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Abstract Background Lung cancer ranks as one of the most rapidly growing malignancies. Which is characterized by its poor prognosis and a low survival rate due to late diagnosis and limited efficacy of conventional treatments. In recent years nanotechnology has emerged as a promising frontier in the management of lung cancer, presenting novel strategies to enhance drug administration, improve therapeutic efficiency, and mitigate side effects. This research comprehensively evaluates the current state and research trends concerning the application of nanomaterials in lung cancer through bibliometric analysis. Materials and methods We employed a systematic approach by retrieving studies from the Scopus database that focused on nanomaterials and lung cancer between 2003 and 2023. Subsequently, we carefully selected relevant articles based on predetermined inclusion criteria. The selected publications were then subjected to bibliometric and visual analysis using softwares such as VOSviewer and Biblioshiny. Results A total of 3523 studies that meet inclusion criteria were selected for bibliometric analysis. We observed a progressive increase in the number of annual publications from 2003 to 2023, indicating the growing interest in this field. According to our analysis, China is the primary contributor to publication output among the countries. The “Ministry of Education of the People's Republic of China” was the most influential institution. Among the authors, "Dr. Jack A. Roth” and “Dr. Huang Leaf” had the highest number of publications and cited publications, respectively. The “International Journal of Nanomedicine” was found to be the most prolific journal in this field. Additionally, “Biomaterials” emerged as the most cited journal. Through keyword analysis, we identified five main research themes and future research directions; nono-immunotherapy and green synthesis are the hot topics in this research field. Conclusion Our study summarized the key characteristics of publications in this field and identified the most influential countries, institutions, authors, journals, hot topics, and trends related to the application of nanomaterials in lung cancer. These findings contribute to the existing body of knowledge and serve as a foundation for future research endeavors in this area. More effective efforts are needed in this field to reduce the burden of lung cancer and help achieve the United Nation’s Sustainable Development Goals.

Abstract Glioblastoma (GBM) is an aggressive form of cancer affecting the Central Nervous System (CNS) of thousands of people every year. Redox alterations have been shown to play a key role in the development and progression of these tumors as Reactive Oxygen Species (ROS) formation is involved in the modulation of several signaling pathways, transcription factors, and cytokine formation. The second-generation oral alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic drug used to treat of GBM, though patients often develop primary and secondary resistance, reducing its efficacy. Antioxidants represent promising and potential coadjutant agents as they can reduce excessive ROS formation derived from chemo- and radiotherapy, while decreasing pharmacological resistance. S-allyl-cysteine (SAC) has been shown to inhibit the proliferation of several types of cancer cells, though its precise antiproliferative mechanisms remain poorly investigated. To date, SAC effects have been poorly explored in GBM cells. Here, we investigated the effects of SAC in vitro, either alone or in combination with TMZ, on several toxic and modulatory endpoints—including oxidative stress markers and transcriptional regulation—in two glioblastoma cell lines from rats, RG2 and C6, to elucidate some of the biochemical and cellular mechanisms underlying its antiproliferative properties. SAC (1–750 µM) decreased cell viability in both cell lines in a concentration-dependent manner, although C6 cells were more resistant to SAC at several of the tested concentrations. TMZ also produced a concentration-dependent effect, decreasing cell viability of both cell lines. In combination, SAC (1 µM or 100 µM) and TMZ (500 µM) enhanced the effects of each other. SAC also augmented the lipoperoxidative effect of TMZ and reduced cell antioxidant resistance in both cell lines by decreasing the TMZ-induced increase in the GSH/GSSG ratio. In RG2 and C6 cells, SAC per se had no effect on Nrf2/ARE binding activity, while in RG2 cells TMZ and the combination of SAC + TMZ decreased this activity. Our results demonstrate that SAC, alone or in combination with TMZ, exerts antitumor effects mediated by regulatory mechanisms of redox activity responses. SAC is also a safe drug for testing in other models as it produces non-toxic effects in primary astrocytes. Combined, these effects suggest that SAC affords antioxidant properties and potential antitumor efficacy against GBM.

Our previous work demonstrated the presence of lead (Pb) and cadmium (Cd) contamination in cow milk (CM) and soy beverages (SBs) in Portugal. These metals share carcinogenic mechanisms, suggesting at least additive effects. Our goals were to assess carcinogenic risks from Pb and Cd intake detected in various CM and SB brands on the Portuguese market and to determine the relative contributions of Pb and Cd. Furthermore, we modeled different consumption scenarios for various age/body weight groups to estimate cumulative Excess Lifetime Carcinogenic Risk (ELCR). ELCR was computed by multiplying chronic daily intake by a cancer slope factor for each metal, with an ELCR > 1 × 10−4 indicating carcinogenic risk. Five CM and three SB brands posed cancer risks in children, with the highest values at 1.75 × 10−4 and 9.12 × 10−5, respectively; Pb had mean relative contributions of 87.8 ± 3.1% in CM and 54.9 ± 12.1% in SB. Carcinogenic risks were observed for children, adolescents, and adults in several CM or SB consumption scenarios, albeit at levels above typical Portuguese intakes. Strict monitoring of metal levels, such as Pb and Cd, is advised because CM is a component of many foods, including baby food.

The utilization of Cobalt (Co) has surged due to it is critical role in renewable energy technologies and other high-tech applications. Concurrently, the potential health risks associated with Co exposure have raised concerns. Previous studies, including our own, have shown that Co can impair learn and memory functions as an epigenetic hazard, even at low concentrations. In this study, we explore the mechanisms of Co-induced ferroptosis in neurodegenerative damage both in vivo and in vitro, focusing on the epigenetic regulation by N6-methyladenosine (m6A) demethylase alkB homolog 5 (ALKBH5). We identify heme oxygenase-1 (HO-1) as a direct target gene of ALKBH5, playing a crucial role in mitigating Co-induced ferroptosis. ALKBH5 deficiency affects the post-transcriptional regulation of HO-1 through m6A modification, which in turn influences mRNA’s stability, intracellular distribution, and alternative splicing, thereby enhancing susceptibility to Co-induced ferroptosis. Additionally, we discuss the potential involvement of heterogeneous nuclear ribonucleoprotein M (hnRNPM) in regulating alternative splicing of HO-1 mRNA, potentially mediated by m6A modifications. This study provides new epigenetic insights into the post-transcriptional regulatory mechanisms involved in Co-induced ferroptosis and highlights the broader implications of environmental hazards in neurodegenerative damage.

Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson's disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro, Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway.

Mercury is a toxic pollutant that poses risks to both human and environmental health, making it a pressing public health concern. This study aimed to summarize the knowledge on mercury toxicology and the biological impairments caused by exposure to mercury in experimental studies and/or diagnosis in humans. The research was conducted on the main collection of Web of Science, employing as a methodological tool a bibliometric analysis. The selected articles were analyzed, and extracted data such as publication year, journal, author, title, number of citations, corresponding author's country, keywords, and the knowledge mapping was performed about the type of study, chemical form of mercury, exposure period, origin of exposure, tissue/fluid of exposure measurement, mercury concentration, evaluation period (age), mercury effect, model experiments, dose, exposure pathway, and time of exposure. The selected articles were published between 1965 and 2021, with Clarkson TW being the most cited author who has also published the most articles. A total of 38% of the publications were from the USA. These studies assessed the prenatal and postnatal effects of mercury, emphasizing the impact of methylmercury on neurodevelopment, including motor and cognitive evaluations, the association between mercury and autism, and an evaluation of its protective effects against mercury toxicity. In observational studies, the blood, umbilical cord, and hair were the most frequently used for measuring mercury levels. Our data analysis reveals that mercury neurotoxicology has been extensively explored, but the association among the outcomes evaluated in experimental studies has yet to be strengthened. Providing metric evidence on what is unexplored allows for new studies that may help governmental and non-governmental organizations develop guidelines and policies.

Copper (Cu) is an essential trace element, however an excess is toxic due to its redox properties. Cu homeostasis therefore needs to be tightly regulated via cellular transporters, storage proteins and exporters. An imbalance in Cu homeostasis has been associated with neurodegenerative disorders such as Wilson’s disease, but also Alzheimer’s or Parkinson’s disease. In our current study, we explored the utility of using Caenorhabditis elegans (C. elegans) as a model of Cu dyshomeostasis. The application of excess Cu dosing and the use of mutants lacking the intracellular Cu chaperone atox-1 and major Cu storage protein ceruloplasmin facilitated the assessment of Cu status, functional markers including total Cu levels, labile Cu levels, Cu distribution and the gene expression of homeostasis-related genes. Our data revealed a decrease in total Cu uptake but an increase in labile Cu levels due to genetic dysfunction, as well as altered gene expression levels of Cu homeostasis-associated genes. In addition, the data uncovered the role ceruloplasmin and atox-1 play in the worm’s Cu homeostasis. This study provides insights into suitable functional Cu markers and Cu homeostasis in C. elegans, with a focus on labile Cu levels, a promising marker of Cu dysregulation during disease progression.

Huntington’s disease (HD) is a rare but progressive and devastating neurodegenerative disease characterized by involuntary movements, cognitive decline, executive dysfunction, and neuropsychiatric conditions such as anxiety and depression. It follows an autosomal dominant inheritance pattern. Thus, a child who has a parent with the mutated huntingtin (mHTT) gene has a 50% chance of developing the disease. Since the HTT protein is involved in many critical cellular processes, including neurogenesis, brain development, energy metabolism, transcriptional regulation, synaptic activity, vesicle trafficking, cell signaling, and autophagy, its aberrant aggregates lead to the disruption of numerous cellular pathways and neurodegeneration. Essential heavy metals are vital at low concentrations; however, at higher concentrations, they can exacerbate HD by disrupting glial–neuronal communication and/or causing dysbiosis (disturbance in the gut microbiota, GM), both of which can lead to neuroinflammation and further neurodegeneration. Here, we discuss in detail the interactions of iron, manganese, and copper with glial–neuron communication and GM and indicate how this knowledge may pave the way for the development of a new generation of disease-modifying therapies in HD.

Sickle cell disease (SCD) is an inherited hemoglobin disorder marked by red blood cell sickling, resulting in severe anemia, painful episodes, extensive organ damage, and shortened life expectancy. In SCD, increased iron levels can trigger ferroptosis, a specific type of cell death characterized by reactive oxygen species (ROS) and lipid peroxide accumulation, leading to damage and organ impairments. The intricate interplay between iron, ferroptosis, inflammation, and oxidative stress in SCD underscores the necessity of thoroughly understanding these processes for the development of innovative therapeutic strategies. This review highlights the importance of balancing the complex interactions among various factors and exploitation of the knowledge in developing novel therapeutics for this devastating disease.

The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association.

[This corrects the article DOI: 10.1371/journal.pone.0210248.].

Background: Manganese (Mn) and iron (Fe) are essential trace elements for humans, yet excessive exposure to Mn or Fe can accumulate in the central nervous system (CNS) and cause neurotoxicity. The purpose of this study was to investigate the effects of Mn and Fe exposure, alone or in combination, on inducing oxidative stress-induced neurological damage in rat cortical and SH-SY5Y cells, and to determine whether combined exposure to these metals increases their individual toxicity. Methods: SH-SY5Y cells and male Sprague-Dawley rats were used to observe the effects of oxidative stress-induced neurological damage induced by exposure to manganese and iron alone or in combination. To detect the expression of anti-oxidative stress-related proteins, Nrf2, HO-1, and NQO1, and the apoptosis-related proteins, Bcl2 and Bax, and the neurological damage-related protein, α-syn. To detect reactive oxygen species generation and apoptosis. To detect the expression of the rat cortical protein Nrf2. To detect the production of proinflammatory cytokines. Results: We demonstrate that juvenile developmental exposure to Mn and Fe and their combination impairs cognitive performance in rats by inducing oxidative stress causing neurodegeneration in the cortex. Mn, Fe, and their combined exposure increased the expression of ROS, Bcl2, Bax, and α-syn, activated the inflammatory factors IL-6 and IL-12, inhibited the activities of SOD and GSH, and induced oxidative stress-induced neurodegeneration both in rats and SH-SY5Y cells. Combined Mn-Fe exposure attenuated the oxidative stress induced by Mn and Fe exposure alone by increasing the expression of antioxidant factors Nrf2, HO-1, and NQO1. Conclusion: In both in vivo and in vitro studies, manganese and iron alone or in combination induced oxidative stress, leading to neuronal damage. In contrast, combined exposure to manganese and iron mitigated the oxidative stress induced by exposure to manganese and iron alone by increasing the expression of antioxidant factors. Therefore, studies to elucidate the main causes of toxicity and establish the molecular mechanisms of toxicity should help to develop more effective therapeutic modalities in the future.

Abstract Background Pre-existing metabolic diseases may predispose individuals to particulate matter (PM)-induced adverse health effects. However, the differences in susceptibility of various metabolic diseases to PM-induced lung injury and their underlying mechanisms have yet to be fully elucidated. Results Type 1 diabetes (T1D) murine models were constructed by streptozotocin injection, while diet-induced obesity (DIO) models were generated by feeding 45% high-fat diet 6 weeks prior to and throughout the experiment. Mice were subjected to real-ambient PM exposure in Shijiazhuang City, China for 4 weeks at a mean PM2.5 concentration of 95.77 µg/m3. Lung and systemic injury were assessed, and the underlying mechanisms were explored through transcriptomics analysis. Compared with normal diet (ND)-fed mice, T1D mice exhibited severe hyperglycemia with a blood glucose of 350 mg/dL, while DIO mice displayed moderate obesity and marked dyslipidemia with a slightly elevated blood glucose of 180 mg/dL. T1D and DIO mice were susceptible to PM-induced lung injury, manifested by inflammatory changes such as interstitial neutrophil infiltration and alveolar septal thickening. Notably, the acute lung injury scores of T1D and DIO mice were higher by 79.57% and 48.47%, respectively, than that of ND-fed mice. Lung transcriptome analysis revealed that increased susceptibility to PM exposure was associated with perturbations in multiple pathways including glucose and lipid metabolism, inflammatory responses, oxidative stress, cellular senescence, and tissue remodeling. Functional experiments confirmed that changes in biomarkers of macrophage (F4/80), lipid peroxidation (4-HNE), cellular senescence (SA-β-gal), and airway repair (CCSP) were most pronounced in the lungs of PM-exposed T1D mice. Furthermore, pathways associated with xenobiotic metabolism showed metabolic state- and tissue-specific perturbation patterns. Upon PM exposure, activation of nuclear receptor (NR) pathways and inhibition of the glutathione (GSH)-mediated detoxification pathway were evident in the lungs of T1D mice, and a significant upregulation of NR pathways was present in the livers of T1D mice. Conclusions These differences might contribute to differential susceptibility to PM exposure between T1D and DIO mice. These findings provide new insights into the health risk assessment of PM exposure in populations with metabolic diseases.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.

The causes of nigrostriatal cell death in idiopathic Parkinson’s disease are unknown, but exposure to toxic chemicals may play some role. We followed up here on suggestions that bacterial secondary metabolites might be selectively cytotoxic to dopaminergic neurons. Extracts from Streptomyces venezuelae were found to kill human dopaminergic neurons (LUHMES cells). Utilizing this model system as a bioassay, we identified a bacterial metabolite known as aerugine (C10H11NO2S; 2-[4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]phenol) and confirmed this finding by chemical re-synthesis. This 2-hydroxyphenyl-thiazoline compound was previously shown to be a product of a wide-spread biosynthetic cluster also found in the human microbiome and in several pathogens. Aerugine triggered half-maximal dopaminergic neurotoxicity at 3–4 µM. It was less toxic for other neurons (10–20 µM), and non-toxic (at

Reproductive disorders and infertility have become more common recently among the general population. Toxic metals are known as endocrine disruptors and as they are widespread in nature they may be linked to reproductive problems. This study was conducted as a cross-sectional study and its aim was to examine the dose–response relationship between cadmium, arsenic, mercury, chromium and nickel and serum hormone levels of testosterone (women) and estradiol and progesterone (men) using the Benchmark dose approach (BMD). Blood samples were collected from 218 women and 217 men digested in a microwave, and the levels of the tested metals were determined by atomic absorption spectrophotometry (AAS) or inductively coupled plasma-mass spectrometry (ICP-MS). Dose–response analysis was performed in PROAST software (version 70.1). The model averaging method was used to calculate the Benchmark dose interval (BMDI). A dose–response relationship has been established between all metals and hormones. The narrowest BMDI was found for the As-testosterone and Hg-testosterone. Levels estimated to produce the extra risk of testosterone serum levels disturbances of 10% were lower than median levels measured in the general population. Moreover, this research suggests the possibility of use of the BMD approach in analyzing data pool generated from extensive human-biomonitoring studies.

Curcumin is an active ingredient isolated from Curcuma longa. It has several pharmacological effects, including anticancer, anti-inflammatory, and antioxidant effects. Due to its low bioavailability, chemical structure instability, and easy oxidation, the application of curcumin has been limited. In this study, to overcome these limitations, curcumin-loaded mesoporous silica nanoparticles (Cur-MSN) were prepared, and the anticancerous effect of Cur-MSNs on head and neck cancer cells, HN5, was investigated. Transmission electron microscopy (TEM) revealed rod-shaped mesoporous nanoparticles with average particle size smaller than 100 nm. Higher cytotoxicity of Cur-MSNs was seen in treated cancer cells compared with free curcumin. The expression of Bcl-2 was significantly reduced in the presence of Cur-MSNs compared to the control (untreated HN5 cells) (p < 0.05). A 3.43-fold increase in the Bax/Bcl-2 ratio was seen in Cur-MSNs treated HN5 cells at the IC50. Cur-MSNs increased intracellular reactive oxygen species (ROS) production. Based on these novel results, we suggest that Cur-MSNs offer efficacy for cancer treatment and future studies should further characterize their properties in various experimental cancer models.

Although there are many studies on the health effects of methylmercury (MeHg) toxicity during in utero and early development, little is known about its effects on mineralized tissues present in the oral cavity, such as enamel structure. Therefore, this study evaluated the effects of MeHg exposure on the physico-chemical, ultrastructural and functional properties of mature tooth enamel. Specifically, we studied offspring of mothers exposed to MeHg during the prenatal and postnatal periods which are the developmental stages associated with tooth enamel formation. Female rats were exposed to MeHg at a dose of 40 μg/kg/day for 42 days of pregnancy and lactation. The enamel of offspring was analyzed by (1) Fourier Transform Infrared Spectroscopy and Raman to assess physicochemical composition, (2) Scanning Electron Microscopy for ultrastructural evaluation, (3) Transmitted Polarizing Light Microscopy for analysis of the enamel extracellular matrix, and (4) resistance and hardness were evaluated by microhardness. The results showed that MeHg exposure during this sensitive enamel formation period induced changes in inorganic and organic content and enamel prisms ultrastructure alterations and disturbed the organic extracellular matrix due to a decreased enamel strength. These novel findings establish for the first time that maternal exposure to MeHg pre and postnatal promoted relevant changes in mature enamel of their offspring rats.

Background: Lead contamination is a major public health concern. Previous studies have demonstrated that lead exposure could affect the hippocampus, which is a complex and heterogeneous structure composed of 12 subregions. Here, we explored volumetric and functional changes in hippocampal subfields and neuropsychological alterations after lead exposure. Methods: We performed a cross-sectional study at a smelting company between September 2020 and December 2021. Blood lead level was recorded, and neuropsychological functions were assessed by Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS). The hippocampus was segmented into 12 subfields in each hemisphere in magnetic resonance images (MRIs). Then, the effect of altered hippocampal subfield volumes on brain functions were studied by seed-based functional connectivity (FC) analysis. Finally, the relationships between the lead level with hippocampal subfield volumes and neuropsychological functions were investigated. Baseline characteristics, hippocampal subfield volumes, and FC analysis were compared between lead-exposed (≥ 300 μg/L) and the control group (≤ 100 μg/L). Results: In 76 participants, lead level positively correlated with SDS(r = 0.422) and negatively correlated with MoCA(r = −0.414), MMSE(r = −0.251), Concentration(r = −0.331), Recall(r = −0.319), Orientation(r = −0.298) and Executive Function/Visuospatial abilities(r = −0.231). Lead group (26 participants) had lower MoCA and MMSE and higher SDS than control group (23 participants). A significantly decreased volume in the left CA4 and GC-ML-DG subfields was found in the lead group compared with the control group. The left GC-ML-DG of the lead group showed a decreased FC with the bilateral postcentral gyrus. The left CA4(r = −0.409) and left GC-ML-DG (r = −0.383) volumes negatively correlated with lead level. The FC between left GC-ML-DG and left postcentral gyrus positively correlated with MoCA(r = 0.318), MMSE(r = 0.379) and Recall(r = 0.311). The FC between left GC-ML-DG and right postcentral gyrus positively correlated with MoCA(r = 0.326), Executive Function/Visuospatial abilities(r = 0.307) and Concentration(r = 0.297). Conclusion: High blood lead level was associated with neuropsychological alterations, hippocampal structural and functional changes. The left GC-ML-DG and CA4 atrophy might serve as predictive imaging markers for neurological damage associated with high lead exposure.

Manganese (Mn) is an essential trace element, but insufficient or excessive bodily amounts can induce neurotoxicity. Mn can directly increase neuronal insulin and activate insulin-like growth factor (IGF) receptors. As an important cofactor, Mn regulates signaling pathways involved in various enzymes. The IGF signaling pathway plays a protective role in the neurotoxicity of Mn, reducing apoptosis in neurons and motor deficits by regulating its downstream protein kinase B (Akt), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR). In recent years, some new mechanisms related to neuroinflammation have been shown to also play an important role in Mn-induced neurotoxicity. For example, DNA-sensing receptor cyclic GMP–AMP synthase (cCAS) and its downstream signal efficient interferon gene stimulator (STING), NOD-like receptor family pyrin domain containing 3(NLRP3)-pro-caspase1, cleaves to the active form capase1 (CASP1), nuclear factor κB (NF-κB), sirtuin (SIRT), and Janus kinase (JAK) and signal transducers and activators of the transcription (STAT) signaling pathway. Moreover, autophagy, as an important downstream protein degradation pathway, determines the fate of neurons and is regulated by these upstream signals. Interestingly, the role of autophagy in Mn-induced neurotoxicity is bidirectional. This review summarizes the molecular signaling pathways of Mn-induced neurotoxicity, providing insight for further understanding of the mechanisms of Mn.

Nowadays, there is an increased consumption of plant-based protein beverages like soy beverages (SBs) as substitutes for cow milk (CM). Both accumulate toxic metals like lead (Pb), cadmium (Cd), and manganese (Mn), which, although essential, are neurotoxic at high levels. Metals can also perturb the normal development of children. This work aimed to evaluate these metal concentrations in CM and SB purchased on the Portuguese market. After validation of the method, linearity of calibration curves, work range, detection and quantification limits, and selectivity, metals were determined in 14 CM and 14 SB brands using atomic absorption spectrometry. The values were compared between CM and SB and with permissible limit values. Soy beverages had significantly (p < 0.05) higher concentrations of Cd (5.6 ± 4.2 µg/L) and Mn (117.4 ± 30.3) µg/L) than CM (2.15 ± 1.84 µg/L and 5.93 ± 1.21 µg/L, respectively); the Pb concentrations in CM (19.3 ± 12.1 µg/L) were not significantly (p > 0.05) higher than in SB (13.4 ± 9.6 µg/L). These values were similar to other studies and close to but under permissible limit values. Nevertheless, due to the toxicity and bioaccumulation of metals, the fact that these foods are routinely ingested by all ages, mainly children, and represent key ingredients in many processed foods, including baby foods, we suggest strict surveying of metal levels in CM and SBs.

This review highlights the significant impact of air quality, specifically particulate matter (PM), on cognitive decline and age-related diseases in the elderly. Despite established links to other pathologies, such as respiratory and cardiovascular illnesses, there is a pressing need for increased attention to the association between air pollution and cognitive aging, given the rising prevalence of neurocognitive disorders. PM sources are from diverse origins, including industrial activities and combustion engines, categorized into PM10, PM2.5, and ultrafine PM (UFPM), and emphasized health risks from both outdoor and indoor exposure. Long-term PM exposure, notably PM2.5, has correlated with declines in cognitive function, with a specific vulnerability observed in women. Recently, extracellular vesicles (EVs) have been explored due to the interplay between them, PM exposure, and human aging, highlighting the crucial role of EVs, especially exosomes, in mediating the complex relationship between PM exposure and chronic diseases, particularly neurological disorders. To sum up, we have compiled the pieces of evidence that show the potential contribution of PM exposure to cognitive aging and the role of EVs in mediating PM-induced cognitive impairment, which presents a promising avenue for future research and development of therapeutic strategies. Finally, this review emphasizes the need for policy changes and increased public awareness to mitigate air pollution, especially among vulnerable populations such as the elderly.

Abstract Background Long-term exposure to fine particulate matter (PM2.5) increases susceptibility to chronic respiratory diseases, including inflammation and interstitial fibrosis. However, the regulatory mechanisms by which the immune response mediates the initiation of pulmonary fibrosis has yet to be fully characterized. This study aimed to illustrate the interplay between different cell clusters and key pathways in triggering chronic lung injuries in mice following PM exposure. Results Six-week-old C57BL/6J male mice were exposed to PM or filtered air for 16 weeks in a real-ambient PM exposure system in Shijiazhuang, China. The transcriptional profiles of whole lung cells following sub-chronic PM exposure were characterized by analysis of single-cell transcriptomics. The IL-17A knockout (IL-17A−/−) mouse model was utilized to determine whether the IL-17 signaling pathway mediated immune dysregulation in PM-induced chronic lung injuries. After 16-week PM exposure, chronic lung injuries with excessive collagen deposition and increased fibroblasts, neutrophils, and monocytes were noted concurrent with a decreased number of major classes of immune cells. Single-cell analysis showed that activation of the IL-17 signaling pathway was involved in the progression of pulmonary fibrosis upon sub-chronic PM exposure. Depletion of IL-17A led to significant decline in chronic lung injuries, which was mainly triggered by reduced recruitment of myeloid-derived suppressor cells (MDSCs) and downregulation of TGF-β. Conclusion These novel findings demonstrate that immunosuppression via the IL-17A pathway plays a critical role in the initiation of chronic lung injuries upon sub-chronic PM exposure.

Thallium (Tl) is a toxic heavy metal responsible for noxious effects in living organisms. As a pollutant, Tl can be found in the environment at high concentrations, especially in industrial areas. Systemic toxicity induced by this toxic metal can affect cell metabolism, including redox alterations, mitochondrial dysfunction, and activation of apoptotic signaling pathways. Recent focus on Tl toxicity has been devoted to the characterization of its effects at the nuclear level, with emphasis on DNA, which, in turn, may be responsible for cytogenetic damage, mutations, and epigenetic changes. In this work, we review and discuss past and recent evidence on the toxic effects of Tl at the systemic level and its effects on DNA. We also address Tl’s role in cancer and its control.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy and affected patients have poor overall survival (OS) rates. Circular RNAs (circRNAs) are a novel class of non-coding RNAs (ncRNAs) with a unique loop structure. In recent years, with the development of high-throughput RNA sequencing, many circRNAs have been identified exhibiting either up-regulation or down-regulation in AML patients compared with healthy controls. Recent studies have reported that circRNAs regulate leukemia cell proliferation, stemness, and apoptosis, both positively and negatively. Additionally, circRNAs could be promising biomarkers and therapeutic targets in AML. In this study, we present a comprehensive review of the regulatory roles and potentials of a number of dysregulated circRNAs in AML.

Vaccination campaigns played a crucial role in reducing the incidence of COVID-19. However, a scant number of studies evaluated the impact of vaccination on case fatality rates (CFRs), including in Brazil. Our study aimed to compare CFRs according to vaccination status among subjects living in Arapongas (Paraná State, Brazil), considering the age composition of the population. Several strategies adopted by the Arapongas City Hall to minimize the spread of the virus were also elaborated upon. We accessed the 2021 database of the Arapongas Municipal Health Department, in which a total of 16,437 confirmed cases and 425 deaths were reported. The CFR was calculated as the ratio between COVID-19 deaths and the number of confirmed cases. Differences in age composition between unvaccinated and fully vaccinated individuals were observed in our study. Considering that CFR is a crude indicator and is highly sensitive to the age composition of the population, we adopted the average age distribution of confirmed cases among the three vaccination statuses (unvaccinated, partially, and fully) as a standard age distribution. The age-standardized CFR for unvaccinated and fully vaccinated groups were 4.55% and 2.42%, respectively. Fully vaccinated individuals showed lower age-specific CFRs in all age groups above 60 years than unvaccinated populations. Our findings strengthen the role of vaccination as a critical measure for preventing deaths among infected people and is particularly important to the ongoing reassessment of public health interventions and policies.

Autism Spectrum Disorder (ASD), a neurodevelopmental disorder characterized by persistent deficits in social interaction and communication, manifests in early childhood and is followed by restricted and stereotyped behaviors, interests, or activities in adolescence and adulthood (DSM-V). Although genetics and environmental factors have been implicated, the exact causes of ASD have yet to be fully characterized. New evidence suggests that dysbiosis or perturbation in gut microbiota (GM) and exposure to lead (Pb) may play important roles in ASD etiology. Pb is a toxic heavy metal that has been linked to a wide range of negative health outcomes, including anemia, encephalopathy, gastroenteric diseases, and, more importantly, cognitive and behavioral problems inherent to ASD. Pb exposure can disrupt GM, which is essential for maintaining overall health. GM, consisting of trillions of microorganisms, has been shown to play a crucial role in the development of various physiological and psychological functions. GM interacts with the brain in a bidirectional manner referred to as the “Gut–Brain Axis (GBA)”. In this review, following a general overview of ASD and GM, the interaction of Pb with GM in the context of ASD is emphasized. The potential exploitation of this interaction for therapeutic purposes is also touched upon.

Titanium dioxide nanoparticles (TiO2NPs) are widely produced and used nanoparticles. Yet, TiO2NP exposure may possess toxic effects to different cells and tissues, including the brain. Recent studies significantly expanded the understanding of the molecular mechanisms underlying TiO2NP neurotoxicity implicating a number of both direct and indirect mechanisms. In view of the significant recent progress in research on TiO2NP neurotoxicity, the objective of the present study is to provide a narrative review on the molecular mechanisms involved in its neurotoxicity, with a special focus on the studies published in the last decade. The existing data demosntrate that although TiO2NP may cross blood-brain barrier and accumulate in brain, its neurotoxic effects may be mediated by systemic toxicity. In addition to neuronal damage and impaired neurogenesis, TiO2NP exposure also results in reduced neurite outgrowth and impaired neurotransmitter metabolism, especially dopamine and glutamate. TiO2NP exposure was also shown to promote α-synuclein and β-amyloid aggregation, thus increasing its toxicity. Recent findings also suggest that epigenetic effects and alterations in gut microbiota biodiversity contribute to TiO2NP neurotoxicity. Correspondingly, in vivo studies demosntrated that TiO2NPs induce a wide spectrum of adverse neurobehavioral effects, while epidemiological data are lacking. In addition, TiO2NPs were shown to promote neurotoxic effects of other toxic compounds. Here we show the contribution of a wide spectrum of molecular mechanisms to TiO2NP-induced neurotoxicity; yet, the role of TiO2NP exposure in adverse neurological outcomes in humans has yet to be fully appreciated.

Mitochondria play a crucial role in cellular respiration, ATP production, and the regulation of various cellular processes. Mitochondrial dysfunctions have been directly linked to pathophysiological conditions, making them a significant target of interest in toxicological research. In recent years, there has been a growing need to understand the intricate effects of xenobiotics on human health, necessitating the use of effective scientific research tools. Caenorhabditis elegans (C. elegans), a nonpathogenic nematode, has emerged as a powerful tool for investigating toxic mechanisms and mitochondrial dysfunction. With remarkable genetic homology to mammals, C. elegans has been used in studies to elucidate the impact of contaminants and drugs on mitochondrial function. This review focuses on the effects of several toxic metals and metalloids, drugs of abuse and pesticides on mitochondria, highlighting the utility of C. elegans as a model organism to investigate mitochondrial dysfunction induced by xenobiotics. Mitochondrial structure, function, and dynamics are discussed, emphasizing their essential role in cellular viability and the regulation of processes such as autophagy, apoptosis, and calcium homeostasis. Additionally, specific toxins and toxicants, such as arsenic, cadmium, and manganese are examined in the context of their impact on mitochondrial function and the utility of C. elegans in elucidating the underlying mechanisms. Furthermore, we demonstrate the utilization of C. elegans as an experimental model providing a promising platform for investigating the intricate relationships between xenobiotics and mitochondrial dysfunction. This knowledge could contribute to the development of strategies to mitigate the adverse effects of contaminants and drugs of abuse, ultimately enhancing our understanding of these complex processes and promoting human health.

Metabolic syndrome (MetS) is an important public health issue that affects millions of people around the world and is growing to pandemic-like proportions. This syndrome is defined by the World Health Organization (WHO) as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Moreover, the etiology of MetS is multifactorial, involving many environmental factors, including toxicant exposures. Several studies have associated MetS with heavy metals exposure, which is the focus of this review. Environmental and/or occupational exposure to heavy metals are a major risk, contributing to the development of chronic diseases. Of particular note, toxic metals such as mercury, lead, and cadmium may contribute to the development of MetS by altering oxidative stress, IL-6 signaling, apoptosis, altered lipoprotein metabolism, fluid shear stress and atherosclerosis, and other mechanisms. In this review, we discuss the known and potential roles of heavy metals in MetS etiology as well as potential targeted pathways that are associated with MetS. Furthermore, we describe how new approaches involving proteomic and transcriptome analysis, as well as bioinformatic tools, may help bring about an understanding of the involvement of heavy metals and metalloids in MetS.

The insulin-like growth factor (IGF)/insulin signaling (IIS) pathway is involved in cellular responses against intracellular divalent manganese ion (Mn2+) accumulation. As a pathway where multiple nodes utilize Mn2+ as a metallic co-factor, how the IIS signaling patterns are affected by Mn2+ overload is unresolved. In our prior studies, acute Mn2+ exposure potentiated IIS kinase activity upon physiological-level stimulation, indicated by elevated phosphorylation of protein kinase B (PKB, also known as AKT). AKT phosphorylation is associated with IIS activity; and provides direct signaling transduction input for the mammalian target of rapamycin complex 1 (mTORC1) and its downstream target ribosomal protein S6 (S6). Here, to better define the impact of Mn2+ exposure on IIS function, Mn2+-induced IIS activation was evaluated with serial concentrations and temporal endpoints. In the wild-type murine striatal neuronal line STHdh, the acute treatment of Mn2+ with IGF induced a Mn2+ concentration-sensitive phosphorylation of S6 at Ser235/236 to as low as 5 μM extracellular Mn2+. This effect required both the essential amino acids and insulin receptor (IR)/IGF receptor (IGFR) signaling input. Similar to simultaneous stimulation of Mn2+ and IGF, when a steady-state elevation of Mn2+ was established via a 24-h pre-exposure, phosphorylation of S6 also displayed higher sensitivity to sub-cytotoxic Mn2+ when compared to AKT phosphorylation at Ser473. This indicates a synergistic effect of sub-cytotoxic Mn2+ on IIS and mTORC1 signaling. Furthermore, elevated intracellular Mn2+, with both durations, led to a prolonged activation in AKT and S6 upon stimulation. Our data demonstrate that the downstream regulator S6 is a highly sensitive target of elevated Mn2+ and is well below the established acute cytotoxicity thresholds (2+ normally serves as an essential co-factor, are dually responsible for the cellular changes in exposures to real-world Mn2+ concentrations.

Background: The effect of opioids administration during lactation on nervous system has not fully understood. Objective: The aim of this study was to evaluate the buprenorphine (BUP) impact on oxidative stress indexes and apoptotic gene expression in the hippocampus of neonates exposed to this drug through breastfeeding. Methods: Lactating female rats were subcutaneously injected with BUP (1 or 0.5 mg/kg). After 28 days, the pups were anesthetized, then their hippocampus were obtained for measurement of oxidative stress parameters [glutathione (GSH), thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAC) and superoxide dismutase (SOD)] and gene expression of apoptotic indices (Bcl2, Bax and caspase 3). Results: This study showed that BUP (0.5 and 1 mg/kg) could not markedly change oxidative stress indices levels and apoptotic markers expression in the hippocampus of pups versus controls. Conclusion: This study did not find BUP effect on the apoptosis and oxidative stress indices in the hippocampus of pups born to mothers exposed to this drug during lactation.

The study investigated the effect of buprenorphine (BUP) on oxidative indices and gene expression of apoptotic molecules in the hippocampus of neonates during the fetal stage. BUP (1 or 0.5 mg/kg) was subcutaneously administrated to pregnant rat dams. After parturition, the pups were maintained to the end of breastfeeding period, then hippocampi were assessed for oxidative stress indices [glutathione (GSH), thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), total antioxidant capacity (TAC)] and mRNA expression of apoptotic markers (Bax, Bcl2 and caspase 3). Our data indicated that BUP (0.5 mg/kg) administration during gestation significantly increased GSH and TAC concentrations in the hippocampus of pups versus control group (p

Abstract Chimeric antigen receptor (CAR) - T cell therapy is a new class of cellular immunotherapies, which has made great achievements in the treatment of malignant tumors. Despite improvements in colorectal cancer (CRC) therapy, treatment of many patients fails because of metastasis and recurrence. The human epidermal growth factor receptor 2 (HER2) is a substantiated target for CAR-T therapy, and has been reported recently to be over-expressed in CRC, which may provide a potential therapeutic target for CRC treatment. Herein, HER2 was a promising target of metastatic colorectal cancer (mCRC) in CAR-T therapy as assessed by flow cytometry and tissue microarray (TMA) with 9-year survival follow-up data. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting ability against CRC cells in vitro. Moreover, through the tumor-bearing model of the NOD-Prkdcem26cd52Il2rgem26Cd22/Nju (NCG) mice, HER2 CAR-T cells showed signs of effectively preventing CRC progression in three different xenograft models. Notably, HER2 CAR-T cells displayed greater aggressiveness in HER2+ CRC in the patient-derived tumor xenograft (PDX) models and had potent immunotherapeutic capacity for mCRC in the metastatic xenograft mouse models. In conclusion, our studies provide scientific evidence that HER2 CAR-T cells represent an emerging immunotherapy for the treatment of mCRC.

Chronic exposure to elevated levels of manganese via occupational or environmental settings causes a neurological disorder known as manganism, resembling the symptoms of Parkinson’s disease, such as motor deficits and cognitive impairment. Numerous studies have been conducted to characterize manganese’s neurotoxicity mechanisms in search of effective therapeutics, including natural and synthetic compounds to treat manganese toxicity. Several potential molecular targets of manganese toxicity at the epigenetic and transcriptional levels have been identified recently, which may contribute to develop more precise and effective gene therapies. This review updates findings on manganese-induced neurotoxicity mechanisms on intracellular insults such as oxidative stress, inflammation, excitotoxicity, and mitophagy, as well as transcriptional dysregulations involving Yin Yang 1, RE1-silencing transcription factor, transcription factor EB, and nuclear factor erythroid 2-related factor 2 that could be targets of manganese neurotoxicity therapies. This review also features intracellular proteins such as PTEN-inducible kinase 1, parkin, sirtuins, leucine-rich repeat kinase 2, and α-synuclein, which are associated with manganese-induced dysregulation of autophagy/mitophagy. In addition, newer therapeutic approaches to treat manganese’s neurotoxicity including natural and synthetic compounds modulating excitotoxicity, autophagy, and mitophagy, were reviewed. Taken together, in-depth mechanistic knowledge accompanied by advances in gene and drug delivery strategies will make significant progress in the development of reliable therapeutic interventions against manganese-induced neurotoxicity.

Abstract The Epstein–Barr virus (EBV) genome encodes a cluster of 22 viral microRNAs, called miR‐BamHI‐A rightward transcripts (miR‐BARTs), which are shown to promote the development of cancer. Here, this study reports that EBV‐miR‐BART18‐3p is highly expressed in colorectal cancer (CRC) and is closely associated with the pathological and advanced clinical stages of CRC. Ectopic expression of EBV‐miR‐BART18‐3p leads to increased migration and invasion capacities of CRC cells in vitro and causes tumor metastasis in vivo. Mechanistically, EBV‐miR‐BART18‐3p activates the hypoxia inducible factor 1 subunit alpha/lactate dehydrogenase A axis by targeting Sirtuin, which promotes lactate accumulation and acetyl‐CoA production in CRC cells under hypoxic condition. Increased acetyl‐CoA utilization subsequently leads to histone acetylation of fatty acid synthase and fatty acid synthase‐dependent fat synthesis, which in turn drives de novo lipogenesis. The oncogenic role of EBV‐miR‐BART18‐3p is confirmed in the patient‐derived tumor xenograft mouse model. Altogether, the findings define a novel mechanism of EBV‐miR‐BART18‐3p in CRC development through the lipogenesis pathway and provide a potential clinical intervention target for CRC.

Cancer is one of the most severe medical conditions in the world, causing millions of deaths each year. Chemotherapy and radiotherapy are critical for treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer requires novel efficacious treatment modalities. Natural remedies offer feasible alternative options against malignancy in contrast to available synthetic medication. Selective killing of cancer cells is privileged mainstream in cancer treatment, and targeted therapy represents the new tool with the potential to pursue this aim. The discovery of innovative therapies targeting essential components of DNA damage signaling and repair pathways such as ataxia telangiectasia mutated and Rad3 related Checkpoint kinase 1 (ATR-CHK1)has offered a possibility of significant therapeutic improvement in oncology. The activation and inhibition of this pathway account for chemopreventive and chemotherapeutic activity, respectively. Targeting this pathway can also aid to overcome the resistance of conventional chemo- or radiotherapy. This review enlightens the anticancer role of natural products by ATR-CHK1 activation and inhibition. Additionally, these compounds have been shown to have chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Ideally, this review will trigger interest in natural products targeting ATR-CHK1 and their potential efficacy and safety as cancer lessening agents.

Abstract Aim and background Cancer represents a major health problem with an exceedingly high toll on the patients, their families, and the economy. Cancers are also associated with high mortality rates. Existing therapies for cancer are generally ineffective with many side effects. Method A search was conducted on Pubmed, Google Scholar, Scopus, and web of science databases, and articles related to anticancer effects of resveratrol were collected. Results Resveratrol is a natural compound that can activate the Nrf2 transcription factor. Nfr2 translocates to the nucleus and induces antioxidant gene expression. In different cell lines, resveratrol can increase apoptosis and inhibit the proliferation of cancer cells. Conclusion We found that resveratrol shows efficacy for the treatment of cancer, but due to high controversy on the Nrf2 signaling pathway and mechanisms of resveratrol action, additional studies should be conducted to better characterize its mode-of-action in cancer. Graphical Abstract

Abstract Signal transducer and activator of transcription 3 (STAT3) induces breast cancer malignancy. Recent clinical and preclinical studies have demonstrated an association between overexpressed and activated STAT3 and breast cancer progression, proliferation, metastasis, and chemoresistance. Resveratrol (RES), a naturally occurring phytoalexin, has demonstrated anti-cancer activity in several disease models. Furthermore, RES has also been shown to regulate the STAT3 signaling cascade via its anti-oxidant and anti-inflammatory effects. In the present review, we describe the STAT3 cascade signaling pathway and address the therapeutic targeting of STAT3 by RES as a tool to mitigate breast cancer.

Ambient fine particulate matter (PM2.5) is linked to an increased risk of chronic obstructive pulmonary disease (COPD) exacerbations, which significantly increase the risk of mortality in COPD patients. Identifying the subtype of COPD patients who are sensitive to environmental aggressions is necessary. Using in vitro and in vivo PM2.5 exposure models, we demonstrate that exosomal hsa_circ_0005045 is upregulated by PM2.5 and binds to the protein cargo peroxiredoxin2, which functionally aggravates hallmarks of COPD by recruiting neutrophil elastase and triggering in situ release of tumor necrosis factor (TNF)-α by inflammatory cells. The biological function of hsa_circ_0005045 associated with aggravation of COPD is validated using exosome-transplantation and conditional circRNA-knockdown murine models. By sorting the major components of PM2.5, we find that PM2.5-bound heavy metals, which are distinguishable from the components of cigarette smoke, trigger the elevation of exosomal hsa_circ_0005045. Finally, using machine learning models in a cohort with 327 COPD patients, the PM2.5 exposure-sensitive COPD patients are characterized by relatively high hsa_circ_0005045 expression, non-smoking, and group C (mMRC 0–1 (or CAT

Ginger (Zingiber officinale Roscoe), a member of the Zingiberaceae family, is one of the most popular spices worldwide, known since ancient times, and used both as a spice and a medicinal plant. The phenolic compounds found in ginger are predominantly gingerols, shogaols, and paradols. Gingerols are the major phenolic compounds found in fresh ginger and contain mainly 6-gingerol as well as 4-, 5-, 8-, 10-, and 12-gingerols. Gingerols possess a wide array of bioactivities, such as antioxidant and anticancer, among others. Regarding the different array of biological activities and published data on the mechanisms underlying its action, the complex interaction between three key events, including inflammation, oxidative stress, and immunity, appears to contribute to a plethora of pharmacological activities of this compound. Among these, the immunomodulatory properties of these compounds, which attract attention due to their effects on the immune system, have been the focus of many studies. Gingerols can alleviate inflammation given their ability to inhibit the activation of protein kinase B (Akt) and nuclear factor kappa B (NF-κB) signaling pathways, causing a decrease in proinflammatory and an increase in anti-inflammatory cytokines. However, given their low bioavailability, it is necessary to develop new and more effective strategies for treatment with gingerols. In order to overcome this problem, recent studies have addressed new drug delivery systems containing gingerols. In this review, the immunomodulatory activities of gingerol and its underlying mechanisms of action combined with the contributions of developed nanodrug delivery systems to this activity will be examined.

Lead (Pb) is a naturally occurring heavy metal, which can damage the brain and affect learning and memory. Sodium para-aminosalicylic acid (PAS-Na), a non-steroidal anti-inflammatory drug, can readily cross the blood-brain barrier. Our previous studies have found that PAS-Na alleviated Pb-induced hippocampal ultrastructural damage and neurodegeneration, but the mechanism has yet to be defined. Here, we investigated the molecular mechanisms that mediate Pb-induced apoptosis in hippocampal neurons, and the efficacy of PAS-Na in alleviating its effects. This work showed that juvenile developmental Pb exposure impaired rats cognitive ability by inducing apoptotic cell death in hippocampal neurons. Pb-induced neuronal apoptosis was accompanied by increased inositol 1,4,5-trisphosphate receptor (IP3R) expression and enhanced intracellular calcium [Ca2+]i levels, which resulted in increased phosphorylation of neuronal apoptosis signal-regulating kinase 1 (ASK1) and p38. Activation of ASK1 and p38 was blocked by IP3R inhibitor and a Ca2+ chelator. Importantly, PAS-Na treatment improved the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. In addition, PAS-Na reduced the expression of IP3R and the ensuing increase in intracellular Ca2+ and decreased the phosphorylation of ASK1 and p38 in Pb-exposed neurons. Taken together, this study demonstrates that the IP3R-Ca2+-ASK1-p38 signaling pathway mediates Pb-induced apoptosis in hippocampal neurons, and that PAS-Na, at a specific dose-range, ameliorates these changes. Collectively, this study sheds novel light on the cellular mechanisms that mediate PAS-Na efficacy, laying the groundwork for future research to examine the treatment potential of PAS-Na upon Pb poisoning.

Neurotransmitters like dopamine (DA), serotonin (SRT), γ-aminobutyric acid (GABA) and acetylcholine (ACh) are messenger molecules that play a pivotal role in transmitting excitation between neurons across chemical synapses, thus enabling complex processes in the central nervous system (CNS). Balance in neurotransmitter homeostasis is essential, and altered neurotransmitter levels are associated with various neurological disorders, e.g., loss of dopaminergic neurons (Parkinson’s disease) or altered ACh synthesis (Alzheimer’s disease). Therefore, it is crucial to possess adequate tools to assess precise neurotransmitter levels, and to apply targeted therapies. An established in vivo model to study neurotoxicity is the model organism Caenorhabditis elegans (C. elegans), as its neurons have been well characterized and functionally are analogous to mammals. We have developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method including a sample preparation assuring neurotransmitter stability, which allows a simultaneous neurotransmitter quantification of DA, SRT, GABA and ACh in C. elegans, but can easily be applied to other matrices. LC-MS/MS combined with isotope-labeled standards is the tool of choice, due to its otherwise unattainable sensitivity and specificity. Using C. elegans together with our analytically validated and verified method provides a powerful tool to evaluate mechanisms of neurotoxicity, and furthermore to identify possible therapeutic approaches.