrates the history of this fundamental concept in the life sciences, its significance, methodologies to detect and predict it, and its application in a broad range of living systems.

The therapeutic action of drugs is predicated on their physical engagement with cellular targets. Here we describe a broadly applicable method using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets within intact cells. Cell-permeable fluorescent tracers are used in a competitive binding format to quantify drug engagement with the target proteins fused to Nanoluc luciferase. The approach enabled us to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. Our analysis was directed particularly to the clinically approved prodrug FK228 (Istodax/Romidepsin) because of its unique and largely unexplained mechanism of sustained intracellular action. Analysis of the binding kinetics by BRET revealed remarkably long intracellular residence times for FK228 at HDAC1, explaining the protracted intracellular behaviour of this prodrug. Our results demonstrate a novel application of BRET for assessing target engagement within the complex milieu of the intracellular environment.

BACKGROUND: A benchmark of near-perfect adherence (≥95%) to antiretroviral therapy (ART) is often cited as necessary for HIV viral suppression. However, given newer, more effective ART medications, the threshold for viral suppression may be lower. We estimated the minimum ART adherence level necessary to achieve viral suppression. SETTINGS: The Patient-centered HIV Care Model demonstration project. METHODS: Adherence to ART was calculated using the proportion of days covered measure for the 365-day period before each viral load test result, and grouped into 5 categories (<50%, 50% to <80%, 80% to <85%, 85% to <90%, and ≥90%). Binomial regression analyses were conducted to determine factors associated with viral suppression (HIV RNA <200 copies/mL); demographics, proportion of days covered category, and ART regimen type were explanatory variables. Generalized estimating equations with an exchangeable working correlation matrix accounted for correlation within subjects. In addition, probit regression models were used to estimate adherence levels required to achieve viral suppression in 90% of HIV viral load tests. RESULTS: The adjusted odds of viral suppression did not differ between persons with an adherence level of 80% to <85% or 85% to <90% and those with an adherence level of ≥90%. In addition, the overall estimated adherence level necessary to achieve viral suppression in 90% of viral load tests was 82% and varied by regimen type; integrase inhibitor- and nonnucleoside reverse transcriptase inhibitor-based regimens achieved 90% viral suppression with adherence levels of 75% and 78%, respectively. CONCLUSIONS: The ART adherence level necessary to reach HIV viral suppression may be lower than previously thought and may be regimen-dependent.

Chronic hyperglycemia and the corresponding glucotoxicity are the main pathogenic mechanisms of diabetes and its complications. Streptozotocin (STZ)-induced diabetic animal models are useful platforms for the understanding of β cell glucotoxicity in diabetes. As diabetes induced by a single STZ injection is often referred to as type 1 diabetes that is caused by STZ's partial destruction of pancreas, one question often being asked is whether the STZ type 1 diabetes animal model is a good model for studying the mitochondrial mechanisms of β cell glucotoxicity. In this mini review, we provide evidence garnered from the literature that the STZ type 1 diabetes is indeed a suitable model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity. Evidence presented includes: 1) continued β cell derangement is due to chronic hyperglycemia after STZ is completely eliminated out of the body; 2) STZ diabetes can be reversed by insulin treatment, which indicates that β cell responds to treatment and shows ability to regenerate; and 3) STZ diabetes can be ameliorated or alleviated by administration of phytochemicals. In addition, mechanisms of STZ action and fundamental gaps in understanding mitochondrial mechanisms of β cell dysfunction are also discussed.

NAD(+) is a fundamental molecule in metabolism and redox signaling. In diabetes and its complications, the balance between NADH and NAD(+) can be severely perturbed. On one hand, NADH is overproduced due to influx of hyperglycemia to the glycolytic and Krebs cycle pathways and activation of the polyol pathway. On the other hand, NAD(+) can be diminished or depleted by overactivation of poly ADP ribose polymerase that uses NAD(+) as its substrate. Moreover, sirtuins, another class of enzymes that also use NAD(+) as their substrate for catalyzing protein deacetylation reactions, can also affect cellular content of NAD(+). Impairment of NAD(+) regeneration enzymes such as lactate dehydrogenase in erythrocytes and complex I in mitochondria can also contribute to NADH accumulation and NAD(+) deficiency. The consequence of NADH/NAD(+) redox imbalance is initially reductive stress that eventually leads to oxidative stress and oxidative damage to macromolecules, including DNA, lipids, and proteins. Accordingly, redox imbalance-triggered oxidative damage has been thought to be a major factor contributing to the development of diabetes and its complications. Future studies on restoring NADH/NAD(+) redox balance could provide further insights into design of novel antidiabetic strategies.

Elevated intraocular pressure (IOP) is the principal risk factor for glaucoma and results from excessive impedance of the fluid outflow from the eye. This abnormality likely originates from outflow pathway tissues such as the trabecular meshwork (TM), but the associated molecular etiology is poorly understood. We discovered what we believe to be a novel role for secreted frizzled-related protein-1 (sFRP-1), an antagonist of Wnt signaling, in regulating IOP. sFRP1 was overexpressed in human glaucomatous TM cells. Genes involved in the Wnt signaling pathway were expressed in cultured TM cells and human TM tissues. Addition of recombinant sFRP-1 to ex vivo perfusion-cultured human eyes decreased outflow facility, concomitant with reduced levels of beta-catenin, the Wnt signaling mediator, in the TM. Intravitreal injection of an adenoviral vector encoding sFRP1 in mice produced a titer-dependent increase in IOP. Five days after vector injection, IOP increased 2 fold, which was significantly reduced by topical ocular administration of an inhibitor of a downstream suppressor of Wnt signaling. Thus, these data indicate that increased expression of sFRP1 in the TM appears to be responsible for elevated IOP in glaucoma and restoring Wnt signaling in the TM may be a novel disease intervention strategy for treating glaucoma.

Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1-5 and 7 (mGlu1-5,7) highlighting key concepts ("molecular switches", signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.

According to DSM-IV, dissociative identity disorder is characterized by the existence within the person of two or more distinctly different identities or personality states that from time to time take executive control of the person's body and behavior, with accompanying amnesia (American Psychiatric Association, 1994). By retrospective patient report, dissociative identity disorder usually occurs in conjunction with severe childhood trauma (Kluft 1985; Putnam et al. 1986; Ross 1989; Ross et al. 1989a, 1990a). The disorder appears to be the most severe form of disturbance on the dissociative disorders continuum (Boon and Draijer 1993; Coons 1992; Ross 1985; Ross et al. 1992). There is evidence that dissociative identity disorder may be more prevalent than once believed in the general population (Ross 1991) and among general adult psychiatric inpatients (Latz et al. 1995; Ross et al. 1991; Saxe et al. 1993).

The pharmacology and pharmacokinetics, adverse effects, drug interactions, efficacy, and dosage and administration of the new selective serotonin reuptake inhibitors paroxetine, sertraline, and fluvoxamine are reviewed. Paroxetine, sertraline, and fluvoxamine all have large volumes of distribution and are highly bound to plasma proteins. In contrast to fluoxetine, these three drugs possess shorter elimination half-lives of approximately one day and are metabolized to clinically inactive compounds. Nausea was the most commonly reported adverse effect for all three agents. Other reported adverse effects are headache, sedation, dry mouth, insomnia, sexual dysfunction, and constipation. Because of their favorable pharmacokinetic profiles, paroxetine, sertraline, and fluvoxaetine are less likely than fluoxamine to interact with other drugs. Paroxetine has been found to be superior to placebo and equivalent to amitriptyline, imipramine, clomipramine, and doxepin in treatment of depression. Sertraline has been found to be superior to placebo and equivalent to amitriptyline in treatment of depression. Fluvoxamine has been found to be superior to placebo and equivalent to imipramine, clomipramine, desipramine, mianserin, and maprotiline in the treatment of depression. Fluvoxamine and sertraline have been shown to be superior to placebo in the treatment of obsessive-compulsive disorder. Clinical experience has demonstrated all three drugs to be effective in treatment of depression. They may be especially useful in elderly patients, in those who cannot tolerate alternative treatments, and in those who do not respond to adequate trials of other antidepressant therapies.

Animal models are useful to elucidate the etiology and pathology of glaucoma and to develop novel and more effective therapies for the disease. Because of the substantial similarities between the rodent and primate eyes, and the advances of relevant study techniques, rat and mouse models of glaucoma have recently become popular as research tools. This review surveys research techniques used in the measurement of rodent intraocular pressure, and also the evaluation of pertinent morphologic, biochemical, and functional changes in the retina, optic nerve head, and optic nerve. This review further describes in detail the individual rodent models, some of which serve as surrogate models and do not entail ocular hypertension, whereas others involve transient or chronic increases of intraocular pressure. The technical considerations and theoretical concerns of these models, their advantages, and limitations, are also discussed.

BACKGROUND: Previous reports concerning the effects of gender and age on steady-state plasma concentrations of clozapine and its major metabolites, norclozapine and clozapine-N-oxide, have been controversial. Since the frequency distribution of the plasma levels is asymmetrical and skewed to the right, the statistical methods (such as analysis of variance and regression analysis) used earlier are actually inappropriate for analyzing the effects of the variables on the concentrations and might contribute to the inconsistent results. The goal of the present study, with befitting statistics, is to measure the potential effect of dose, gender, age, and body weight on plasma levels of clozapine and its 2 major metabolites. METHOD: We retrospectively analyzed data from a therapeutic drug monitoring study for steady-state plasma clozapine, norclozapine, and clozapine-N-oxide levels that was conducted in a large group of Chinese schizophrenic inpatients (male:female ratio = 83:79; age range, 33.8 +/- 9.3 years). The daily doses of clozapine had ranged from 100 to 900 mg, with a mean +/- SD value of 379.5 +/- 142.2 mg. Plasma concentrations had been measured using high-performance liquid chromatography with ultraviolet detection. Multiple linear regression was adopted to quantify the effects of various factors on the plasma levels. The natural logarithm of the plasma level was used as the dependent variable to overcome the skewness problem. RESULTS: After adjusting the effects of gender, age, and body weight by multiple linear regression, each 1-mg increment in the daily dose could raise the clozapine level by 0.31%, norclozapine by 0.27%, and clozapine-N-oxide by 0.16%. Female patients had 34.9% higher clozapine levels and 36.3% higher norclozapine, with other variables being controlled. No sex differences were demonstrated for clozapine-N-oxide levels. Each 1-year increment in age would elevate the clozapine level by 1.1%, norclozapine by 1.0%, and clozapine-N-oxide by 1.0%. Body weight could not influence the levels of these compounds. CONCLUSION: The present results suggest that women possess higher plasma levels (about one third higher) of clozapine and norclozapine, but not the N-oxide metabolite. Each addition of 1 year in age elevated clozapine and either metabolite's levels by about 1%. Furthermore, every 1-mg increase in the daily dose raised clozapine and norclozapine concentrations by approximately 0.3%. These findings could assist clinicians in optimizing clozapine dosing strategies.

Polo-like kinase 1 (PLK1) plays key roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation, and cytokinesis. PLK1 expression and activity are strongly linked to proliferating cells. Many studies have shown that PLK1 expression is elevated in a variety of tumors, and high expression often correlates with poor prognosis. Using a variety of methods, including small-molecule inhibition of PLK1 function and/or activity, apoptosis in cancer cell lines, cell cycle arrest in normal cell lines, and antitumor activity in vivo have been observed. In the present study, we have examined the in vitro biological activity of a novel and selective thiophene benzimidazole ATP-competitive inhibitor of PLK1 and PLK3 (5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide, called compound 1). Compound 1 has low nanomolar activity against the PLK1 and PLK3 enzymes and potently inhibits the proliferation of a wide variety of tumor cell lines. In the lung adenocarcinoma cell line NCI-H460, compound 1 induces a transient G(2)-M arrest, mitotic spindle defects, and a multinucleate phenotype resulting in apoptosis, whereas normal human diploid fibroblasts arrest in G(2)-M and show little apoptosis. We also describe a cellular mechanistic assay that was developed to identify potent intracellular inhibitors of PLK1. In addition to its potential as a therapeutic agent for treating cancer, compound 1 is also a useful tool molecule for further investigation of the biological functions of PLK1 and PLK3.