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Schizophrenia (SCH) and bipolar disorder (BD) are two of the most important psychiatric pathologies due to their high population incidence and disabling power, but they also present, mainly in their debut, high clinical similarities that make their discrimination difficult. In this work, the differential oxidative stress, present in both disorders, is shown as a concatenator of the systemic alterations—both plasma and erythrocyte, and even at the level of peripheral blood mononuclear cells (PBMC)—in which, for the first time, the different affectations that both disorders cause at the level of the cellular interactome were observed. A marked erythrocyte antioxidant imbalance only present in SCH generalizes to oxidative damage at the plasma level and shows a clear impact on cellular involvement. From the alteration of protein synthesis to the induction of death by apoptosis, including proteasomal damage, mitochondrial imbalance, and autophagic alteration, all the data show a greater cellular affectation in SCH than in BD, which could be linked to increased oxidative stress. Thus, patients with SCH in our study show increased endoplasmic reticulum (ER)stress that induces increased proteasomal activity and a multifactorial response to misfolded proteins (UPR), which, together with altered mitochondrial activity, generating free radicals and leading to insufficient energy production, is associated with defective autophagy and ultimately leads the cell to a high apoptotic predisposition. In BD, however, oxidative damage is much milder and without significant activation of survival mechanisms or inhibition of apoptosis. These clear differences identified at the molecular and cellular level between the two disorders, resulting from progressive afflictions in which oxidative stress can be both a cause and a consequence, significantly improve the understanding of both disorders to date and are essential for the development of targeted and preventive treatments. [ABSTRACT FROM AUTHOR]

Gastrointestinal diseases exert a profound impact on global health, leading to millions of healthcare interventions and a significant number of fatalities annually. This, coupled with escalating healthcare expenditures, underscores the need for identifying and addressing potential exacerbating factors. One emerging concern is the pervasive presence of microplastics and nano-plastics in the environment, largely attributed to the indiscriminate usage of disposable plastic items. These nano-plastics, having infiltrated our food chain, pose a potential threat to gastrointestinal health. To understand this better, we co-cultured human gastric fibroblasts (HGF) with polystyrene nano-plastics (PS-NPs) of diverse sizes (80, 500, 650 nm) and meticulously investigated their cellular responses over a 24-hour period. Our findings revealed PS particles were ingested by the cells, with a notable increase in ingestion as the particle size decreased. The cellular death induced by these PS particles, encompassing both apoptosis and necrosis, showcased a clear dependence on both the particle size and its concentration. Notably, the larger PS particles manifested more potent cytotoxic effects. Further analysis indicated a concerning reduction in cellular membrane potential, alongside a marked increase in ROS levels upon PS particles exposure. This suggests a significant disruption of mitochondrial function and heightened oxidative stress. The larger PS particles were especially detrimental in causing mitochondrial dysfunction. In-depth exploration into the PS particles impact on genes linked with the permeability transition pore (PTP) elucidated that these PS particles instigated an internal calcium rush. This surge led to a compromise in the mitochondrial membrane potential, which in tandem with raised ROS levels, further catalyzed DNA damage and initiated cell death pathways. In essence, this study unveils the intricate mechanisms underpinning cell death caused by PS particles in gastric epithelial cells and highlighting the implications of PS particles on gastrointestinal health. The revelations from this research bear significant potential to shape future healthcare strategies and inform pertinent environmental policies.

Three-dimensional (3D) cell culture systems are reported to be more physiologically similar to the in vivo state than 2-dimensional (2D) models, which are extensively employed in periodontal research. Herein, we developed a 3D gingival tissue model with both epithelial and lamina propria layers using human gingival epithelial Ca9-22 cells and primary gingival fibroblasts. The epithelial layer of the developed 3D gingival tissue culture was treated with butyrate, a metabolite of oral bacteria, and the treatment induced the release of damage-associated molecular patterns, such as DNA and Sin3A associated protein 130 kDa (SAP130). Taken together, butyrate exposure to the epithelium of 3D gingival epithelial-connective tissue hybrid systems could induce epithelial cell death and the subsequent release of damage-associated molecular patterns.

Dental plaque bacteria produce high concentrations of short-chain fatty acids (SCFAs), as bacterial metabolites. SCFA-treated gingival epithelial cells undergo cell death. Our previous reports demonstrated that butyrate-induced cell death depends on autophagy and reactive oxygen species (ROS). However, the precise mechanisms underlying SCFA-induced gingival epithelial cell death is poorly understood. Butyrate is a strong histone deacetylase (HDAC) inhibitor. Therefore, we determined the involvement of HDAC inhibitory activity in SCFA-induced gingival epithelial cells. Ca9-22 cells were used as an in vitro counterpart of gingival epithelial cells. Ca9-22 cells were treated with HDAC inhibitors in the presence or absence of C646, a P300 histone acetyltransferase (HAT) inhibitor, and compared the number of dead cells, which are measured using SYTOX Green dye. Acetylation levels of histone H3 were examined using western blotting. Changes in transcriptomes during the butyrate and C646 treatment were examined using RNA sequencing analysis. The butyrate or propionate-treatment of Ca9-22 cells induced acetylation of histone H3, while the C646 treatment strongly reduced the elevated acetylation levels. Accordingly, butyrate or propionate-induced cell death was inhibited by the C646 treatment. Similar results were obtained when other HDAC inhibitors were used. Whole transcriptome analysis revealed that the expression of numerous genes was altered by butyrate-induced histone acetylation. Moreover, some autophagy and ROS-related genes found in the altered genes might induce cell death. This study suggests the need for HDAC-inhibitory activity of bacterial metabolites to induce cell death, and the effects might enhance autophagy and ROS production. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) cell culture systems are reported to be more physiologically similar to the in vivo state than 2-dimensional (2D) models, which are extensively employed in periodontal research. Herein, we developed a 3D gingival tissue model with both epithelial and lamina propria layers using human gingival epithelial Ca9-22 cells and primary gingival fibroblasts. The epithelial layer of the developed 3D gingival tissue culture was treated with butyrate, a metabolite of oral bacteria, and the treatment induced the release of damage-associated molecular patterns, such as DNA and Sin3A associated protein 130 kDa (SAP130). Taken together, butyrate exposure to the epithelium of 3D gingival epithelial-connective tissue hybrid systems could induce epithelial cell death and the subsequent release of damage-associated molecular patterns. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCH) and bipolar disorder (BD) are two of the most important psychiatric pathologies due to their high population incidence and disabling power, but they also present, mainly in their debut, high clinical similarities that make their discrimination difficult. In this work, the differential oxidative stress, present in both disorders, is shown as a concatenator of the systemic alterations—both plasma and erythrocyte, and even at the level of peripheral blood mononuclear cells (PBMC)—in which, for the first time, the different affectations that both disorders cause at the level of the cellular interactome were observed. A marked erythrocyte antioxidant imbalance only present in SCH generalizes to oxidative damage at the plasma level and shows a clear impact on cellular involvement. From the alteration of protein synthesis to the induction of death by apoptosis, including proteasomal damage, mitochondrial imbalance, and autophagic alteration, all the data show a greater cellular affectation in SCH than in BD, which could be linked to increased oxidative stress. Thus, patients with SCH in our study show increased endoplasmic reticulum (ER)stress that induces increased proteasomal activity and a multifactorial response to misfolded proteins (UPR), which, together with altered mitochondrial activity, generating free radicals and leading to insufficient energy production, is associated with defective autophagy and ultimately leads the cell to a high apoptotic predisposition. In BD, however, oxidative damage is much milder and without significant activation of survival mechanisms or inhibition of apoptosis. These clear differences identified at the molecular and cellular level between the two disorders, resulting from progressive afflictions in which oxidative stress can be both a cause and a consequence, significantly improve the understanding of both disorders to date and are essential for the development of targeted and preventive treatments.

Phytophthora nicotianae is a devastating pathogen in citrus and tolerant rootstocks are required for its management. Seven Jatti Khatti (JK, a rough lemon strain; susceptible) × Poncirus trifoliata (PT; tolerant) hybrids were screened against P. nicotianae. In feeder root rot based evaluation, three hybrids were found moderately tolerant (MT) while four were moderately susceptible (MS). The H 2 O 2 in plant pathogen interactions contributes in resistance/susceptibility to the biotrophic/necrotrophic pathogens. To comprehend its role in citrus against Phytophthora (a hemi-biotrophic pathogen), H 2 O 2 , lipid peroxidation, and peroxidase (POD) activity were determined in Phytophthora inoculated and non-inoculated roots of JK, PT, three MT and one MS hybrids at 10, 20 and 30 days post inoculation (dpi). The tolerant parent, PT and MT hybrids exhibited lower or stable H 2 O 2 content in Phytophthora inoculated plants at 20 or 30-dpi. Their POD activity increased at 10-dpi, depicting its role in H 2 O 2 homoeostasis. At 30-dpi, JK and MS hybrid showed significantly higher H 2 O 2 content (4.10 and 3.62 μmol g−1 FW), compared to 1.88 μmol g−1 FW in PT. The lipid peroxidation content significantly increased in JK or MS hybrid at 20 or 30-dpi. The susceptible or MS individuals displayed significantly higher (18–25 % higher) electrolyte leakage than their control. A strong positive association (r = 0.89) was found between electrolytes leakage and H 2 O 2 accumulation at 30-dpi. The POD activity and H 2 O 2 at 10-dpi showed strong negative correlation (r = −0.86). Results infer that high H 2 O 2 causes cellular death and contributes to Phytophthora susceptibility in citrus. It can serve as a biomarker for predicting relative sensitivity to Phytophthora. • Three citrus hybrids with moderate tolerance to Phytophthora nicotianae identified. • Oxidative stress (H 2 O 2 , MDA, peroxidase activity) examined in citrus under P. nicotianae infection. • Susceptible genotypes showed higher H 2 O 2 accumulation than tolerant ones. • Tolerant genotype recorded initial higher peroxidase activity. [ABSTRACT FROM AUTHOR]

Inhaled particulate matter (PM) is a key factor in millions of yearly air pollution-related deaths worldwide. The oxidative potential of PM indicates its ability to promote an oxidative environment. Excessive reactive oxygen species (ROS) can cause cell damage via oxidative stress, leading to inflammation, endoplasmic reticulum stress, airway remodeling, and various cell death modes (apoptosis, ferroptosis, pyroptosis). ROS can also interact with macromolecules, inducing DNA damage and epigenetic modifications, disrupting homeostasis. These effects have been studied extensively in vitro and confirmed in vivo. This review explores the oxidative potential of airborne particles and PM-induced ROS-mediated cellular damage observed in vitro, highlighting the link between oxidative stress, inflammation, and cell death modes described in the latest literature. The review also analyzes the effects of ROS on DNA damage, repair, carcinogenicity, and epigenetics. Additionally, the latest developments on the potential of antioxidants to prevent ROS's harmful effects are described, providing future perspectives on the topic. [ABSTRACT FROM AUTHOR]

Etnopharmacological Relevance: Lantana camara L. is a species known for its broad spectrum of bioactivities and is commonly used in folk therapy to address inflammatory, dermatological, gastrointestinal, intestinal worms and protozoan diseases. It boasts a diverse array of secondary metabolites such as terpenes, flavonoids, and saponins. However, despite its rich chemical profile, there remains a scarcity of studies investigating its antileishmanial properties., Aim of the Study: This research aims to explore the antileishmanial potential of L. camara, focusing also on its mechanism of action against Leishmania amazonensis., Material and Methods: The ethanolic extract of L. camara leaves (LCE) was obtained through static maceration, and its phytoconstituents were identified using UFLC-QTOF-MS. The colorimetric MTT method was conducted to determine the effect of LCE on promastigotes of L. amazonensis and murine macrophages. The anti-amastigote activity was evaluated by counting intracellular parasites in macrophages after Giemsa staining. Additionally, investigations into the mechanisms underlying its action were conducted using cellular and biochemical approaches., Results: LCE exhibited significant activity against both promastigotes and intracellular amastigotes of L. amazonensis, with IC 50 values of 12.20 μg/mL ± 0.12 and 7.09 μg/mL ± 1.24, respectively. These IC 50 values indicate very promising antileishmanial activity, comparable to those found for the positive control miltefosine (5.10 μg/mL ± 1.79 and 8.96 μg/mL ± 0.50, respectively). Notably, LCE exhibited negligible cytotoxicity on macrophages (IC 50  = 223.40 μg/mL ± 47.02), demonstrating selectivity towards host cells (SI = 31.50). The antileishmanial activity of LCE involved a multi-targeted cell death process, characterized by morphological and ultrastructural alterations observed through SEM and TEM analyses, as well as oxidative effects evidenced by the inhibition of trypanothione reductase, elevation of ROS and lipid levels, and mitochondrial dysfunction evaluated using DTNB, H 2 DCFDA, Nile red, and JC-1 assays. Additionally, extraction of ergosterol and double labeling with annexin V and PI revealed modifications to the organization and permeability of the treated parasite's plasma membrane. LCE was found to consist predominantly of terpenes, with lantadenes A, B, and C being among the eleven compounds identified through UFLC-QTOF-MS analysis., Conclusions: The extract of L. camara presents a diverse array of chemical constituents, prominently featuring high terpene content, which may underlie its antileishmanial properties through a combination of apoptotic and non-apoptotic mechanisms of cell death induced by LCE. This study underscores the therapeutic potential of L. camara as a candidate for antileishmanial treatment, pending further validation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The knowledge regarding the neurological and behavioral toxic effects associated with microplastics (MPs) and heavy metals exposure is still scarce. The present study aimed to evaluate the potential chronic (30 days) toxic effects of MPs (2 mg/L) and copper (Cu, 25 µg/L), alone or combined, in the zebrafish (Danio rerio) brain antioxidant system, cell proliferation/death, cholinergic-, serotonergic- and dopaminergic pathways and, consequently, in locomotor, anxiety, and social behaviors.Our findings showed that MPs and Cu exposure modulated the antioxidant system of zebrafish brain, with superoxide dismutase (SOD) and glutathione reductase (GR) having higher activity in the Cu25 +MPs group, but glutathione peroxidase (GPx) being inhibited in MPs, Cu25 and Cu25 +MPs. Moreover, an increase in acetylcholinesterase (AChE) activity was observed in all exposed groups. When considering neurogenesis genes, a downregulation of proliferating cell nuclear antigen (pcna) was noticed in zebrafish exposed to the mixture treatment, while for dopaminergic system-related genes (th and slc6a3) an upregulation was observed in MPs, Cu25 and Cu25 +MPs groups. An increase in apoptosis-related genes expression (casp8, casp9 and casp3) was observed in the MPs exposed group. Changes in zebrafish behavior, particularly in mean speed, total distance moved, inactivity in the aquaria, and social/shoaling behavior was also observed in the MPs and Cu exposed groups. Overall, our results highlight the multiplicity of toxic effects of MPs, alone or combined with Cu, in zebrafish brain, namely apoptosis and alterations in adult neurogenesis, neurocircuits and, consequently, behavior.

MicroRNA-29a (miR-29a) has been suggested to serve a potential protective function against Parkinson's disease (PD); however, the exact molecular mechanisms remain elusive. This study explored the protective role of miR-29a in a cellular model of PD using SH-SY5Y cell lines through iTRAQ-based quantitative proteomic and biochemistry analysis. The findings showed that using a miR-29a mimic in SH-SY5Y cells treated with 1-methyl-4-phenylpyridinium (MPP+) significantly decreased cell death and increased mitochondrial membrane potential. It also reduced mitochondrial reactive oxygen species (ROS) and the production of α-synuclein. Subsequent heatmap analysis using iTRAQ-based quantitative proteomics revealed remarkably contrasting protein expression profiles for 882 genes when comparing the groups treated with miR-29a mimic plus MPP + against the control group treated solely with MPP+. The KEGG pathway analysis of these 882 genes indicated the substantial role of miR-29a in the PD pathway (P = 1.58x10−5) and highlighted its function in mitochondrial genes. Furthermore, treatment with a miR-29a mimic in SH-SY5Y cells reduced the levels of GSK-3β, phosphorylated GSK-3β, and cleaved caspase-7 following exposure to MPP+. The miR-29a mimic also upregulated the expressions of α-synuclein clearance proteins FYCO1 and Rab7 in this cellular PD model, thereby inhibiting the production of α-synuclein. Luciferase activity analysis confirmed the specific binding of miR-29a to the 3′ untranslated region (3′UTR) of GSK-3β, leading to its repression. Our findings demonstrated miR-29a′s neuroprotective role in mitochondrial function and highlighted its potential to inhibit ROS and α-synuclein production, offering possible therapeutic avenues for PD treatment. • miR-29a reduces cell death and ROS production and lowers α-synuclein levels following MPP+ exposure in SH-SY5Y cells. • MiR-29a specifically binds to the 3′UTR of GSK-3β, resulting in the repression of its expression. • miR-29a shows promise as a neuroprotective agent, potentially improving Parkinson's disease treatments. [ABSTRACT FROM AUTHOR]

To evaluate the concentration of hyaluronan acid and proliferation/cellular death in mammary gland of ovariectomized female rat after estroprogestative therapy. Forty ovariectomized female rats were divided into four groups with 10 animals/each: OG (vehicle); EG: (Estradiol, 7 days of treatment), PG (Progesterone acetate, 23 days of treatment), and EPG: (Estradiol, 7 days of treatment, and next Progesterone acetate, 23 days of treatment). Twenty-four hours after the last treatment, all animals were euthanized, the mammary gland removed, then, a fragment was immersed in acetone to quantifying of the hyaluronan acid biochemical method (ELISA-Like fluorometric assay), and a fragment fixed for 24 h in 10% formaldehyde in phosphate-buffered saline (PBS) processed for immunohistochemistry method for detection of the cell marker proliferation (Ki67) and cellular marker death by DNA fragmentation the TUNEL method. The estradiol-treatment alone (EG) or associated with progesterone (EPG) affected the concentration of hyaluronan acid, increased cell proliferation, and decreased cell death compared to OG and PG (p <.05) in the mammary tissue. Our results suggest that the excessive reduction of HA in mammary tissue, as occurred with progesterone treatment, can lead to a breakdown of the extracellular matrix. These changes may be indicative of mammary pathology such as the development of tumor. [ABSTRACT FROM AUTHOR]

Swine enteric coronaviruses, such as porcine epidemic diarrhea virus (PEDV) or transmissible gastroenteritis virus (TGEV), have risen concern for the porcine industry and research community due to the increase in their virulence, their potential recombination capacity and the emergence of new variants. This in vivo study aims to compare the impact of three different strains of swine enteric coronaviruses [(two G1b (S-INDEL) PEDV strains and a recombinant TGEV-PEDV or Swine enteric coronavirus (SeCoV)] in the intestine of 3-weeks-old infected piglets, focusing on the pathology and main components of the intestinal barrier, including the number of goblet cells, and the expression of IgA as well as FoxP3, a regulatory T cell marker. Severity of lesions was evidenced in the three infected groups and was highly correlated with the viral load in feces and the frequency of viral antigen-positive cells. Furthermore, higher cellular death together with an increase in the expression of the FoxP3 marker was detected in the duodenum and jejunum of infected animals at 3 days post-infection. Our results highlight a recruitment of FoxP3+ cells in the small intestine of infected animals which may represent a response to the tissue damage caused by viral replication and cell death. Further studies should be addressed to determine the potential role of these cells during swine enteric coronavirus infections. • Swine enteric coronaviruses have risen concern for the porcine industry. • The immunopathogenesis of three strains of swine coronavirus was investigated. • Similar lesions, high tropism and cellular death were found in all infected groups. • FoxP3+ cells could be controlling the inflammation and the tissue damage caused by viral replication. [ABSTRACT FROM AUTHOR]

Carbon nanotubes represent one of the best examples of novel nanostructures, exhibit a range of extraordinary physical properties, strong antimicrobial activity and can pierce bacterial cell walls. This investigation handles the antimicrobial activity of functionalised multiwall carbon nanotubes (F‐MWNTs) as an alternative antimicrobial material compared to the commercial antibiotics. Antibacterial activities of F‐MWNTs are investigated through two different kinds of bacteria, E. coli and S. aureus. The results demonstrate that the best concentration of F‐MWNTs for the maximum inhibition and antibacterial functionality is 80 and 60 μg/ml for E. coli and S. aureus, respectively. The transmission electron microscope reveals the morphological changes damage mechanism for the cellular reliability on these microorganisms. F‐MWNTs are capable of biologically isolating the cell from their microenvironment, contributing to the development of toxic substances and placing the cell under oxidative stress leading to cellular death. The efficiency of F‐MWNTs is compared with the common antibiotics and shows an enhancement in the inhibitory effect with percentages reaches 85%. To account for the bactericidal performance of F‐MWNTs towards these pathogens, the dielectric conductivity and the bacterial growth measurements are conducted. The present study endeavour that F‐MWNTs could be exploited in biomedical devices and altering systems for hospital and industrial cleaning applications. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most widespread form of dementia, characterized by memory loss and reduction of cognitive functions that strongly interfere with normal daily life. Numerous evidences show that aggregates of the amyloid beta peptide, formed by 39 to 42 amino acid residues (Aβ39–43), from soluble small oligomers to large fibrils are characteristic markers of this pathology. However, AD is a complex disease and its neurodegenerative molecular mechanism is not yet fully understood. Growing evidence suggests a link between Aβ polymorphic nature, oligomers and fibrils, and specific mechanisms of neurodegeneration. The Aβ variable nature and its multiplicity of interactions with different proteins and organelles reflect the complexity of this pathology. In this review, we analyze the effects of the interaction between Aβ peptide and different cellular compartments in relation to the different kinds and sizes of amyloid aggregates. In particular, Aβ interaction with different cell structures such as the plasma membrane, mitochondria, lysosomes, nucleus, and endoplasmic reticulum is discussed. Further, we analyze the Aβ peptide ability to modify the structure and function of the target organelle, inducing alteration of its physiological role thus contributing to the pathological event. Dysfunction of cellular components terminating with the activation of the cellular death mechanism and subsequent neurodegeneration is also taken into consideration. [ABSTRACT FROM AUTHOR]

Cytoplasmic TDP-43 aggregates are a hallmark of amyotrophic lateral sclerosis (ALS). Today, only two drugs are available for ALS treatment, and their modest effect prompts researchers to search for new therapeutic options. TDP-43 represents one of the most promising targets for therapeutic intervention, but reliable and reproducible in vitro protocols for TDP-43-mediated toxicity are lacking. Here, we used HEK293T cells transfected with increasing concentrations of TDP-43-expressing plasmid to evaluate different parameters of toxicity and alterations in cellular metabolism. Overexpression of TDP-43 induced aggregates occurrence followed by the detection of 25- and 35-kDa forms of TDP-43. TDP-43 overexpression decreased cell viability and increased cells arrested at G2/M phase and nuclear fragmentation. Analysis of the energetic metabolism showed a tendency to decrease oxidative phosphorylation and increase glycolysis, but no statistical differences were observed. Metabolomics revealed alterations in different metabolites (mainly sphingolipids and glycerophospholipids) in cells overexpressing TDP-43. Our data reveal the main role of TDP-43 aggregation in cellular death and highlight novel insight into the mechanism of cellular toxicity induced by TDP-43. Here, we provide a simple, sensitive, and reliable protocol in a human-derived cell line to be used in high-throughput screenings of potential therapeutic molecules for ALS treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cells internalized PS-NPs through phagocytosis, with the content of PS-NPs increasing over time. • As the size of PS-NPs decreased, their uptake by HGF correspondingly increased. • Larger PS-NPs exhibited a more pronounced toxic effect on mitochondrial function. • Cell death modalities differed based on the size and concentration of PS-NPs. Gastrointestinal diseases exert a profound impact on global health, leading to millions of healthcare interventions and a significant number of fatalities annually. This, coupled with escalating healthcare expenditures, underscores the need for identifying and addressing potential exacerbating factors. One emerging concern is the pervasive presence of microplastics and nano-plastics in the environment, largely attributed to the indiscriminate usage of disposable plastic items. These nano-plastics, having infiltrated our food chain, pose a potential threat to gastrointestinal health. To understand this better, we co-cultured human gastric fibroblasts (HGF) with polystyrene nano-plastics (PS-NPs) of diverse sizes (80, 500, 650 nm) and meticulously investigated their cellular responses over a 24-hour period. Our findings revealed PS particles were ingested by the cells, with a notable increase in ingestion as the particle size decreased. The cellular death induced by these PS particles, encompassing both apoptosis and necrosis, showcased a clear dependence on both the particle size and its concentration. Notably, the larger PS particles manifested more potent cytotoxic effects. Further analysis indicated a concerning reduction in cellular membrane potential, alongside a marked increase in ROS levels upon PS particles exposure. This suggests a significant disruption of mitochondrial function and heightened oxidative stress. The larger PS particles were especially detrimental in causing mitochondrial dysfunction. In-depth exploration into the PS particles impact on genes linked with the permeability transition pore (PTP) elucidated that these PS particles instigated an internal calcium rush. This surge led to a compromise in the mitochondrial membrane potential, which in tandem with raised ROS levels, further catalyzed DNA damage and initiated cell death pathways. In essence, this study unveils the intricate mechanisms underpinning cell death caused by PS particles in gastric epithelial cells and highlighting the implications of PS particles on gastrointestinal health. The revelations from this research bear significant potential to shape future healthcare strategies and inform pertinent environmental policies. [ABSTRACT FROM AUTHOR]

Available cancer therapies are limited due to undesirable side effects, non-specific cellular toxicity as well as treatment failure. Therefore, there is urgent need for newer treatment strategies. In this study, we comparatively determined the in vitro anti-cancer potential of inorganic nanoparticles (NPs) in MDA-MB-231 cancer cells. Flow cytometry, confocal microscopy, and reactive oxygen species (ROS) assays were employed to probe likely mechanism of anti-cancer action of NPs. Study demonstrated dose-dependent toxicity of NPs to MDA-MB-231 cells. The NPs promoted production of ROS and might have caused early apoptotic clearance of MDA-MB-231 cells. Considered together, the findings support anti-cancer potential of inorganic NPs. Furthermore, preliminary evidence suggests that the anti-cancer potential of these NPs may be linked with capacity to cause ROS production as well as cellular apoptosis. Further studies to clearly define the mechanistic cellular actions of these nanoparticles are warranted. [ABSTRACT FROM AUTHOR]

Abstract Neonates can develop hypoxic-ischaemic encephalopathy (HIE) due to lack of blood supply or oxygen, resulting in a major cause of death and disability among term newborns. However, current definitive treatment of therapeutic hypothermia, will only benefit one out of nine babies. Furthermore, the mechanisms of HIE and therapeutic hypothermia are not fully understood. Recently, microRNAs (miRNAs) have become of interest to many researchers due to their important role in post-transcriptional control and deep evolutionary history. Despite this, role of miRNAs in newborns with HIE remains largely unknown due to limited research in this field. Therefore, this review aims to understand the role of miRNAs in normal brain development and HIE pathophysiology with reliance on extrapolated data from other diseases, ages and species due to current limited data. This will provide us with an overview of how miRNAs in normal brain development changes after HIE. Furthermore, it will indicate how miRNAs are affected specifically or globally by the various pathophysiological events. In addition, we discuss about how drugs and commercially available agents can specifically target certain miRNAs as a mechanism of action and potential safety issue with off-target effects. Improving our understanding of the role of miRNAs on the cellular response after HIE would enhance the success of effective diagnosis, prognosis, and treatment of newborns with HIE. Highlights • MicroRNAs are important in normal newborn brain development and during brain injury, especially cell death and inflammation. • The changes involving microRNAs in newborn brain injury are complex due to the additional ongoing newborn brain development. • MicroRNAs are potential targets for treatment of brain injury in newborns. [ABSTRACT FROM AUTHOR]

Treating the gingival epithelial Ca9-22 cell with butyrate, a short-chain fatty acid (SCFA) produced by bacteria within mature dental plaque, induces necrotic cellular death. In this report, it was examined whether SCFA-mediated cellular death is accompanied by a release of damage-associated molecular patterns (DAMPs). In addition, the role of reactive oxygen species (ROS) in the release of DAMPs was evaluated. Human gingival epithelial Ca9-22 cells were treated with butyrate or propionate. The amounts of dead cells were then measured using SYTOX-green dye. Released DAMPs were detected by western blot. The role of ROS scavengers, ascorbic acid and N-acetylcysteine, on DAMP-release was evaluated. Dose and time-dependent induction of Ca9-22 cell death was observed during butyrate and propionate treatments. This was accompanied by the release of DAMPs. Ascorbic acid or N-acetylcysteine reduced cellular death and inhibited DAMP-release induced by exposure to butyrate or propionate. These data collectively suggest that SCFA-induced death of gingival epithelial Ca9-22 cells and accompanying release of DAMPs are dependent on ROS. [ABSTRACT FROM AUTHOR]

• PET-MFs exposure at 500 MFs/mL induced increased mortality in D. carinata. • 50 MFs/mL exposure caused mitochondrial damage, apoptosis and oxidative stress. • Apoptosis and ferroptosis pathway induced the injury of PET-MFs to D. carinata. With the widespread utilization of plastic products, microplastics (MPs) have merged as a newfound environmental contaminant in the United States, and the bulk of these MPs in the environment manifest as fibrous structures. Concerns have also been voiced regarding the potential hazards posed by microplastic fibers (MFs). However, research examining the toxicity of MFs, particularly in relation to planktonic organisms, remains severely limited. Meanwhile, polyester fiber materials find extensive applications across diverse industries. As a result, this investigation delved into the toxicology of polyester microplastic fibers (PET-MFs) with a focus on their impact on Daphnia carinata (D. carinata), a freshwater crustacean. Newly hatched D. carinata were subjected to varying concentrations of PET-MFs (0, 50, and 500 MFs/mL) to scrutinize the accumulation of PET-MFs within these organisms and their resultant toxicity. The outcomes revealed that D. carinata was capable of ingesting PET-MFs, leading to diminished rates of survival and reproduction. These effects were accompanied by mitochondrial impairment, heightened mitochondrial count, apoptosis, escalated generation of reactive oxygen species, augmented activity of antioxidant enzymes, and distinct patterns of gene expression. Interestingly, when comparing the group exposed to 50 MFs/mL with the one exposed to 500 MFs/mL, it was observed that the former triggered a more pronounced degree of mitochondrial damage, apoptosis, and oxidative stress. This phenomenon could be attributed to the fact that brief exposure to 500 MFs/mL resulted in greater mortality, eliminating individuals with lower adaptability. Those that survived managed to regulate elevated in vivo reactive oxygen species levels through an increase in glutathione S-transferase content, thereby establishing an adaptive mechanism. Low concentrations did not induce direct mortality, yet PET-MFs continued to inflict harm within the organism. RNA-seq analysis unveiled significant alterations in 279 and 55 genes in the 50 MFs/mL and 500 MFs/mL exposure groups, respectively. Functional enrichment analysis of the 50 MFs/mL group indicated involvement of the apoptosis pathway and ferroptosis pathway in the toxic effects exerted by PET-MFs on D. carinata. This study imparts valuable insights into the toxicological ramifications of PET-MFs on D. carinata , underscoring their potential risks within aquatic ecosystems. [ABSTRACT FROM AUTHOR]

Health risks which result from exposure to pesticides have sparked awareness among researchers, triggering the idea of developing nanoencapsulation pesticides with the aim to enhance cytoprotection as well as genoprotection of the pesticides. In addition, nanocapsules of pesticides have slow release capability, high bioavailability, and site-specific delivery, which has attracted great interest from researchers. Hence, the objective of this work is to synthesize a nanoformulation of a fungicide of different sizes, namely, chitosan-hexaconazole nanoparticles (18 nm), chitosan-dazomet nanoparticles (7 nm), and chitosan-hexaconazole-dazomet nanoparticles (5 nm), which were then subjected to toxicological evaluations, including cytotoxicity, genotoxicity, cell death assay, and dermal irritation assays. Incubation of chitosan-based nanofungicides with V79-4 hamster lung cell did not reveal cytotoxicity or genotoxicity, potentially suggesting that encapsulation with chitosan reduces direct toxicity of the toxic fungicides. Meanwhile, pure fungicide revealed its high cytotoxic effect on V79-4 hamster lung cells. In addition, dermal exposure assessment on rabbits revealed that chitosan-hexaconazole nanoparticles are classified under corrosive subcategory 1C, while chitosan-dazomet nanoparticles are classified under corrosive subcategory 1B. Moreover, both chitosan-hexaconazole nanoparticles and chitosan-dazomet nanoparticles are classified as causing mild irritation.

Cytoplasmic TDP-43 aggregates are a hallmark of amyotrophic lateral sclerosis (ALS). Today, only two drugs are available for ALS treatment, and their modest effect prompts researchers to search for new therapeutic options. TDP-43 represents one of the most promising targets for therapeutic intervention, but reliable and reproducible in vitro protocols for TDP-43-mediated toxicity are lacking. Here, we used HEK293T cells transfected with increasing concentrations of TDP-43-expressing plasmid to evaluate different parameters of toxicity and alterations in cellular metabolism. Overexpression of TDP-43 induced aggregates occurrence followed by the detection of 25- and 35-kDa forms of TDP-43. TDP-43 overexpression decreased cell viability and increased cells arrested at G2/M phase and nuclear fragmentation. Analysis of the energetic metabolism showed a tendency to decrease oxidative phosphorylation and increase glycolysis, but no statistical differences were observed. Metabolomics revealed alterations in different metabolites (mainly sphingolipids and glycerophospholipids) in cells overexpressing TDP-43. Our data reveal the main role of TDP-43 aggregation in cellular death and highlight novel insight into the mechanism of cellular toxicity induced by TDP-43. Here, we provide a simple, sensitive, and reliable protocol in a human-derived cell line to be used in high-throughput screenings of potential therapeutic molecules for ALS treatment.

Purpose: Bone metastases are a common cause of cancer-related pain. The aim of this study is to determine the optimal radiotherapy schedule for the treatment of painful bone metastases and verify if could cause different biological effects on bone. This has been achieved using functional Magnetic Resonance Imaging (MRI) with diffusion-weighted imaging (DWI).Patients and Methods: Fifteen patients received Multiple Fractions Radiation Therapy (MFRT) with a total dose of 30Gy in 10 daily fractions of 3Gy given over 2 weeks and 15 patients received a Single Fraction Radiation Therapy (SFRT) with a dose of 8Gy. Quantitative Apparent Diffusion Coefficient (ADC) values after SFRT or MFRT were compared with response to treatment (pain relief), assessed by Visual Analogue Scale (VAS) before radiotherapy and at 1 and 3 months after the completion of treatment.Results: The two schedules had equal efficacy in terms of pain control, without any difference at 1 and 3 months post radiotherapy. In both treatments, pain reduction was related to an increase in the ADC. However, the median ADC value had an increase of 575 points between the baseline and 3 months (from 1010 to 1585, p=0.02) in the 30Gy group, while it was only 178 points (from 1417 to 1595) in the 8Gy group.Conclusions: The increase in the ADC values after radiotherapy corresponds to increased cell death. Despite an equal pain control, MFRT treatment seems to be more effective to achieve cancer cells kill. Our preliminary data could also explain the higher retreatment rates in SFRT vs MFRT in long survivors. [ABSTRACT FROM AUTHOR]

In this study, we report the synthesis and structural characterization of a series of thiosemicarbazone and 4-thiazolidinones derivatives, as well as their in vitro antiproliferative activity against eight human tumor cell lines. For the most potent compound further studies were performed evaluating cell death induction, cell cycle profile, ctDNA interaction and topoisomerase IIα inhibition. A synthetic three-step route was established for compounds ( 2a-e and 3a-d ) with yields ranging from 32 to 95%. Regarding antiproliferative activity, compounds 2a-e and 3a-d showed mean GI 50 values ranging between 1.1 μM ( 2b ) - 84.65 μM ( 3d ). Compound 2b was the most promising especially against colorectal adenocarcinoma (HT-29) and leukemia (K562) cells (GI 50 = 0.01 μM for both cell lines). Mechanism studies demonstrated that 24 h-treatment with compound 2b (5 μM) induced phosphatidylserine residues exposition and G2/M arrest on HT-29 cells. Moreover, 2b (50 μM) was able to interact with ctDNA and inhibited topoisomerase IIα activity. These results demonstrate the importance of thiosemicarbazone, especially the derivative 2b , as a promising candidate for anticancer therapy. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) primarily affects the motor system and is the second most common age-related neurodegenerative disorder after Alzheimer's disease. Mitochondrial complex I deficiency and functional abnormalities are implicated in the development of PD. MicroRNA-29a (miR-29a) has emerged as a critical miRNA in PD. This study aims to investigate the protective role of miR-29a in MPP+ in SH-SY5Y cell lines in vitro PD model by targeting mitochondrial antiviral signaling protein (MAVS). Administration of MPP + inhibited miR-29a expression in SH-SY5Y cell lines. Our findings prove that miR-29a mimic treatment decreased cell death, ROS production, MAVS, p-IRF3, p-NFκBp65, IL-6, cleaved caspase-3, cleaved-PARP, LC3BII, and death while increasing glutathione peroxidase 1 and manganese superoxide dismutase after MPP + treatment in SH-SY5Y cells. Furthermore, MAVS expression was significantly corrected with the above genes in our in vitro model of PD. Luciferase activity analysis also confirmed that miR-29a specific binding 3′UTR of MAVS repressed expression. In conclusion, this research provides novel insight into a neuroprotective pathway of miR-29a and could thus serve as a possible therapeutic target for improving the treatment of PD. • miR-29a mimic treatment decreased cell death, ROS production, MAVS-, IL-6, cleaved caspase-3, LC3BII, and death, while increasing glutathione peroxidase 1 and manganese superoxide dismutase after MPP + treatment in SH-SY5Y cells. • Luciferase activity analysis also confirmed that miR-29a specific binding 3′UTR of MAVS repressed expression. • miR-29a can serve as a neuroprotective and therapeutic target for improving the treatment of PD. [ABSTRACT FROM AUTHOR]

SIRT3 belongs to a highly conserved protein family of histone deacetylases and it is rich in mitochondria. As acetyl-modification is one of the important post-translational modifications that prevail in the mitochondria, it is not surprising that SIRT3 plays a key regulatory role in this organelle. SIRT3 has a wide range of substrates that are involved in the physiological and pathological processes of oxidative stress, ischemia–reperfusion injury, mitochondrial metabolism homeostasis and cellular death. These pathophysiological processes are considered as the underlying mechanisms of diseases like cardiac hypertrophy, myocardial infarction and heart failure, indicating the potential roles of SIRT3 in cardiovascular diseases. In this review, we will summarize the emerging roles and therapeutic implications of SIRT3 in cardiovascular diseases by providing an update on the latest understanding of its functions. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurodegenerative disorder, primarily affecting dopaminergic neurons in the substantia nigra. There is currently no cure for PD and present medications aim to alleviate clinical symptoms, thus prevention remains the ideal strategy to reduce the prevalence of this disease. The goal of this study was to investigate whether oleuropein (OLE), the major phenolic compound in olive derivatives, may prevent neuronal degeneration in a cellular dopaminergic model of PD, differentiated PC12 cells exposed to the potent parkinsonian toxin 6-hydroxydopamine (6-OHDA). We also investigated OLE's ability to mitigate mitochondrial oxidative stress and modulate the autophagic flux. Our results obtained by measuring cytotoxicity and apoptotic events demonstrate that OLE significantly decreases neuronal death. OLE could also reduce mitochondrial production of reactive oxygen species resulting from blocking superoxide dismutase activity. Moreover, quantification of autophagic and acidic vesicles in the cytoplasm alongside expression of specific autophagic markers uncovered a regulatory role for OLE against autophagic flux impairment induced by bafilomycin A1. Altogether, our results define OLE as a neuroprotective, anti-oxidative and autophagy-regulating molecule, in a neuronal dopaminergic cellular model. [ABSTRACT FROM AUTHOR]

Yessotoxin (YTX) is a polyether compound produced by dinoflagellates and accumulated in filter feeding shellfish. No records about human intoxications induced by this compound have been published, however it is considered a toxin. Modifications in second messenger levels, protein levels, immune cells, cytoskeleton or activation of different cellular death types have been published as consequence of YTX exposure. This review summarizes the main intracellular pathways modulated by YTX and their pharmacological and therapeutic implications. [ABSTRACT FROM AUTHOR]

The effluent of the ornamental rock industry is characterized by presenting great concentrations of total solids, high contents of iron, and elevated pH, all responsible for the contamination of the superficial and ground waters, destruction of the soil, the vegetation, and the silting of the rivers. The purpose of this study is to assess the cytotoxic and genotoxic effects and the anatomical changes caused by the effluents arising from the ornamental rock polishing industry in root apex cells of Allium cepa L. (Amaryllidaceae). The samples of the effluent were collected in a polishing industry located in Nova Venécia, State of Espírito Santo, and were analyzed by mass spectrometry and atomic emission. Bulbs of A. cepa were exposed to the effluent at 12.5, 25, 37.5, 50, 75, and 100 % concentrations (residue in raw form) ( v/ v) for a period of 20 days. For the positive control, metilmethanesulfonate (MMS) at 4 × 10-M concentration was used, and distilled water was used for the negative control. The experiment was assessed taking into consideration the following parameters: mitotic index, frequency of chromosomal and nuclear abnormalities in the root apical meristem, and root anatomy. The mitotic index suffered a decrease proportional to the increase in the concentration of effluent. All the concentrations of the effluent led to chromosomal and nuclear abnormalities being stickiness and nuclear shoots the most frequent. The root apex evidenced changes that reflected on the decrease of the percentage area of the protoderm and the fundamental meristem and the increase in the areas of the cap and quiescent center. The symptoms of toxicity are related to the high frequency of cell in cellular death process observed in the roots exposed to the higher concentrations and to the decrease in the mitotic index of the apical root meristem. [ABSTRACT FROM AUTHOR]

The knowledge regarding the neurological and behavioral toxic effects associated with microplastics (MPs) and heavy metals exposure is still scarce. The present study aimed to evaluate the potential chronic (30 days) toxic effects of MPs (2 mg/L) and copper (Cu, 25 µg/L), alone or combined, in the zebrafish (Danio rerio) brain antioxidant system, cell proliferation/death, cholinergic-, serotonergic- and dopaminergic pathways and, consequently, in locomotor, anxiety, and social behaviors. Our findings showed that MPs and Cu exposure modulated the antioxidant system of zebrafish brain, with superoxide dismutase (SOD) and glutathione reductase (GR) having higher activity in the Cu25 +MPs group, but glutathione peroxidase (GPx) being inhibited in MPs, Cu25 and Cu25 +MPs. Moreover, an increase in acetylcholinesterase (AChE) activity was observed in all exposed groups. When considering neurogenesis genes, a downregulation of proliferating cell nuclear antigen (pcna) was noticed in zebrafish exposed to the mixture treatment, while for dopaminergic system-related genes (th and slc6a3) an upregulation was observed in MPs, Cu25 and Cu25 +MPs groups. An increase in apoptosis-related genes expression (casp8 , casp9 and casp3) was observed in the MPs exposed group. Changes in zebrafish behavior, particularly in mean speed, total distance moved, inactivity in the aquaria, and social/shoaling behavior was also observed in the MPs and Cu exposed groups. Overall, our results highlight the multiplicity of toxic effects of MPs, alone or combined with Cu, in zebrafish brain, namely apoptosis and alterations in adult neurogenesis, neurocircuits and, consequently, behavior. [Display omitted] • The antioxidant system overcame the oxidative stress induced by MPs and Cu. • The AChE activity was increased in MPs, Cu25 and Cu25 +MPs. • MPs induced apoptosis through the upregulation of caspase genes. • MPs and Cu dysregulated fish behavior by modulating dopaminergic pathways. • Synergistic toxic effects were found between MPs and Cu. [ABSTRACT FROM AUTHOR]

Aims and Objective: To compare serum LDH levels in the normal pregnant women and in women with preeclampsia and eclampsia in antepartum period and to study the correlation of maternal and perinatal outcomes with serum LDH levels. Methods: A prospective comparative study was conducted in Department of Obstetrics and Gynaecology in cooperation with Department of Biochemistry at S.C.B medical college, Cuttack from October 2012- September 2014 where 200 pregnant women in the third trimester of pregnancy were enrolled and divided into 4 groups i.e. control, mild preeclampsia, severe preeclampsia and eclampsia with 50 subjects in each group. All were thoroughly examined and subjected to routine and specific investigations. Plain blood sample on empty stomach were collected for analysis of LDH which was done in fully automated biochemistry analyser. All women were followed up until delivery and early postpartum period and their babies were followed up till early neonatal period. Results: In our study lowest mean age for eclampsia subjects was 22.78±2.12 years. Mild preeclampsia was found in 64% of primigravida which increased to 66% in severe preeclampsia and to 70% in eclampsia group. Mean Serum LDH (S.LDH) levels were found to be higher in the severe preeclampsia and eclampsia group, 1120+725.68IU/L and 1016.94± 533.38IU/L respectively. Systolic and diastolic BP were higher in subjects with higher S.LDH levels. Mean gestation age was 37.56±2.35 weeks with S.LDH<600IU/L and decreased to 34.86±4.02 weeks in S.LDH>800IU/L. Birth weight decreased from 2.60+0.61kg to 1.85±0.57kg with S.LDH<600IU/L&>800IU/LAPGAR score at 5min were 7.15±1.58, 6.17+1.92, 6.25+1.37 with S.LDH <600IU/L, 600-8001U/L and >800IU/L. Acute respiratory distress syndrome (ARDS), was more prevalent with S.LDH >800IU/L and was found to be 20.3%. With S.LDH>800IU/L maternal morbidity like postpartum haemorrhage (PPH) 22.8%, HELLP syndrome 6.3%, Abruptio placentae 8.9% and Acute renal failure (ARF) 7.6% were found to be in higher proportion than those who had S.LDH <800IU/L. Conclusion: Higher S. LDH level correlates well with the severity of disease and poor outcome in patients with preeclampsia and eclampsia. Hence, it can be used as a biochemical marker to assess the fetomaternal outcome in patients of preeclampsia and eclampsia. [ABSTRACT FROM AUTHOR]