The Carcinogenic Effects of Formaldehyde Occupational Exposure: A Systematic Review

Background: Formaldehyde, classified as a carcinogen in 2004, as of today is widely used in many work activities. From its classification, further studies were performed to evaluate its carcinogenicity. The aim of the systematic review is to update the evidence on occupational exposure to formaldehyde and cancer onset. Methods: The review, in accordance with the PRISMA statement, includes articles in English reporting original results of studies conducted on workers exposed to formaldehyde, considering all types of cancer, published from 1 January 2000 to 30 July 2021 and selected from the Pubmed and Scopus databases. The studies’ quality was assessed by the Newcastle–Ottawa Scale. Results: A total of 21 articles were included, conducted in different European, American, and Asian countries. The most investigated occupational areas are those characterized by a deliberate use of formaldehyde. Some studies evaluated all types of cancer, whereas others focused on specific sites such as thyroid and respiratory, lymphohematopoietic, or central nervous systems. The results showed weak associations with lung cancer, nasopharyngeal cancer, leukemia, and non-Hodgkin’s lymphoma. Conclusions: The results demonstrate the need for further original studies carried out on representative samples of workers exposed to measured levels of FA. These studies should be designed to reduce the bias due to co-exposure to other carcinogens.

Extracting temporal relationships between weakly coupled peptidergic and motoneuronal signaling: Application to Drosophila ecdysis behavior

Neuromodulators, such as neuropeptides, can regulate and reconfigure neural circuits to alter their output, affecting in this way animal physiology and behavior. The interplay between the activity of neuronal circuits, their modulation by neuropeptides, and the resulting behavior, is still poorly understood. Here, we present a quantitative framework to study the relationships between the temporal pattern of activity of peptidergic neurons and of motoneurons during Drosophila ecdysis behavior, a highly stereotyped motor sequence that is critical for insect growth. We analyzed, in the time and frequency domains, simultaneous intracellular calcium recordings of peptidergic CCAP (crustacean cardioactive peptide) neurons and motoneurons obtained from isolated central nervous systems throughout fictive ecdysis behavior induced ex vivo by Ecdysis triggering hormone. We found that the activity of both neuronal populations is tightly coupled in a cross-frequency manner, suggesting that CCAP neurons modulate the frequency of motoneuron firing. To explore this idea further, we used a probabilistic logistic model to show that calcium dynamics in CCAP neurons can predict the oscillation of motoneurons, both in a simple model and in a conductance-base model capable of simulating many features of the observed neural dynamics. Finally, we developed an algorithm to quantify the motor behavior observed in videos of pupal ecdysis, and compared their features to the patterns of neuronal calcium activity recorded ex vivo. We found that the motor activity of the intact animal is more regular than the motoneuronal activity recorded from ex vivo preparations during fictive ecdysis behavior; the analysis of the patterns of movement also allowed us to identify a new post-ecdysis phase.

Biomaterial and Therapeutic Approaches for the Manipulation of Macrophage Phenotype in Peripheral and Central Nerve Repair

Injury to the peripheral or central nervous systems often results in extensive loss of motor and sensory function that can greatly diminish quality of life. In both cases, macrophage infiltration into the injury site plays an integral role in the host tissue inflammatory response. In particular, the temporally related transition of macrophage phenotype between the M1/M2 inflammatory/repair states is critical for successful tissue repair. In recent years, biomaterial implants have emerged as a novel approach to bridge lesion sites and provide a growth-inductive environment for regenerating axons. This has more recently seen these two areas of research increasingly intersecting in the creation of ‘immune-modulatory’ biomaterials. These synthetic or naturally derived materials are fabricated to drive macrophages towards a pro-repair phenotype. This review considers the macrophage-mediated inflammatory events that occur following nervous tissue injury and outlines the latest developments in biomaterial-based strategies to influence macrophage phenotype and enhance repair.

TNFα in MS and Its Animal Models: Implications for Chronic Pain in the Disease

Multiple Sclerosis (MS) is a debilitating autoimmune disease often accompanied by severe chronic pain. The most common type of pain in MS, called neuropathic pain, arises from disease processes affecting the peripheral and central nervous systems. It is incredibly difficult to study these processes in patients, so animal models such as experimental autoimmune encephalomyelitis (EAE) mice are used to dissect the complex mechanisms of neuropathic pain in MS. The pleiotropic cytokine tumor necrosis factor α (TNFα) is a critical factor mediating neuropathic pain identified by these animal studies. The TNF signaling pathway is complex, and can lead to cell death, inflammation, or survival. In complex diseases such as MS, signaling through the TNFR1 receptor tends to be pro-inflammation and death, whereas signaling through the TNFR2 receptor is pro-homeostatic. However, most TNFα-targeted therapies indiscriminately block both arms of the pathway, and thus are not therapeutic in MS. This review explores pain in MS, inflammatory TNF signaling, the link between the two, and how it could be exploited to develop more effective TNFα-targeting pain therapies.

The KEAP1-NRF2 System in Healthy Aging and Longevity

Aging is inevitable, but the inherently and genetically programmed aging process is markedly influenced by environmental factors. All organisms are constantly exposed to various stresses, either exogenous or endogenous, throughout their lives, and the quality and quantity of the stresses generate diverse impacts on the organismal aging process. In the current oxygenic atmosphere on earth, oxidative stress caused by reactive oxygen species is one of the most common and critical environmental factors for life. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (KEAP1-NRF2) system is a critical defense mechanism of cells and organisms in response to redox perturbations. In the presence of oxidative and electrophilic insults, the thiol moieties of cysteine in KEAP1 are modified, and consequently NRF2 activates its target genes for detoxification and cytoprotection. A number of studies have clarified the contributions of the KEAP1-NRF2 system to the prevention and attenuation of physiological aging and aging-related diseases. Accumulating knowledge to control stress-induced damage may provide a clue for extending healthspan and treating aging-related diseases. In this review, we focus on the relationships between oxidative stress and aging-related alterations in the sensory, glandular, muscular, and central nervous systems and the roles of the KEAP1-NRF2 system in aging processes.

Insulin Resistance Is Associated with Multiple Chemical Sensitivity in a Danish Population-Based Study—DanFunD

Multiple chemical sensitivity (MCS) is a multisystem syndrome, and limited knowledge of its pathophysiology exists. Based on the population-based Danish cohort DanFunD, this study investigated metabolic health in people with MCS compared to individuals who did not have MCS. From 9656 cohort participants aged 18–76 years old, 1.95% were categorized as MCS individuals with comorbid functional somatic disorders (MCS + FSD, n = 188), and 1.13% were categorized as MCS without functional somatic disorders (MCS ÷ FSD, n = 109). MCS was characterized based on three criteria: the experience of symptoms upon exposure to common odors and airborne chemicals, symptoms related the central nervous systems and others organ symptoms, and significant impact on every day, social, and occupational life. The remaining study population without MCS or any other functional somatic disorders were regarded as controls. We used adjusted multiple linear regression with link-function to evaluate the associations between lipid and glucose metabolism markers and MCS. We also tested the odds ratio of metabolic syndrome in MCS. Results did not point to statistically significant associations between lipid biomarkers or metabolic syndrome and both MCS groups compared to the controls. We found that MCS individuals may be more insulin resistant and that MCS ÷ FSD may have an impaired glucose metabolism when compared to controls.

New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases

The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by the Wittig reaction, converted to aldehydes by Vilsmeier formylation, and transformed to the corresponding uncharged oximes in very high yields. Eight trans,anti- and trans,syn-isomers of oximes were tested as reactivators of nerve-agent-inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, and in silico evaluated ADME properties regarding lipophilicity and CNS activity, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.

In-Silico Molecular Docking and Pharmaco-Kinetic Activity Analysis of Potential Inhibitors against SARS-CoV-2 Spike Glycoproteins

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) is a causative agent of the potentially fatal coronavirus disease (COVID-19). Coronavirus targets the human respiratory system primarily. It can also infect the gastrointestinal, hepatic, and central nervous systems of humans, avians, bats, livestock, mice, and many other wild animals, as these are primary targets of the pathogen. This study aims to screen out the most potent inhibitor for SARS-CoV-2 (COVID-19) spike glycoproteins among the selected drugs, and computational tools have been utilized for this purpose. The selected drugs have been designed to explore their structural properties in this study by molecular orbital calculation. To inhibit the spike glycoproteins, the performance of these drugs was also examined by molecular docking calculation. In improving the performance of drugs, non-bond interactions play a significant role. To determine the chemical reactivity of all the medicines, HOMO and LUMO energy values were also calculated. The combined calculations exhibited that Ledipasvir among the selected drugs can be the most potent drug to treat SARS-CoV-2 compared to other medications.

Application of integrative physiological approach to evaluate human physiological responses to the inhalation of essential oils of Japanese citrus fruits iyokan (Citrus iyo) and yuzu (Citrus junos)

This study investigated the effects of essential oil odors from Japanese citrus fruits, iyokan (Citrus iyo) and yuzu (Citrus junos), on human psychology and both the autonomic and central nervous systems. The inhalation of both essential oils significantly increased miosis rate and fingertip temperature and could induce parasympathetic dominance by suppressing sympathetic nerve activity. Oxyhemoglobin concentration in the prefrontal cortex increased after the inhalation of yuzu essential oil and decreased after the inhalation of iyokan essential oil. Subjectively, the inhalation of both essential oils reduced the feelings of fatigue and improved the feelings of refreshment, suggesting that the effect of autonomic nervous activity might involve in these psychological changes directly. Moreover, we observed that task performance improved after inhaling yuzu essential oil, which may be due to the increase in oxyhemoglobin concentration in the prefrontal cortex.