Role of oxidative stress in the pathology and management of human tuberculosis

Copyright © 2018 Madhur D. Shastri et al. Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols and especially infects the alveolar macrophages in the lungs. The lung has evolved various biological mechanisms, including oxidative stress (OS) responses, to counteract TB infection. M. tuberculosis infection triggers the generation of reactive oxygen species by host phagocytic cells (primarily macrophages). The development of resistance to commonly prescribed antibiotics poses a challenge to treat TB; this commonly manifests as multidrug resistant tuberculosis (MDR-TB). OS and antioxidant defense mechanisms play key roles during TB infection and treatment. For instance, several established first-/second-line antitubercle antibiotics are administered in an inactive form and subsequently transformed into their active form by components of the OS responses of both host (nitric oxide, S-oxidation) and pathogen (catalase/peroxidase enzyme, EthA). Additionally, M. tuberculosis has developed mechanisms to survive high OS burden in the host, including the increased bacterial NADH/NAD+ ratio and enhanced intracellular survival (Eis) protein, peroxiredoxin, superoxide dismutases, and catalases. Here, we review the interplay between lung OS and its effects on both activation of antitubercle antibiotics and the strategies employed by M. tuberculosis that are essential for survival of both drug-susceptible and drug-resistant bacterial subtypes. We then outline potential new therapies that are based on combining standard antitubercular antibiotics with adjuvant agents that could limit the ability of M. tuberculosis to counter the host's OS response

CSTX-1, a toxin from the venom of the hunting spider Cupiennius salei, is a selective blocker of L-type calcium channels in mammalian neurons

The inhibitor cystine-knot motif identified in the structure of CSTX-1 from Cupiennius salei venom suggests that this toxin may act as a blocker of ion channels. Whole-cell patch-clamp experiments performed on cockroach neurons revealed that CSTX-1 produced a slow voltage-independent block of both mid/low- (M-LVA) and high-voltage-activated (HVA) insect Cav channels. Since C. salei venom affects both insect as well as rodent species, we investigated whether Cav channel currents of rat neurons are also inhibited by CSTX-1. CSTX-1 blocked rat neuronal L-type, but no other types of HVA Cav channels, and failed to modulate LVA Cav channel currents. Using neuroendocrine GH3 and GH4 cells, CSTX-1 produced a rapid voltage-independent block of L-type Cav channel currents. The concentration-response curve was biphasic in GH4 neurons and the subnanomolar IC50 values were at least 1000-fold lower than in GH3 cells. L-type Cav channel currents of skeletal muscle myoballs and other voltage-gated ion currents of rat neurons, such as INa(v) or IK(v) were not affected by CSTX-1. The high potency and selectivity of CSTX-1 for a subset of L-type channels in mammalian neurons may enable the toxin to be used as a molecular tool for the investigation of this family of Cav channels. © 2007 Elsevier Ltd. All rights reserved

Emerging concepts and directed therapeutics for the management of asthma: regulating the regulators.

Asthma is a common, heterogeneous and serious disease, its prevalence has steadily risen in most parts of the world, and the condition is often inadequately controlled in many patients. Hence, there is a major need for new therapeutic approaches. Mild-to-moderate asthma is considered a T-helper cell type-2-mediated inflammatory disorder that develops due to abnormal immune responses to otherwise innocuous allergens. Prolonged exposure to allergens and persistent inflammation results in myofibroblast infiltration and airway remodelling with mucus hypersecretion, airway smooth muscle hypertrophy, and excess collagen deposition. The airways become hyper-responsive to provocation resulting in the characteristic wheezing and obstructed airflow experienced by patients. Extensive research has progressed the understanding of the underlying mechanisms and the development of new treatments for the management of asthma. Here, we review the basis of the disease, covering new areas such as the role of vascularisation and microRNAs, as well as associated potential therapeutic interventions utilising reports from animal and human studies. We also cover novel drug delivery strategies that are being developed to enhance therapeutic efficacy and patient compliance. Potential avenues to explore to improve the future of asthma management are highlighted

Evaluation of chemical strategies for improving the stability and oral toxicity of insecticidal peptides

© 2018 by the authors. Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been hampered due to concerns about potential lack of stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies to increase the stability and oral potency of the potent insecticidal spider-venom peptide !-HXTX-Hv1a (Hv1a). Selective chemical replacement of disulfide bridges with diselenide bonds and N- to C-terminal cyclization were anticipated to improve Hv1a resistance to proteolytic digestion, and thereby its activity when delivered orally. We found that native Hv1a is orally active in blowflies, but 91-fold less potent than when administered by injection. Introduction of a single diselenide bond had no effect on the susceptibility to scrambling or the oral activity of Hv1a. N- to C-terminal cyclization of the peptide backbone did not significantly improve the potency of Hv1a when injected into blowflies and it led to a significant decrease in oral activity. We show that this is likely due to a dramatically reduced rate of translocation of cyclic Hv1a across the insect midgut, highlighting the importance of testing bioavailability in addition to toxin stability

Modular and predictable assembly of porous organic molecular crystals

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules

The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders.

Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders

Survey of attitudes, materials and methods employed in endodontic treatment by general dental practitioners in North Jordan

BACKGROUND: General dental practitioners provide the majority of endodontic treatment in Jordan. The aim of this study was to gather information on the methods, materials and attitudes employed in root canal treatment by dentists in North Jordan, in order to evaluate and improve the quality of current practice. METHODS: A questionnaire was posted to all registered general dental practitioners working in private practice in Irbid Governate in North Jordan (n = 181). The questionnaire included information on methods, materials and techniques used in endodontic treatment. RESULTS: Reply rate was 72% (n = 131). The results demonstrated that only five dentists used rubber dam occasionally and not routinely. The majority used cotton rolls for isolation solely or in combination with a high volume saliva ejector (n = 116). The most widely used irrigants were sodium hypochlorite and hydrogen peroxide, which were used by 32.9% (n = 43) and 33.6% (n = 44) of the respondents, respectively. Forty eight percent of the respondents (n = 61) used the cold lateral condensation technique for canal obturation, 31.3% (n = 41) used single cone, 9.9% (n = 13) used vertical condensation and 12.2% (n = 16) used paste or cement only for the obturation. The majority used zinc oxide eugenol as a sealer (72.5%). All, but one, respondents used hand instruments for canal preparation and the technique of choice was step back (52.7%). More than 50% (n = 70) of the dentists took one radiograph for determining the working length, whilst 22.9% (n = 30) did not take any radiograph at all. Most practitioners performed treatment in three visits for teeth with two or more root canals, and in two visits for teeth with a single root canal. CONCLUSIONS: This study indicates that dentists practicing in North Jordan do not comply with international quality standards and do not use recently introduced techniques. Many clinicians never take a radiograph for determining the working length and never used rubber dam or intra-canal medicaments

Clinical and physiological effects of transcranial electrical stimulation position on motor evoked potentials in scoliosis surgery

<p>Abstract</p> <p>Background</p> <p>During intraoperative monitoring for scoliosis surgery, we have previously elicited ipsilateral and contralateral motor evoked potentials (MEP) with cross scalp stimulation. Ipsilateral MEPs, which may have comprised summation of early ipsilaterally conducted components and transcallosally or deep white matter stimulated components, can show larger amplitudes than those derived purely from contralateral motor cortex stimulation. We tested this hypothesis using two stimulating positions. We compared intraoperative MEPs in 14 neurologically normal subjects undergoing scoliosis surgery using total intravenous anesthetic regimens.</p> <p>Methods</p> <p>Trancranial electrical stimulation was applied with both cross scalp (C3C4 or C4C3) or midline (C3Cz or C4Cz) positions. The latter was assumed to be more focal and result in little transcallosal/deep white matter stimulation. A train of 5 square wave stimuli 0.5 ms in duration at up to 200 mA was delivered with 4 ms (250 Hz) interstimulus intervals. Averaged supramaximal MEPs were obtained from the tibialis anterior bilaterally.</p> <p>Results</p> <p>The cross scalp stimulating position resulted in supramaximal MEPs that were of significantly higher amplitude, shorter latency and required lower stimulating intensity to elicit overall (Wilcoxon Signed Rank test, p < 0.05 for all), as compared to the midline stimulating position. However, no significant differences were found for all 3 parameters comparing ipsilaterally and contralaterally recorded MEPs (p > 0.05 for all), seen for both stimulating positions individually.</p> <p>Conclusions</p> <p>Our findings suggest that cross scalp stimulation resulted in MEPs obtained ipsilaterally and contralaterally which may be contributed to by summation of ipsilateral and simultaneous transcallosally or deep white matter conducted stimulation of the opposite motor cortex. Use of this stimulating position is advocated to elicit MEPs under operative circumstances where anesthetic agents may cause suppression of cortical and spinal excitability. Although less focal in nature, cross scalp stimulation would be most suitable for infratentorial or spinal surgery, in contrast to supratentorial neurosurgical procedures.</p

Narratives for drug design

We explore the role of narratives of complex systems in anti-cancer drug design. We set out the value of narratives relating to cancer in promoting awareness of risky behaviour and in supporting decision-making regarding treatment options. We present cancer as a dysregulated, complex system that has emergent behaviours at multiple scales, and is governed by dynamical spatio-temporal processes. We show that this system changes structure and function in response to anti-cancer drugs, and explain that these changes are sufficiently complex to impede effective drug design. We pose what narrative might offer to support the process of drug design, providing an example of work done to date that might serve as a foundation for narrating complexity. We suggest ways of using this work combined with that of others to begin to consider narrating drug design