Low Molecular Weight Agents Research Articles

Increasing the aqueous solubility of N-acyl-substituted amino acid esters using iron(II) ions as inhibitors of viral replication in vitro

New aromatic and heterocyclic derivatives of N-acylated esters of l-amino acids with aromatic carboxylic acids are proposed as antiviral low molecular weight agents. To increase the aqueous solubility of inhibitors that are insoluble in aqueous solutions, the target compounds were used as iron(II) chloride complexes. It was shown that compounds in the form of coordinated ligands are able to suppress the replication of the strain of influenza A virus resistant to adamantane. The presumed target of inhibitor compounds is viroporin M2 in the envelope of the influenza A virus. At the same time, these compounds were found to be inactive in relation to the SARS-CoV-2 coronavirus strain.

Effect of small molecular crowders on dynamics of kinesin molecular motors

Kinesin is a motor protein that can convert chemical energy of ATP hydrolysis into mechanical energy of moving processively on microtubules. Apart from the load and ATP concentration affecting the dynamics of the motor such as velocity, run length, dissociation rate, etc., the increase of solution viscosity by supplementing crowding agents of low molecular weight into the buffer can also affect the dynamics. Here, based on our proposed model for the chemomechanical coupling of the kinesin motor, a systematically theoretical study of the motor dynamics under the variation of the viscosity and load is presented. Both the load on the motor’s stalk and that on one of the two heads are considered. The theoretical results provide a consistent explanation of the available contradictory experimental results, with some showing that increasing viscosity decreases sensitively the velocity whereas others showing that increasing viscosity has little effect on the velocity. The theoretical results reproduce quantitatively the puzzling experimental data showing that under different directions of the load on the stalk, increasing viscosity has very different effects on the change of run length or dissociation rate. The theoretical results predict that in both the pure and crowded buffers the dependence of the run length on the load acting one of the two heads has very different feature from that on the load acting on the stalk.

Phenotyping occupational asthma caused by platinum salts compared with other low-molecular weight agents.

Phenotyping occupational asthma caused by platinum salts compared with other low-molecular weight agents.

Loss to 5-year follow-up in the population-based Telemark Study: risk factors and potential for bias

ObjectivesThis study aimed to characterise participants lost to follow-up and identify possible factors associated with non-participation in a prospective population-based study of respiratory health in Norway. We also aimed to...

Impact of occupational asthma on health and employment status: a long-term follow-up study

ObjectivesThe aim of this study was to assess the predictors of a favourable prognosis of occupational asthma (OA) and the employment status of patients with OA at least 2 years...

Carborane-Containing Folic Acid bis-Amides: Synthesis and In Vitro Evaluation of Novel Promising Agents for Boron Delivery to Tumour Cells.

The design of highly selective low-toxic, low-molecular weight agents for boron delivery to tumour cells is of decisive importance for the development of boron neutron capture therapy (BNCT), a modern efficient combined method for cancer treatment. In this work, we developed a simple method for the preparation of new closo- and nido-carborane-containing folic acid bis-amides containing 18-20 boron atoms per molecule. Folic acid derivatives containing nido-carborane residues were characterised by high water solubility, low cytotoxicity, and demonstrated a good ability to deliver boron to tumour cells in in vitro experiments (up to 7.0 µg B/106 cells in the case of U87 MG human glioblastoma cells). The results obtained demonstrate the high potential of folic acid-nido-carborane conjugates as boron delivery agents to tumour cells for application in BNCT.

Modeling Blood-Brain Barrier Permeability to Solutes and Drugs In Vivo.

Our understanding of the pharmacokinetic principles governing the uptake of endogenous substances, xenobiotics, and biologicals across the blood–brain barrier (BBB) has advanced significantly over the past few decades. There is now a spectrum of experimental techniques available in experimental animals and humans which, together with pharmacokinetic models of low to high complexity, can be applied to describe the transport processes at the BBB of low molecular weight agents and macromolecules. This review provides an overview of the models in current use, from initial rate uptake studies over compartmental models to physiologically based models and points out the advantages and shortcomings associated with the different methods. A comprehensive pharmacokinetic profile of a compound with respect to brain exposure requires the knowledge of BBB uptake clearance, intra-brain distribution, and extent of equilibration across the BBB. The application of proper pharmacokinetic analysis and suitable models is a requirement not only in the drug development process, but in all of the studies where the brain uptake of drugs or markers is used to make statements about the function or integrity of the BBB.

Characterizing Inflammatory Cell Asthma Associated Phenotypes in Dental Health Workers Using Cytokine Profiling.

Cytokines elicit a pro-inflammatory response by modifying the airway microenvironment in patients with acute or chronic asthma. The expression pattern of several distinct cytokines could be a useful discriminator in asthma. This study aimed to identify asthma subject groupings based on common inflammatory patterns and to determine the relationship between these identified patterns and asthma-associated clinical indices. A sub-group of 76 dental healthcare workers (HCWs) identified from a larger cross-sectional study of 454 dental HCWs in five dental institutions were evaluated further. A self-administered questionnaire elicited the health and employment history of subjects. Sera were analyzed for atopic status, latex sensitization, and 12 cytokines (IL-1β, 3, 4, 5, 6, 7, 8, 10, 12p70, eotaxin, GM-CSF, TNF-α). Pre and post-bronchodilator spirometry was performed on all HCWs. Data clustering and factor analysis were used to identify inflammatory cluster patterns of cytokines. Associations between the cytokine cluster groupings and relevant asthma-associated clinical indices were determined using multivariate logistic regression. The classification of asthma subtype based on cytokine patterns demonstrated both eosinophilic and neutrophilic inflammatory responses. Four phenotypically distinct subgroups relating to the severity of inflammation (acute or chronic) of the cell types were identified. Cytokine determinants for the neutrophilic subtype included IL-1β, 6, 8, 10, 12p70, and TNF-α whereas for the eosinophilic subtype these included IL-3, 4, 5, 7, eotaxin, and GM-CSF. The multivariate models showed a significant association between work-related chest symptoms and all four inflammatory patterns. However, stronger associations were observed for the acute neutrophilic (OR = 6.00, p < 0.05) compared to acute and chronic eosinophilic responses (OR = 4.30, p < 0.05; OR = 4.93, p < 0.05), respectively. Subjects with airway obstruction were more likely to have a mixed cellular infiltrate. The odds of work-exacerbated asthma were increased in acute or chronic eosinophilia (OR = 7.75 and 8.12; p < 0.05), respectively as well as with acute neutrophilia (OR = 6) sub-type. This study demonstrated that neutrophilic inflammatory cell asthma phenotypes coexist with eosinophilic inflammatory phenotypes suggesting a possible dual pathway for asthma in dental health workers, probably due to mixed exposures to high molecular weight (e.g., latex) and low molecular weight (e.g., acrylates) agents.

Trimellitic anhydride facilitates transepithelial permeability disrupting tight junctions in sinonasal epithelial cells

Trimellitic anhydride (TMA) is a chemical agent classified as a low molecular weight (LMW) agent causing occupational rhinitis (OR) or asthma. Although TMA is recognized as a respiratory sensitizer, the direct and non-immunologic effects of TMA remain unclear. Air- liquid interface (ALI) cultured human nasal epithelial cells (HNECs) derived from control subjects were treated with TMA, followed by measurement of the transepithelial electrical resistance (TEER), paracellular permeability of fluorescein isothiocyanate (FITC)-dextran and immunofluorescence of tight junction proteins claudin-1 and zonula occludens-1 (ZO-1). The cytotoxicity of TMA was evaluated by lactate dehydrogenase (LDH) assay. TMA at concentrations of 2 and 4 mg/mL significantly reduced the TEER within 10 min (p = 0.0177 on 2 mg/mL; p < 0.0001 on 4 mg/mL). The paracellular permeability of FITC-dextran was significantly increased upon challenge with 4 mg/mL TMA for 3 h (p = 0.0088) and 6 h (p = 0.0004). TMA treatment induced a reduction in the fluorescence intensity of claudin-1 and ZO-1 in a dose-dependent manner. LDH assay revealed 4 mg/mL TMA induced cytotoxicity only after 6 h incubation, while 1 or 2 mg/mL TMA caused no cytotoxicity. Our results suggest that TMA has a potential to penetrate the epithelial barrier by disrupting claudin-1 and ZO-1, indicating an important role for sensitization and OR development.

Receptor-Targeted Fluorescence-Guided Surgery With Low Molecular Weight Agents.

Cancer surgery remains the primary treatment option for most solid tumors and can be curative if all malignant cells are removed. Surgeons have historically relied on visual and tactile cues to maximize tumor resection, but clinical data suggest that relapse occurs partially due to incomplete cancer removal. As a result, the introduction of technologies that enhance the ability to visualize tumors in the operating room represents a pressing need. Such technologies have the potential to revolutionize the surgical standard-of-care by enabling real-time detection of surgical margins, subclinical residual disease, lymph node metastases and synchronous/metachronous tumors. Fluorescence-guided surgery (FGS) in the near-infrared (NIRF) spectrum has shown tremendous promise as an intraoperative imaging modality. An increasing number of clinical studies have demonstrated that tumor-selective FGS agents can improve the predictive value of fluorescence over non-targeted dyes. Whereas NIRF-labeled macromolecules (i.e., antibodies) spearheaded the widespread clinical translation of tumor-selective FGS drugs, peptides and small-molecules are emerging as valuable alternatives. Here, we first review the state-of-the-art of promising low molecular weight agents that are in clinical development for FGS; we then discuss the significance, application and constraints of emerging tumor-selective FGS technologies.

Occupational Asthma Caused by Quaternary Ammonium Compounds: A Multicenter Cohort Study

Quaternary ammonium compounds (QACs) are used extensively for cleaning and disinfection and have been documented in scattered reports as a cause of occupational asthma (OA) through bronchoprovocation tests (BPTs). To examine the clinical, functional, and inflammatory profile of QAC-induced OA compared with OA caused by other low-molecular weight (LMW) agents. The study was conducted in a retrospective multicenter cohort of 871 subjects with OA ascertained by a positive BPT. Subjects with QAC-induced OA (n= 22) were identified based on a positive BPT to QACs after exclusion of those challenged with cleaning products or disinfectants that contained other potential respiratory sensitizers. They were compared with 289 subjects with OA caused by other LMW agents. Most subjects with QAC-induced OA were working in the health care sector (n= 14). A twofold or greater increase in the postchallenge level of nonspecific bronchial hyperresponsiveness was recorded in eight of 11 subjects with QAC-induced OA (72.7%) and in 49.7% of those with OA caused by other LMW agents. Although sputum assessment was available in only eight subjects with QAC-induced OA, they showed a significantly greater median (interquartile) increase in sputum eosinophils (18.1% [range, 12.1% to 21.1%]) compared with those with OA caused by other LMW agents (2.0% [range, 0% to 5.2%]; P < .001). This study indicates that QAC-induced OA is associated with a highly eosinophilic pattern of airway response and provides further evidence supporting the sensitizing potential of QACs. The findings highlight the heterogeneous nature of the pathobiologic pathways involved in OA caused by LMW agents.

Inhalation Challenge Tests in Occupational Asthma: Why Are Multiple Tests Needed?

Occupational and environmental lung diseases are on the rise because of the widespread use of various toxic agents in industry. Asthma etiopathogenesis is unclear because of exposure to high and low molecular agents in workplaces. Approximately 15-25% of asthma in adults is reported to be related to occupational exposure. The prevalence of occupational asthma (OA) is predicted to be high. The difficulties in diagnosing OA results in inadequate treatment, permanent airway damage, and medicolegal and social problems. As with other occupational diseases, it is necessary to demonstrate a direct causal relationship between the suspected agent and OA. Spirometry, peak expiratory flow rate, and/or non-specific bronchial hyperresponsiveness are frequently used to show airway hyperresponsiveness at the workplace and away from work. However, there are some controversies about the specificity and sensitivity of these test methods. Furthermore, these tests do not identify the exposure agent, which could be the causative agent. Specific inhalation challenge (SIC) tests that demonstrate the direct causal relationship are currently the gold standard. However, their positive and negative predictive values have not yet been established; therefore, many low molecular weight agents could cause late or atypical reactions. Therefore, a negative SIC test cannot exclude the disease. This review describes the procedures for the SIC test and discusses the importance of using the combined test methods with the SIC test.

A prognostic model of excessive lung function decline among Québec apprentices: a cohort exposed to occupational sensitizing agents

BACKGROUND Forced expiratory volume in 1 second (FEV1) decline as a predictor of lung-related health problems is widely observed, but not fully investigated. This study aimed to develop models to predict FEV1 decline among apprentices exposed to sensitizing agents. METHODS Of 692 apprentices recruited and followed in 3.6–17.3 years, 292 were exposed to low-molecular weight agents. The analysis was restricted to 357 apprentices with complete lung function assessment at the end of their training with a minimum of 5-year follow-up. According to the American Thoracic Society guideline, a mean FEV₁ decline &gt;60 ml/year was defined as “accelerated.” Descriptive statistics and Cox regression analysis were utilized to determine its predictors. To develop the prognostic models, we used a logistic regression analysis adjusted for the follow-up duration. The accuracy of the models was quantified using calibration and discrimination measures. RESULTS Of 357 subjects, 62 (17.4%) had an excessive FEV1 decline post-apprenticeship. The questionnaire model (model 1), which included male sex, wheezing, and exposure to isocyanate or animal allergens during the apprenticeship, showed a reasonable discriminative ability (area under the receiver operating characteristics curve [AUC] of 0.67, 95% CI = 0.59–0.75). Adding the percent-predicted FEV₁ value at the end of apprenticeship significantly increased the discriminative ability of the model (model 4) (AUC = 0.762, 95% CI = 0.694–0.829) with a good calibration and reasonable internal validity. CONCLUSIONS We developed a model for accelerated lung function decline with a good accuracy and internal validity. However, external validation of the model is necessary.

Occupational Respiratory Allergy: Risk Factors, Diagnosis, and Management.

Occupational allergies are among the most common recorded occupational diseases. The skin and the upper and lower respiratory tract are the classical manifestation organs. More than 400 occupational agents are currently documented as being potential "respiratory sensitizers" and new reported causative agents are reported each year. These agents may induce occupational rhinitis (OR) or occupational asthma (OA) and can be divided into high-molecular weight (HMW) and low-molecular weight (LMW) agents. The most common occupational HMW agents are (glycol)proteins found in flour and grains, enzymes, laboratory animals, fish and seafood, molds, and Hevea brasiliensis latex. Typical LMW substances are isocyanates, metals, quaternary ammonium persulfate, acid anhydrides, and cleaning products/disinfectants. Diagnosis of occupational respiratory allergy is made by a combination of medical history, physical examination, positive methacholine challenge result or bronchodilator responsiveness, determination of IgE-mediated sensitization, and specific inhalation challenge tests as the gold standard. Accurate diagnosis of asthma is the first step to managing OA as shown above. Removal from the causative agent is of central importance for the management of OA. The best strategy to avoid OA is primary prevention, ideally by avoiding the use of and exposure to the sensitizer or substituting safer substances for these agents.

Novel approaches in occupational asthma diagnosis and management.

To describe the recent findings of the last 2 years on the epidemiology and phenotypes of occupational asthma, as well as new developments in its diagnosis and management. Data from nine longitudinal studies showed a population attributable fraction for the occupational contribution to incident asthma of 16%. The main phenotypes of occupational asthma are: occupational asthma caused by high-molecular-weight (HMW) or low-molecular-weight (LMW) agents, irritant-induced asthma and occupational asthma-chronic obstructive pulmonary disease overlap. Among the variety of causative agents of occupational asthma, food-derived components are increasingly being reported, accounting for up to 25% cases of occupational asthma and/or occupational rhinitis. Recently, a specific inhalation challenge (SIC)-independent model has been developed to calculate the probability of occupational asthma diagnosis in workers exposed to HMW agents. In this model, work-specific sensitization, bronchial hyperresponsiveness, inhaled corticosteroid use, rhinoconjunctivitis and age 40 years or less were the most relevant predictive factors. Specific IgE measurements showed a pooled sensitivity of 0.74 and a specificity of 0.71 in the diagnosis of occupational asthma for HMW agents, while a lower sensitivity (0.28) and a higher specificity (0.89) was shown for LMW agents. Cessation of exposure to workplace sensitizers is the cornerstone of management of work-related conditions. An early and precise diagnosis of occupational asthma is crucial, allowing appropriate management and implementation of preventive strategies.

ROS Scavenging Biopolymers for Anti‐Inflammatory Diseases: Classification and Formulation

AbstractReactive oxygen species (ROS), the byproducts of aerobic metabolism, is a class of crucial molecules in physiological processes, nevertheless, would induce a series of inflammatory responses when overexpression. Excessive or inappropriate inflammation contributes to a range of acute and chronic human inflammatory diseases. In recent years, ROS scavenging agents have been widely regarded as a kind of potential therapeutic substances due to their abilities of delaying and/or inhibiting the oxidative stress in physiological microenvironments. ROS scavenging biopolymers are a group of agents that commonly have strong ROS scavenging ability and pharmacokinetic potential compared to similar low molecular weight agents. In this review, the generation and clearance of ROS in physiological processes, as well as the effects of ROS inflammatory diseases are introduced. Furthermore, the classification, macromolecular structure, and scavenging mechanism of those antioxidant polymers are systematically described and discussed, which aim to provide a guiding theoretical reference of designing effectively ROS scavenging biopolymers for anti‐inflammatory disease therapy.

Occupational Exposure to Metals and Solvents: Allergy and Airway Diseases.

Occupational allergic diseases (OAD) such as occupational contact dermatitis (OCD), occupational asthma (OA), and occupational rhinitis (OR) are the most prevalent occupational diseases in industrialized countries. The purpose of this review is to provide an update about the main occupational metal and solvent exposures related to allergy and airway diseases and to discuss newly defined causative agents and industries in this field. Currently for over 400 causative agents for OA and OCD, several hundreds of agents for OR have been identified. Although many studies have reported an overall decline in OAD related to known agents after implementation of efficient and effective workplace preventive measures, the constant development of new products continuously introduces to the market potential unknown respiratory hazards. Workplace allergens are often high molecular weight (HMW) agents that are > 10kDa molecular weight and capable of eliciting IgE sensitization. Sensitizing low molecular weight (LMW) agents are often reactive chemicals. Metals and solvents are two large causative agent groups related to OADs that mainly behave as LMW (< 10kDa) sensitizers and/or irritants. Avoidance of causative exposures through control strategies is the primary prevention approach for OADs. These strategies must be applied and covered for all known and newly defined causative agents. This review aims to summarize current status of known occupational metal and solvent exposures related to allergy and airway diseases and to discuss newly defined causative agents and industries in this field.

Innate lymphoid cells in isocyanate-induced asthma: role of microRNA-155.

Occupational asthma, induced by workplace exposures to low molecular weight agents such as toluene 2,4-diisocyanate (TDI), causes a significant burden to patients and society. Little is known about innate lymphoid cells (ILCs) in TDI-induced asthma. A critical regulator of ILC function is microRNA-155, a microRNA associated with asthma. To determine whether TDI exposure modifies the number of ILCs in the lung and whether microRNA-155 contributes to TDI-induced airway inflammation and hyperresponsiveness. C57BL/6 wild-type and microRNA-155 knockout mice were sensitised and challenged with TDI or vehicle. Intracellular cytokine expression in ILCs and T-cells was evaluated in bronchoalveolar lavage (BAL) fluid using flow cytometry. Peribronchial eosinophilia and goblet cells were evaluated on lung tissue, and airway hyperresponsiveness was measured using the forced oscillation technique. Putative type 2 ILCs (ILC2) were identified in bronchial biopsies of subjects with TDI-induced occupational asthma using immunohistochemistry. Human bronchial epithelial cells were exposed to TDI or vehicle. TDI-exposed mice had higher numbers of airway goblet cells, BAL eosinophils, CD4+ T-cells and ILCs, with a predominant type 2 response, and tended to have airway hyperresponsiveness. In TDI-exposed microRNA-155 knockout mice, inflammation and airway hyperresponsiveness were attenuated. TDI exposure induced IL-33 expression in human bronchial epithelial cells and in murine lungs, which was microRNA-155 dependent in mice. GATA3+CD3- cells, presumably ILC2, were present in bronchial biopsies. TDI exposure is associated with increased numbers of ILCs. The proinflammatory microRNA-155 is crucial in a murine model of TDI asthma, suggesting its involvement in the pathogenesis of occupational asthma due to low molecular weight agents.

Progress in Occupational Asthma.

Occupational asthma (OA) represents one of the major public health problems due to its high prevalence, important social and economic burden. The aim of this review is to summarize current data about clinical phenotypes, biomarkers, diagnosis and management of OA, a subtype of work-related asthma. Most studies have identified two phenotypes of OA. One is sensitizer-induced asthma, occuring after a latency period and caused by hypersensitivity to high- or low-molecular weight agents. The other is irritant-induced asthma, which can occur after one or more exposures to high concentrations of irritants without latency period. More than 400 agents causing OA have been identified and its list is growing fast. The best diagnostic approach for OA is a combination of clinical history and objective tests. An important tool is a specific inhalation challenge. Additional tests include assessments of bronchial hyperresponsiveness to methacholine/histamine in patients without airflow limitations, monitoring peak expiratory flow at- and off-work, sputum eosinophil count, exhaled nitric oxide measurement, skin prick tests with occupational allergens and serum specific IgE. Treatment of OA implies avoidance of exposure, pharmacotherapy and education. OA is a heterogeneous disease. Mechanisms of its different phenotypes, their diagnosis, role of new biomarkers and treatment require further investigation.

Entanglement Locking in the Unique Elasticity of Polydimethylsiloxane Rubbers

AbstractThe viscoelasticity behavior of the polydimethylsiloxane (PDMS) rubber blends of high molecular weight polymers modified by low molecular weight agents is studied in compression mode by stress–strain curves, the creep and step‐strain, and dynamic‐mechanical experiments. The strain spectra highlight the dynamics of active chains at high frequencies and of dangling ends in the low frequencies field. At low deformation, the blending agent enhances the elastic properties by increasing the density of the active chains in the rubber network, in agreement with the classical theories of elasticity. At high deformation, in analogy with the rheological studies on similar liquid blends, the Entanglement Locking model is proposed: the short chains of the blending agent are adsorbed on entanglement sites of long dangling chains, giving effective crosslinks via high entropy dynamics. In this way, the long‐term entanglement locking enhances the density of active chains and elastic behavior. At high deformation, the entanglement locking model enriches the rubber elasticity theories according to the tube network model and Mooney–Rivlin equation. The models herein and the possibility they offer for improving rubber viscoelasticity are valuable for the development of polymer physics and technology.