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Background: Fibroblast growth factor 21 (FGF21) has a protective effect against cardiovascular disease. However, the role of FGF21 in hypertension remains elusive., Methods: Ten-week-old male C57BL/6 mice were randomly divided into normal-salt (NS) group, NS+FGF21 group, deoxycorticosterone acetate-salt (DOCA) group and DOCA+FGF21 group. The mice in NS group underwent uninephrectomy without receiving DOCA and 1% NaCl and the mice in DOCA group were subjected to uninephrectomy and DOCA-salt (DOCA and 1% NaCl) treatment for 6 weeks. At the same time, the mice were infused with vehicle (artificial cerebrospinal fluid, aCSF) or FGF21 (1 mg/kg) into the bilateral paraventricular nucleus (PVN) of mice., Results: Here, we showed that FGF21 treatment lowered DOCA salt-induced inflammation and oxidative stress in the PVN, which reduced sympathetic nerve activity and hypertension. Mechanistically, FGF21 treatment decreased the expression of HNF4α and inhibited the binding activity of HNF4α to the promoter region of ACE2 in the PVN of DOCA salt-treated mice, which further up-regulated ACE2/Ang (1-7) signals in the PVN. In addition, ACE2 deficiency abolished the protective effect of FGF21 in DOCA salt-treated mice, suggesting that FGF21-mediated antihypertensive effect was dependent on ACE2., Conclusions: The results demonstrate that FGF21 protects against salt-sensitive hypertension via regulating HNF4α/ACE2/Ang (1-7) axis in the PVN of DOCA salt-treated mice via multi-organ crosstalk between liver, brain and blood vessels.

This study is to investigate the therapeutical effect and mechanisms of human-derived adipose mesenchymal stem cells (ADSC) in relieving adriamycin (ADR)-induced nephropathy (AN). SD rats were separated into normal group, ADR group, ADR+Losartan group (20 mg/kg), and ADR + ADSC group. AN rats were induced by intravenous injection with adriamycin (8 mg/kg), and 4 d later, ADSC (2 × 10 5 cells/mouse) were administrated twice with 2 weeks interval time (i.v.). The rats were euthanized after the 6 weeks' treatment. Biochemical indicators reflecting renal injury, such as blood urea nitrogen (BUN), neutrophil gelatinase alpha (NGAL), serum creatinine (Scr), inflammation, oxidative stress, and pro-fibrosis molecules, were evaluated. Results demonstrated that we obtained high qualified ADSCs for treatment determined by flow cytometry, and ADSCs treatment significantly ameliorated renal injuries in DN rats by decreasing BUN, Scr and NGAL in peripheral blood, as well as renal histopathological injuries, especially protecting the integrity of podocytes by immunofluorescence. Furthermore, ADSCs treatment also remarkably reduced the renal inflammation, oxidative stress, and fibrosis in DN rats. Preliminary mechanism study suggested that the ADSCs treatment significantly increased renal neovascularization via enhancing proangiogenic VEGF production. Pharmacodynamics study using in vivo imaging confirmed that ADSCs via intravenous injection could accumulate into the kidneys and be alive at least 2 weeks. In a conclusion, ADSC can significantly alleviate ADR-induced nephropathy, and mainly through reducing oxidative stress, inflammation and fibrosis, as well as enhancing VEGF production.

MYB transcription factor is one of the largest families in plants. There are more and more studies on plants responding to abiotic stress through MYB transcription factors, but the mechanism of some family members responding to salt stress is unclear. In this study, physiological and transcriptome techniques were used to analyze the effects of the R2R3-MYB transcription factor AtMYB72 on the growth and development, physiological function, and key gene response of Arabidopsis thaliana . Phenotypic observation showed that the damage of overexpression strain was more serious than that of Col-0 after salt treatment, while the mutant strain showed less salt injury symptoms. Under salt stress, the decrease of chlorophyll content, the degree of photoinhibition of photosystem II (PSII) and photosystem I (PSI) and the degree of oxidative damage of overexpressed lines were significantly higher than those of Col-0. Transcriptome data showed that the number of differentially expressed genes (DEGs) induced by salt stress in overexpressed lines was significantly higher than that in Col-0. GO enrichment analysis showed that the response of AtMYB72 to salt stress was mainly by affecting gene expression in cell wall ectoplast, photosystem I and photosystem II, and other biological processes related to photosynthesis. Compared with Col-0, the overexpression of AtMYB72 under salt stress further inhibited the synthesis of chlorophyll a (Chla) and down-regulated most of the genes related to photosynthesis, which made the photosynthetic system more sensitive to salt stress. AtMYB72 also caused the outbreak of reactive oxygen species and the accumulation of malondialdehyde under salt stress, which decreased the activity and gene expression of key enzymes in SOD, POD, and AsA-GSH cycle, thus destroying the ability of antioxidant system to maintain redox balance. AtMYB72 negatively regulates the accumulation of osmotic regulatory substances such as soluble sugar (SS) and soluble protein (SP) in A. thaliana leaves under salt stress, which enhances the sensitivity of Arabidopsis leaves to salt. To sum up, MYB72 negatively regulates the salt tolerance of A. thaliana by destroying the light energy capture, electron transport, and antioxidant capacity of Arabidopsis.

Paederosidic acid (PA) has shown beneficial effects in anti-inflammatory studies, but it is unclear whether PA has positive impacts on bone loss induced by lipopolysaccharide (LPS). This study aims to investigate the influence of PA on bone loss in LPS-treated rats. The study assesses changes in the viability and osteogenic potential of MC3T3-E1 cells, as well as osteoclast differentiation in RAW264.7 cells in the presence of LPS using CCK-8, ALP staining, AR staining, and Tartrate-resistant acid phosphatase (TRAP) staining. In vitro experiments indicate that LPS-induced inhibition of osteoclasts (OC) and Superoxide Dismutase 2 (SOD2) correlates with heightened levels of inflammation and oxidative stress. Furthermore, PA has demonstrated the ability to alleviate oxidative stress and inflammation, enhance osteogenic differentiation, and suppress osteoclast differentiation. Animal experiments also show that PA significantly upregulates SOD2 expression while downregulating TNF-α expression (all, p < 0.05), leading to the restoration of impaired bone metabolism, improved bone strength, and increased bone mineral density (all, p < 0.05), compared to the control group. The collective experimental findings strongly suggest that PA can enhance osteogenic activity in the presence of LPS by reducing inflammation and oxidative stress, hindering osteoclast differentiation; hence mitigating bone loss in LPS-treated rat models., 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.)

Co-crystallization of a therapeutic ingredient with an appropriate co-former is a powerful technique to augment the physicochemical and pharmacokinetic properties and the effectiveness of Active Pharmaceutical Ingredients (APIs). Biochanin A (BCA), a flavonoid with medicinal potential, is limited by poor solubility and low oral bioavailability. This study aimed to design and develop a novel BCA-nicotinamide cocrystal as BCC to enhance BCA's oral bioavailability and explore its therapeutic potential for ameliorating cerulein-induced acute pancreatitis (CIAP) by elucidating the target identification utilizing tissue/serum metabolite profiles. The cocrystal was designed by the supramolecular synthon approach and characterized by single-crystal X-ray diffraction that confirms a robust three-dimensional hydrogen-bonded network of BCA and Nicotinamide (NCT) in the crystal. FT-IR and DSC were used to analyze the cocrystal's intermolecular interactions and thermal behavior. BCC exhibited enhanced solubility and drug release compared to BCA alone, resulting in enhanced oral bioavailability and pancreatic tissue concentration. Comparing BCC to BCA in the CIAP model, BCC therapy remarkably reduced cerulein-induced pancreatitis, evidenced by significant reductions in inflammation, acinar cell atrophy, and amylase levels in pancreatic tissues. Further, the cocrystal formulation also down-regulated the oxidative stress markers, inflammatory cytokines and macrophage-related proteins. The study has identified distinct metabolomic signatures linked with AP with the help of Orbitrap Exploris mass spectrometry, which could pave the way for creating focused diagnostic tools for a better prognosis. In conclusion, these results offer new insights into exploring mechanistic pathways associated with specific biomarkers and underscore BCC cocrystal as a promising approach to enhance BCA's therapeutic potential., 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.)

Despite the remarkable biological effects of berberine (BBR), particularly on fertility, its bioavailability is low. This study aims to test the effectiveness of novel nanostructured biloalbuminosomes (BILS) of BBR and its metabolite berberrubine (M1) in treatment of testicular and prostatic lesions. M1 was semi-synthesized from BBR using microwave-assisted reaction. The solvent evaporation method was used to prepare BBR-BILS and M1-BILS by three different concentrations of sodium cholate (SC) or glycocholate (SG), along with the incorporation of bovine serum albumin (BSA). The prepared BILS were fully characterized. Male infertility was induced by cadmium (Cd) at 5 mg/kg and lead (Pb) at 20 mg/kg contaminated water for 90 days, followed by treatment with BBR, M1, and their BILS (BBR-BILS and M1-BILS) for 45 days. Blood male infertility markers, testicular and prostatic oxidative stress status, autophagy, inflammation, along with testicular and prostatic concentrations of Cd and Pb, and histopathology of both tested tissues were determined using standardized protocols. The optimal BBR-BILS and M1-BILS nano-preparations, containing 30 mg SC, were chosen based on the best characterization properties of the preparations. Both nano-preparations improved heavy metals-induced testicular and prostatic deformities, as they reduced Bax and elevated Bcl-2 expressions in both tissues. Moreover, they activated the mTOR/PI3K pathway with a marked reduction in AMPK and activated LC-3II protein levels. Consequently, testicular and prostatic architecture and functions were improved. This study is the first to report the preparation of BBR and M1 BILS nano-preparations and proved their superior efficacy compared to free drugs against testicular and prostatic deformities by attenuating oxidative stress-induced excessive autophagy, offering a new hope to manage male infertility., 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.)

Intestinal ischemia-reperfusion (I/R) injury is a critical condition in the abdomen that has significant morbidity and fatality rates. Prior studies have noted the defensive role of the coenzymatic antioxidant reduced nicotinamide adenine dinucleotide phosphate (NADPH) in heart and brain I/R damage, yet its impact on intestinal I/R trauma required further exploration. Through the application of an in vitro oxygen-glucose deprivation-reoxygenation model and a mouse model of short-term intestinal I/R, this study clarified the defensive mechanisms of NADPH against intestinal I/R injury. We demonstrated that intraperitoneal NADPH administration markedly reduced interleukin-1β (IL-1β) levels and blocked NLRP3 inflammasome activation, hence reducing inflammation. The antioxidative properties of NADPH were established by the reduction of oxidative stress markers and enhancement of glutathione levels. Importantly, NADPH improved intestinal barrier integrity, indicated by an upregulation of zonula occludens-1 and the promotion of a balanced gut microbiome profile. Furthermore, we identified the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1(HO-1) pathway as a crucial conduit for NADPH's beneficence. When this pathway was inhibited by ML385, the favorable outcomes conferred by NADPH were significantly abrogated. These results demonstrate that NADPH functions as an antioxidative, anti-inflammatory, microbiota-balancing, barrier-strengthening, and anti-inflammatory agent against intestinal I/R damage through activation of the Nrf2/HO-1 signaling pathway., 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.)

Liver fibrosis is a reversible process that can be delayed or even reversed through appropriate intervention during its development. The protein RECK, encoded by the Reck gene, regulates matrix metalloproteinase (MMP) activity and plays a crucial role in extracellular matrix (ECM) degradation and remodeling. Reduced RECK expression is found in various fibrotic tissues. However, the impact of restoring RECK expression on the development and progression of liver fibrosis has not yet been determined. This study found that the restoration of RECK expression attenuated TGF-β1-induced hepatic stellate cell (HSC) activation and mitigated carbon tetrachloride (CCl 4 )-induced acute liver injury. In a mouse model of liver fibrosis induced by CCl 4 , restoration of RECK expression reduced the degree of fibrosis, collagen deposition, and level of oxidative stress. RECK competes with Nrf2 for binding to Keap1, resulting in a decrease in the degradation of Nrf2 by Keap1 and an increase in the accumulation of Nrf2 in the cytoplasm. Under oxidative stress conditions, Nrf2 can be translocated to the nucleus for expression, initiating an antioxidant stress response, furthermore, Nrf2 can also activate MMP-9 and degrade the over-deposited collagen, thereby achieving the effect of alleviating liver fibrosis. Our study reveals a novel mechanism by which restoration of RECK expression ameliorates liver fibrosis, providing a promising target for combating liver fibrosis., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Diabetes mellitus (DM) represents a highly prevalent metabolic disorder across the globe. This study aimed to determine the ameliorative efficacy of glibenclamide (Gli) and obeticholic acid (OCA) against biochemical and pathological changes related to alloxan-induced diabetes. Twenty male Wistar rats were allocated into four groups; Control group, Diabetic group: received intraperitoneal injection of alloxan (120 mg/kg) for induction of diabetes, Diabetic + Gli group: Diabetic rats treated daily with oral Gli (5 mg/kg) and Diabetic + OCA group: Diabetic rats treated daily with oral OCA (10 mg/kg). All rats were subjected to 30 days treatments. Our results indicated that Gli successfully ameliorated hyperglycemia and dyslipidemia with a significant decline in serum pancreatic lipase activity and increased insulin level, while OCA had the same effect but without any enhancement in serum insulin levels. Additionally, the disturbances in liver function-related parameters and the evoked oxidative stress, interleukin(IL)-6 and IL-10 in the liver and pancreas were abrogated upon treatment with Gli and OCA. Furthermore, Gli and OCA increased AMP-activated protein kinase (P-AMPK), insulin receptor substrate 1 (IRS1), farnesoid X receptor (FXR), and glucagon-like peptide-1 receptor (GLP-1R) expressions and downregulated sterol regulatory element binding protein-1c mRNA expression. Besides, Gli and OCA have alleviated diabetes-induced histopathological distortions in hepatic and pancreatic tissues and enhanced the immunoexpression of insulin, and proliferating cell nuclear antigen with decreased immune reactivity of glucagon within pancreatic tissues. Gli and OCA decreased the immune reactivity of nuclear factor kappa B and increased the glycogen content of hepatic tissues. In conclusion, OCA is efficacious in the management of dyslipidemia and hyperglycemia of DM and its related oxidative stress., 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.)

Severe acute pancreatitis (SAP) is an acute inflammatory injury disease with significant mortality rate and currently without effective strategy being available. Inflammation and oxidative stress play central roles in the etiology of SAP. Micheliolide (MCL), an active monomeric component isolated from Michelia champaca, has been proved its multiple therapeutic properties including anti-inflammatory, antioxidant and anti-cancer. Nevertheless, the therapeutic effect and underlying mechanism of MCL in SAP still remain unclear. Here, we found that caerulein with lipopolysaccharide (LPS)-induced SAP murine models exhibited severe pancreatic injury, including necrosis, edema, and vacuolation of acinar cells in the pancreas, elevated serum levels of amylase and lipase, and reduced number of the exocrine cells. As expected, MCL treatment alleviated these side effects. Mechanistically, MCL triggered nuclear factor erythroid 2-related factor 2 (Nrf2) activation, thereby activating Nrf2-regulated antioxidative pathways and inhibiting nuclear factor kappa B p65 (NF-κB p65)-mediated inflammatory response, resulting in protection against pancreatic injury in SAP mice. In addition, Nrf2 gene deficiency abolished the beneficial effects of MCL on SAP-induced pancreatic inflammation and oxidative stress and blocked the ability of MCL to alleviate the pancreatic injury in SAP mice. Collectively, these findings indicated that the suppression of SAP-induced pancreatic injury by MCL was at least in part due to Nrf2-mediated anti-oxidation effect and inhibition of inflammation., 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.)

Currently, LCCP is widely present in environmental media as well as animal and human samples, suggesting that exposure to LCCP may have posed a threat to the health of animals and humans. Skin is one of the important pathways for LCCP exposure. To clarify the effects of LCCP exposure on the skin, we have utilized two skin cell models, HaCaT and L929, to investigate the complex impacts of LCCP exposure on skin cell senescence and its potential regulatory mechanism(s). Firstly, the expression of senescence-related markers, including SA-β-Gal staining, p16, p21, and p53 proteins, were evaluated, and the results showed that skin cell senescence occurred under the treatment of LCCP. Moreover, our findings revealed that LCCP exposure triggered the activation of the NF-κB signaling pathway, prompting an inflammatory response in skin cells. To further understand the potential molecular mechanism of skin cell senescence induced by LCCP, according to our preliminary experimental results, we hypothesized that mtROS and Ca 2+ might have played an important role in the LCCP-induced senescence of skin cells. Based on this hypothesis, the use of mtROS and Ca 2+ inhibitors revealed a reduction in LCCP-triggered cell senescence and oxidative stress, validating our speculation. Similarly, in vivo experiments showed that LCCP enhanced the expression of inflammatory factors in mouse skin tissue, inhibiting skin proliferation and collagen level. This discovery was consistent with the findings from in vitro experiments. In summary, our experiments emphasized that both in vitro and in vivo, exposure to LCCP could induce skin aging, potentially through oxidative stress mediated by Ca 2+ overload, leading to skin aging damage. The research presented here establishes an important foundation for continued examination of the toxicology characteristics of LCCP., 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.)

Diabetes mellitus, a chronic metabolic disorder, poses a significantly public health challenge. Extensive research highlights that contemporary dietary patterns, characterized by excessive intake of sugar, fat, and protein, are major contributors to the onset and progression of diabetes. The central element to this process is the aberrant activation of the advanced glycation end products (AGEs) - receptor for AGEs (RAGE) - oxidative stress axis, which plays a pivotal role in disrupting normal carbohydrate metabolism. This pathway presents a critical target for developing interventions aimed at mitigating diabetes and its complications. In recent years, natural polysaccharides have emerged as promising agents in the prevention and treatment of diabetes, due to their ability to inhibit AGE formation, regulate RAGE expression, and modulate the AGEs-RAGE-oxidative stress axis. In this paper, we explore the pathogenic mechanism of this axis and review the therapeutic potential of natural polysaccharides in managing diabetes and its complications. Our goal is to provide new insights for the effective management of diabetes and its associated health challenges., 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.)

Background: Matrine is a tetracyclic quinolizidine alkaloid with diverse bioactive properties, including anti-inflammatory and neuroprotective properties. However, the underlying anti-inflammatory mechanisms remain unclear., Purpose: This study aimed to explore how matrine reduces Lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 cells and to assess its protective effects against LPS-induced intestinal damage., Methods: The effect of matrine on cell viability was assessed using the cell counting kit-8 (CCK-8) assay. Additionally, its impact on inflammatory cytokines and macrophage polarization was assessed using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. The effects on intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), nitric oxide (NO) production, and oxidative stress were evaluated using 2',7'-dichlorodihydrofluorescein diacetate staining and JC-1 and Griess assays. Immunofluorescence staining was used to observe the translocation of the NF-κB p65 subunit. Western blotting (WB) and qRT-PCR were employed to analyze the expression levels of proteins related to the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathway. An LPS-induced mouse model was established to study the intestinal inflammation and barrier injury. Mouse feces characteristics, colon length, and disease activity index (DAI) were recorded. Hematoxylin-eosin (H&E) and alcian blue/periodic acid schiff (AB/PAS) staining were used to observe morphological changes and barrier damage in the duodenum, jejunum, ileum, and colon and to measure villus length, crypt depth, goblet cell count, and positive areas in the duodenum, jejunum, and ileum. The content of short-chain fatty acids (SCFAs) in the colon was determined using gas chromatography (GC)., Results: Matrine inhibited LPS-induced inflammatory cytokine levels, suppressed macrophage M1 polarization, and promoted M2 macrophage polarization. Matrine reduced LPS-induced increases in ROS and NO levels and regulates oxidative stress. Additionally, matrine inhibited the nuclear translocation of the NF-κB p65 subunit and exerted anti-inflammatory effects by suppressing the activation of the TLR4/NF-κB/MAPK pathway. In vivo experiments indicated that matrine significantly alleviated LPS-induced diarrhea, increased DAI, and shortened the colon. Matrine reduced the production of the pro-inflammatory cytokine interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α and the pro-inflammatory mediator NO in mouse intestinal tissues while promoting the content of the anti-inflammatory cytokine IL-10. Furthermore, it improved intestinal tissue structure and alleviated LPS-induced intestinal barrier damage. Finally, matrine increased the SCFA levels in the intestine., Conclusion: Matrine exerted its anti-inflammatory effects and protects against intestinal injury through the TLR4/NF-κB/MAPK signaling pathway., 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.)

Tricetin (TRI) has been reported to have anti-inflammatory and antioxidant effects; however, its therapeutic potential and molecular mechanisms in atherosclerosis remain unclear. In this study, we aimed to investigate the effects of TRI on atherosclerosis. Our findings revealed that TRI inhibits macrophage ferroptosis by activating the NRF2 pathway. In vivo, ApoE -/- mice fed a high-fat diet and injected with TRI showed improved atherosclerosis progression through reduced oxidative stress and suppression of macrophage ferroptosis. In vitro experiments demonstrated that TRI administration increases GPX4 and xCT levels, attenuates oxidative stress, improves mitochondrial function, and inhibits lipid peroxidation, thereby suppressing ox-LDL-induced macrophage ferroptosis. Furthermore, TRI enhanced the nuclear translocation of NRF2. Notably, the protective effects of TRI on antioxidant capacity and ferroptosis were reversed in macrophages treated with ML385 (a specific NRF2 inhibitor). NRF2 knockdown in ApoE -/- mice using AAV-sh-NRF2 significantly reversed TRI-mediated inhibition of atherosclerosis progression and exacerbated macrophage ferroptosis in the plaque. Conclusively, this study identifies TRI as a potential therapeutic agent for atherosclerosis by inhibiting macrophage ferroptosis and oxidative stress through activation of the NRF2 pathway, offering a novel strategy to combat disease progression., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Renal IRI is one of the leading causes of AKI. How to effectively mitigate renal IRI is important for the recovery of renal function. The regulatory mechanism of lycopene, a natural antioxidant, in renal IRI is currently unknown. Therefore, we utilized network pharmacology and animal experiments to explore the possible mechanisms and potential targets of lycopene for alleviating renal IRI., Methods: We obtained lycopene-regulated genes and renal IRI-related genes from the CTD database and GeneCards database, respectively. Subsequently, the two were intersected and the intersecting genes we defined as lycopene-regulated genes in renal IRI. Next, we explored their potential biological functions and mechanisms through enrichment analysis. Meanwhile, we constructed a rat renal IRI model and validated the protective effects of lycopene and related mechanisms. To further explore the Hub genes regulated by lycopene, we constructed a PPI protein interactions network and characterized the Hub genes using Cytoscape software. We also verified the expression of Hub genes using animal experiments and molecular docking techniques. Finally, we constructed TF-Hub gene and miRNA-Hub gene regulatory networks., Results: We obtained a total of 255 lycopene-regulated genes and 327 renal IRI-related genes. The enrichment analysis revealed that they were closely related to the regulation of oxidative stress as well as the regulation of inflammatory factors. At the same time, the MAPK signaling pathway was significantly enriched. Next, we found in animal experiments that lycopene significantly alleviated the level of oxidative stress and inflammation during renal IRI, and had a protective effect on kidney damage. Also, we found that this protective effect may be achieved by inhibiting the MAPK signaling pathway. Next, we identified a total of five Hub genes using Cytoscape software: TNF, AKT1, MAPK3, IL6 and CASP3. Both animal experiments and molecular docking techniques demonstrated that lycopene can effectively regulate the expression of Hub genes. Finally, our constructed TF-Hub gene and miRNA-Hub gene regulatory network provide a theoretical basis for further regulation of Hub genes in follow-up., Conclusions: This study suggests that lycopene is a promising option in mitigating renal IRI. Lycopene may exert protective effects by inhibiting the MAPK signaling pathway., 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.)

Ischemia/reperfusion (I/R) injury has been demonstrated to exert a significant role in acute myocardial infarction (AMI), which constitutes a crucial cause of AMI. Ferroptosis represents a novel form of cell death that is intimately linked to myocardial ischemia-reperfusion (MIR) injury. Urolithin A (UA), an intestinal metabolite of ellagitannins, has not been fully elucidated for its role in MIR injury. In the present study, we analyzed the effects of UA on ischemia-reperfusion-induced oxidative stress and ferroptosis both in vitro and in vivo, and explored the potential mechanisms of UA action. The results indicated that UA was capable of protecting the heart from ischemia-reperfusion injury and enhancing cardiac function both in vitro and in vivo. In addition, UA also attenuated oxidative stress, mitochondrial damage, and ferroptosis during MIR. Mechanistically, UA not only augmented the Nrf2 expression but also promoted Nrf2 entry into the nucleus and activated the downstream antioxidant defense system. Moreover, after the inhibition of Nrf2, the myocardial protective function of UA was lost, and its function of attenuating oxidative stress and ferroptosis was suppressed. In conclusion, we found that UA protected the heart from ischemia-reperfusion injury by attenuating oxidative stress and ferroptosis through the Nrf2 signaling pathway, suggesting that UA might be a potential therapeutic agent for the treatment of AMI., 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.)

Sepsis is a major cause of mortality among critical patients. Acute kidney injury (AKI) is the common complication in patients with sepsis, characterized by rapid deterioration of renal function. The purpose of this study is to assess the impact of inhaling high concentration hydrogen on septic mice with AKI and to examine the involvement of mitochondria in this process. High concentration hydrogen does not cause hypoxia and can alleviate AKI and improve 7-day survival in septic mice. Inflammatory factors are markedly elevated in the serum and renal tissues in CLP group which are dramatically down-regulated by hydrogen. The activities of both antioxidant enzymes are significantly reduced after CLP, whereas hydrogen markedly increases the activities of SOD and CAT. MMP is found to be significantly lower in CLP group whereas this effect is reversed by hydrogen. The trend of ATP content in renal tissues corresponded with that of MMP. There is a substantial downregulation of PGC-1α, Nrf2, and TFAM protein in CLP group. Drp1 expression is significantly higher in CLP group compared to Sham group, while the opposite trend is observed for MFN2. Hydrogen can reverse these changes. Inhalation of high concentration hydrogen can improve acute kidney injury, 7-day survival, inflammatory response and oxidative stress in septic mice. The mechanism may be related to inhibit renal mitochondrial fission and promote mitochondrial fusion and biogenesis., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Systemic inflammatory response syndrome and respiratory distress syndrome can be induced by lung injury caused by intestinal ischemia/reperfusion (II/R). There is no effective medical treatment for II/R-induced lung injury. Studies have shown that asiaticoside (AS) protects against lung injury and ischemia/reperfusion injury in several organs. We established a rat II/R damage model and collected lung tissue. Six groups (n = 10) were created: (1) the sham group; (2) the II/R group; (3) the II/R + AS (40) group; (4) the II/R + AS (80) group; (5) the II/R + TST group; and (6) the II/R + AS + TST group. To assess the degree of lung damage induced by II/R, we also evaluated HE staining, the wet/dry ratio, oxidative stress, inflammation and apoptosis in the lung tissues. Our results indicated that the severity of lung injury score, wet/dry ratio, oxidative stress, inflammatory factor expression and amount of apoptosis were greater in the II/R-induced lung injury group than in the sham group. Furthermore, when AS was administered, lung injury, oxidative stress, inflammation and amount of apoptosis in the lung tissues were obviously lower than those in the II/R group. Additionally, compared with that in the sham group, the expression of FoxM1 in the lung tissue in the II/R group was significantly greater, and FoxM1 expression in the lung tissue was significantly greater following AS administration. Compared with the AS alone, the administration of thiostrepton (a FoxM1 inhibitor) and AS exacerbated the lung damage induced by II/R. According to our research, AS prevents the lung damage induced by II/R by reducing oxidative stress, inflammation and apoptosis by activating FoxM1 expression., 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.)

Alcohol-induced liver injury (ALI) is a serious global health issue. Diammonium glycyrrhizinate (DG), a pharmaceutical form of glycyrrhizic acid, has been reported to have anti-inflammatory and anti-oxidative stress properties. We investigated the potential hepatoprotective effects of DG against ALI and explored the mechanisms of it. In vivo, C57BL/6J mice were used to investigate the protective effect of DG on ALI induced by chronic plus binge alcohol exposure. In vitro, AML-12 cells were applied to evaluate the role of DDX5 in the hepatic protection of DG and explore the possible mechanism of STAT1 activation regulated by DDX5. The results showed that DG significantly alleviated liver injury, inflammation, and lipid deposition in hepatocytes. It also beneficially influenced oxidative stress dysregulation. RNA-seq expression in mouse liver tissue indicated that Dead-box helicase 5 (DDX5) might be a potential target of DG. Compared with the control group, the expression of DDX5 decreased significantly in the ethanol-fed group, while DDX5 was restored in the DG treatment group. In addition, the protective effects of DG against ALI were impaired by DDX5 deficiency. DDX5 inhibited the phosphorylation of signal transducer and activator of transcription 1 (STAT1) by recruiting the protein inhibitor of activated STAT1 (PIAS1) to STAT1. The protective effect of DG against ALI associated with oxidative stress, steatosis, and inflammation was probably via regulating the DDX5/STAT1 axis., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

UC, also known as ulcerative colitis, is an inflammatory bowel disease that is chronic and nonspecific. Palmatine (PAL), a natural alkaloid active ingredient, has demonstrated predominant protective effects on UC. In spite of this, PAL on UC is unclear in terms of its underlying mechanisms. Thus, this study aimed to investigate its effects and mechanism. By inducing rats with 5 % dextran sulfate sodium (DSS), an in vivo model of UC was developed. and then oral PAL administration. In vitro viability of NCM460 cells was measured using Cell Counting Kit-8. An enzyme-linked immunosorbent assay was used to determine the levels of inflammatory factores. The levels of oxidative stress parameters were also assessed, and the expression level of cyclooxygenase-2 (COX-2), acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), NF-E2-related factor 2(Nrf2), phospho-Nrf2, and heme oxygenase-1 (HO-1) was detected by Western blot. An iron kit was employed to measure iron content in cells and colonic tissues. Results indicated that PAL treatment significantly improved UC in rats, as shown by reduced disease activity index scores and increased colon length, which decreased IL-18, IL-1β, IL-6, TNF-α, MDA, NO, and LDH levels, but increased GSH level in DSS-induced rats and NCM460 cells. Further, PAL treatment markedly decreased COX-2, ACSL4, Nrf2, and HO-1 expression levels while increasing that of GPX4 and phospho-Nrf2. Furthermore, PAL inhibited the iron overload in the cells and colonic tissues. PAL may protect against UC by inhibiting the inflammatory response, oxidative stress, iron load, and suppressing ferroptosis pathway., 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.)

Rationale: Hepatotoxicity and nephrotoxicity are significant adverse effects caused in cancer patients treated with 5-Flurouracil (5-FU), a pyrimidine analogue anti-metabolite anticancer drug. The purpose of this research was to evaluate the impact of PPAR α/γ agonist (Saroglitazar; SARO) on 5-FU-induced hepatorenal damage in rats., Methods: Male rats were randomly assigned to four groups: control, 5-FU, 5-FU + SARO (2 mg/kg), and 5-FU + SARO (4 mg/kg). Rats received 75 mg/kg 5-FU intraperitoneally once weekly for three weeks. Saroglitazar (2 and 4 mg/kg/day) was orally supplied by oral syringe for three consecutive weeks. On day 22, rats were euthanized and their livers and kidneys were subjected to morphological, biochemical, histological, and immunohistochemical analysis., Results: Saroglitazar treatment significantly decreased serum liver and kidney function biomarkers. In addition, it successfully modulated liver and kidney levels of inflammatory mediators and markers (NF-κB P65, TNF-α, cleaved caspase-1, IL-1β and p-p38 MAPK) and oxidative stress-related parameters (MDA, GSH, SOD, Keap1, Nrf-2 and HO-1) in a dose dependent manner. Furthermore, SARO could attenuate 5-FU-induced activation of cleaved caspase-3 as well as improved histopathological examination of both liver and kidney tissues., Significance: Saroglitazar may be a viable therapy option for 5-FU toxicity as it halts the interaction network of NF-kB and Nrf2 signaling pathways and apoptosis., 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.)

Oxidative stress is critically involved in the cognitive dysfunction and neuronal progressive degeneration in the vascular cognitive impairment (VCI). The natural lignan molecular isoamericanin A (ISOA) containing multiple hydroxyl groups has great potential for suppressing oxidative stress in VCI. The primary objective of this study was to delve into the pharmacological properties of ISOA against VCI, as well as to elucidate the mechanisms driving this effect from the perspective of antioxidative stress. Transient bilateral common carotid arteries occlusion (tBCCAO) mice model and hydrogen peroxide (H 2 O 2 ) treated N2a cells were employed in vivo and in vitro, respectively. Behavioral tests showed that ISOA (5, 10 mg/kg) treatment alleviated learning, memorizing, and recognition in tBCCAO model mice. ISOA alleviated the neuronal damages by increasing the number of NeuN-positive cells, decreasing the TUNEL-positive cells density, up-regulating MAP-2 expression, lighting the damage of neuronal nucleus and synapse. Mechanistically, we found that ISOA reduced the oxidative stress in neurons, which manifested by reduction on the expressions of superoxide, H 2 O 2 , intercellular reactive oxygen species (ROS) and malondialdehyde (MDA) level, and up-regulations on the expressions of anti-oxidant enzymes superoxide dismutase, heme oxygenase-1, glutathione peroxidase 4, glutathione, and NAD(P)H: quinone oxidoreductase 1. Further investigation showed that ISOA activated nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by downregulating the expression of kelch-like ECH-associated protein 1, upregulating the nuclear translocation and expression of Nrf2, and augmenting antioxidant response elements (ARE) promotor activity. The ISOA-mediated promotion on ARE promotor activity and anti-oxidant enzymes expressions, and suppression on superoxide and ROS expressions and MDA levels were weakened by pharmacological inhibition or genetic knockdown of Nrf2. These effects were enhanced after knockdown Keap1 in H 2 O 2 -treated cells. Our study demonstrates that ISOA alleviates the cognitive impairments and neuronal loss in VCI by attenuating oxidative stress through promoting the activation of Nrf2 pathway., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The investigation into specific treatments for jellyfish stings has consistently presented a significant medical challenge. Sika Deer antler protein (DAP), a valuable component of traditional Chinese medicine (TCM) known for its various pharmacological properties, has been widely utilized for the prevention and treatment of numerous diseases. In this study, proteome analysis and biological activity assays of DAP identified 94 distinct protein components and demonstrated its capability to scavenge free radicals. Moreover, administration of 50 mg/kg DAP notably enhanced survival rates in mice, mitigated increases in hematological indicators and inflammatory markers (IL-6, IL-1β, and TNF-α), and alleviated pathological abnormalities induced by jellyfish venom. Additionally, DAP intervention significantly decreased the hemolysis rate and improved the viability of RAW264.7 cells, while reducing cell apoptosis and oxidative stress. Transcriptome analysis and western blotting of RAW264.7 cells further confirmed that DAP inhibited the activation of the NF-κB and MAPK signaling pathways. Overall, DAP effectively countered the toxicity of jellyfish venom by reducing oxidative damage and inflammatory response, highlighting the potential of TCM in treating jellyfish stings., 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.)

Calcium oxalate (CaOx) crystals are the main constituents of renal crystals in humans and induce tubular lumen damage in renal tubules, leading to renal calcium deposition and kidney stone formation. Oxidative stress and inflammation play important roles in regulating calcium oxalate-induced injury. Here, we evaluated the efficacy in inhibiting oxidation and inflammation of pectinolinarigenin, a biologically active natural metabolite, in CaOx nephrocalcinosis and further explored its targets of action. First, we developed cellular and mouse models of calcium oxalate renal nephrocalcinosis and identified the onset of oxidative stress and inflammation according to experimental data. We found that pectolinarigenin inhibited this onset while reducing renal crystal deposition. Network pharmacology was subsequently utilized to screen for hypoxia-inducible factor-1α (HIF-1α), a regulator involved in the body's release and over-oxidation of inflammatory factors. Finally, molecular docking, cellular thermal shift assay, and other experiments to detect HIF-1α expression showed that pectolinarigenin directly combined with HIF-1α and prevented downstream reactive oxygen species activation and release. Our results indicate that pectolinarigenin can target and inhibit HIF-1α-mediated inflammatory responses and oxidative stress damage and be a novel drug for CaOx nephrocalcinosis treatment., 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.)

Background: Synovial inflammation, Cartilage erosion, and subchondral osteosclerosis, which are collectively referred to as the triad of pathogenesis, contribute to osteoarthritis (OA) progression. Specifically, the M1 macrophage in the synovium worsens the development of the illness and is a significant factor in the deterioration and functioning of cartilage., Objective: To investigate whether Ruscogenin attenuates progressive degeneration of articular cartilage in rats with anterior cruciate ligament transection (ACLT)-induced osteoarthritis (OA) by modulating macrophage reprogramming and to explore its specific mechanism of action., Methods: In vitro, SW1353 cells and RAW264.7 cells were applied to elucidate the mechanisms by which Ruscogenin protects articular cartilage. Specifically, the expression levels of molecules related to cartilage ECM synthesis and degradation enzymes and macrophages were analysed. In vivo, a rat osteoarthritis model was established using ACLT. The protective effect of Ruscogenin on articular cartilage was observed., Results: Ruscogenin significantly reversed LPS-induced macrophage inflammatory response and promoted cartilage regeneration-related factors. In addition, Ruscogenin had a significant protective effect on the knee joint of ACLT rats, effectively preventing cartilage degeneration. These positive therapeutic effects were achieved on the one hand by Ruscogenin regulating macrophage reprogramming by targeting Sirt3, and on the other hand Ruscogenin could attenuate the ROS level of chondrocytes thereby inhibiting chondrocyte ferroptosis., Conclusions: Ruscogenin exerts chondroprotective effects by regulating macrophage reprogramming and inhibiting chondrocyte ferroptosis., 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.)

Hepatopulmonary syndrome (HPS) is a liver disease-induced pulmonary complication manifested with arterial hypoxemia. Hepatic cholestasis, encountered in several clinical situations, leads to biliary cirrhosis and HPS, both of which are best reproduced by rat common bile duct ligation (CBDL). Experience from liver transplantation suggests hepatoprotective-based therapy would be most effective in HPS treatment Dipeptidyl peptidase-4 (DPP-4) enzyme is involved in different pathogenic mechanisms of liver diseases. Vildagliptin (Vild) is a DPP-4 inhibitor which possesses favorable anti-inflammatory, anti-oxidant and anti-fibrotic effects. The present work explored hepatoprotective mechanisms of Vild and their participation in its prophylactic effectiveness in HPS induced by CBDL in rats. Male Wistar rats weighing 220-280 g were allocated into 4 groups: normal control, sham, CBDL and CBDL + Vild groups. i.p. saline was administered to the first 3 groups and i.p. Vild (10 mg/kg/day) was given to the fourth group for 6 weeks starting 2 week before CBDL. CBDL produced liver fibrosis, arterial hypoxemia and decreased survivability of rats. It altered liver functions and induced oxidative stress, pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)], vasodilatory molecules [endothelin-1 (ET-1), and inducible and endothelial nitric oxide synthases] and angiogenesis-associated protein [vascular endothelial growth factor-A (VEGF-A)] in liver and lung. Vild ameliorated liver fibrosis, and improved hypoxemia and survivability of CBDL rats and reversed these biochemical alterations. Prophylactic Vild administration attenuated CBDL-induced HPS in rats via direct hepatoprotective effects in the form of anti-oxidant, anti-inflammatory, anti-angiogenic and anti-fibrotic effects beside inhibition of pathological intrahepatic vasodilatation., 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.)

Metabolic diseases may be prevented by reducing carbohydrate intake and replacing plant-based diets with animal-based ones low in carbohydrates but high in protein, fat, and iron. While the effects of sugars on metabolic diseases are well-known, the role of iron remains unclear. This study aimed to explore the effects of a high-fat high-iron animal diet on body metabolism in mice. Micro-PET imaging was used to assess 18-F-labelled glucose uptake in BAT, and the morphology, respiratory function, and oxidative stress of BAT mitochondria were examined. The underlying mechanisms were elucidated by analyzing the expression of UCP-1, PGC-1α and PPARα. The high-iron high-fat diet increased appetite, impaired glucose tolerance, and reduced insulin sensitivity. Additionally, the high-iron diet promoted gluconeogenesis only in the absence of high-fat levels. Both high-iron and high-fat diets suppressed BAT activity, increased mitochondrial oxidative stress, decreased mitochondrial respiratory function, and lowered thermogenic gene expression. Weight loss strategies focusing solely on reducing carbohydrates and increasing animal foods, like ketogenic diets, may have long-term detrimental effects on metabolic health. Prioritizing dietary diversity and monitoring overall caloric intake is advisable for optimal outcomes., Competing Interests: Declaration of competing interest We affirm that there are no conflicts of interest associated with this work. None of the authors have any financial or personal relationships that could inappropriately influence or bias the content of this research. We have not received any funding or support from any entity that could create a potential conflict of interest. Additionally, we have not engaged in any activities that might raise concerns regarding the objectivity and integrity of our study. We are committed to presenting accurate and reliable scientific findings and ensuring the highest standards of research ethics and integrity., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Type 2 diabetes development has been associated with islet amyloid polypeptide (IAPP) fibrillation. IAPP fibrils have various deleterious effects, such as oxidative stress and disruption of cellular membrane integrity, resulting in pancreatic β-cell toxicity. Rutin, a plant polyphenol, possesses promising cytoprotective effects as a fibrillation inhibitor. Similarly, bioactive peptides have been identified as potential inhibitors to IAPP fibrillation. In this study, the effect of peptide/polyphenol mixtures consisting of rutin and each peptide, TNGQ, MANT, and YMSV, on anti-fibrillation activity and cellular response was elucidated. Results indicated a 54.7-75.1 % decrease in thioflavin T fluorescence, confirming anti-fibrillation activity. The combination decreased the average particle diameters of IAPP more than the single inhibitors, suggesting a combined effect of peptide/rutin mixtures in enhancing anti-fibrillation activity. IAPP fibrillation-induced rat insulinoma RIN-m cell death was minimized in the presence of the peptide/rutin mixture, but the activity was lower relative to rutin alone, suggesting a non-additive effect of the mixtures. Transmission electron microscopy showed a near-complete inhibition of IAPP fibrillation by TNGQ/rutin mixtures, which translated to a decreased production of membrane-bound IAPP oligomers in RIN-m cells based on immunofluorescence staining. Additionally, TNGQ/rutin mixtures significantly decreased reactive oxygen species production by 30 %, higher than the effects of single inhibitors, but no effect was observed on glucose-stimulated insulin secretion. The results demonstrate the potential of multifunctional compounds as dual inhibitor systems in controlling IAPP fibrillation and provide insight into the implications of peptide/polyphenol mixtures towards the rational development of novel anti-diabetic nutraceutical combinations., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Although numerous approaches have emerged to address the challenges of critical limb ischemia (CLI), their clinical trials have proven elusive. Stem cell therapy has been utilized for CLI; however, its efficacy is limited, resulting in low survival rates in patients. Here, we investigated the impact of polydeoxyribonucleotide (PDRN) on the bioactivities of stem cells derived from human exfoliated deciduous teeth (SHED) against oxidative stress. PDRN treatment increased the proliferation, migration, antioxidant properties, and mitochondrial respiration of SHED. These beneficial effects were regulated by Akt activation. Through a murine hindlimb ischemia model, PDRN treatment demonstrated augmented the survival and proliferation of transplanted SHED at ischemic injury sites, whereas the inhibition of Akt suppressed these effects. Our findings revealed that PDRN promoted the therapeutic potential of SHED via Akt phosphorylation, suggesting PDRN-primed SHED as promising candidates for the development of novel stem cell therapeutics., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute lung injury (ALI) caused by sepsis is one of the most common critical diseases, which is difficult to treat and has a high fatality rate. Koumine is one of the main active components of Gelsemium plants and has been confirmed to have potential for drug development; however, its therapeutic effects on ALI have not yet been studied. This study established ALI due to sepsis using cecal ligation and puncture (CLP) and assessed the therapeutic effects of koumine by measuring mouse survival rates, lung tissue pathological damage, inflammatory factors, and oxidative stress levels. Additionally, network pharmacology was utilized to explore the underlying mechanisms. The results showed that koumine inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β), thereby inhibiting inflammatory response, reducing lung injury score and lung wet to dry ratio. In addition, koumine reduced oxidative stress in mice by reducing myeloperoxidase (MPO) and malondialdehyde (MDA) and increasing superoxide dismutase (SOD) content. Network pharmacology analysis showed that 52 putative targets were relevant, and SLC6A4, HTR3A, JAK2 and JAK3 were the key targets. GO and KEGG pathway enrichment analysis showed that the related mechanisms involved neuroactive ligand-receptor interaction, calcium signaling pathway, serotonergic synapses, cholinergic synapses, etc. In summary, this study confirmed the potential therapeutic effect of koumine in sepsis induced ALI, suggesting its development prospect as a novel candidate drug for ALI, and providing data support., 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 Inc. All rights reserved.)

Epoxyazadiradione is an important limonoid with immense pharmacological potential. We have reported previously that epoxyazadiradione (EAD) induces apoptosis in triple negative breast cancer cells (MDA-MB 231) by modulating diverse cellular targets. Here, we identify the key genes/pathways responsible for this effect through next-generation sequencing of the transcriptome from EAD treated cells and integrated molecular data analysis using bioinformatics. In silico analysis indicated that EAD displayed favourable drug-like properties and could target multiple macromolecules relevant to TNBC. RNA sequencing revealed that EAD treatment results in the differential expression of 1838 genes in MDA-MB 231 cells, with 752 downregulated and 1086 upregulated. Gene set enrichment analysis of these genes suggested that EAD disrupts protein folding in the endoplasmic reticulum, triggering the unfolded protein response (UPR) and potentially leading to cell death. EAD also induced oxidative stress and DNA damage, downregulated pathways linked to metabolism, cell cycle progression, pro-survival signalling, cell adhesion, motility and inflammatory response. The identification of protein cluster and hub genes were also done. The validation of the identified hub genes gave an inverse correlation between their expression in EAD treated cells and TNBC patient samples. Thus, the identified hub genes could be explored as therapeutic or diagnostic markers for TNBC. Hence, EAD appears to be a promising therapeutic candidate for TNBC by targeting various hallmarks of cancer, including cell death resistance, uncontrolled proliferation and metastasis. To conclude, the identified pathways and validated targets for EAD will provide a roadmap for further in vivo studies and preclinical/clinical validation required for potential drug development., 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.)

Intervertebral disc degeneration (IDD) is a common cause of low back pain and disability. Recent studies have highlighted the critical role of mitochondrial dysfunction in the progression of IDD. In this study, we investigated the therapeutic potential of taurine in delaying IDD through the activation of mitophagy via the PINK1/Parkin pathway. Our in vitro and in vivo experiments demonstrate that taurine treatment significantly enhances mitophagy, reduces oxidative stress, delays cell senescence, and promotes the removal of damaged mitochondria in nucleus pulposus cells (NPC). Additionally, taurine-mediated activation of the PINK1/Parkin pathway leads to improved mitochondrial homeostasis and slows the progression of disc degeneration. These findings provide new insights into the protective effects of taurine and highlight its potential as a therapeutic agent for IDD., Competing Interests: Declaration of competing interest All authors declare no financial or personal relationships with other individuals or organizations., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of agricultural technologies has intensified the use of plastic in this sector. Products of plastic degradation, such as microplastics (MPs), potentially threaten living organisms, biodiversity and agricultural ecosystem functioning. Thus, biodegradable plastic materials have been introduced to agriculture. However, the effects of biodegradable plastic substitutes on soil ecosystems are even less known than those of traditional ones. Here, we studied the effects of environmentally relevant concentrations of MPs prepared from a biodegradable plastic (a starch-polybutylene adipate terephthalate blend, PBAT-BD-MPs) on the growth and defense mechanisms of lettuce (Lactuca sativa) in CLIMECS system (CLImatic Manipulation of ECosystem Samples). PBAT-BD-MPs in the highest concentrations negatively affected some traits of growth, i.e., dry weight percentage, specific leaf area, and both C and N contents. We observed more profound changes in plant physiology and biochemistry, as PBAT-BD-MPs decreased chlorophyll content and triggered a concerted response of plant defense mechanisms against oxidative stress. In conclusion, exposure to PBAT-BD-MPs induced plant oxidative stress and activated plant defense mechanisms, leading to oxidative homeostasis that sustained plant growth and functioning. Our study highlights the need for in-depth understanding of the effect of bioplastics on plants., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Microbial secondary metabolites are crucial in plant-microorganism interactions, regulating plant growth and stress responses. In this study, we found that cyclo(-Phe-Pro), a proline-based cyclic dipeptide secreted by many microorganisms, alleviated aluminum toxicity in wheat roots by increasing root growth, decreasing callose deposition, and decreasing Al accumulation. Cyclo(-Phe-Pro) also significantly reduced Al-induced reactive oxygen species (ROS) with H 2 O 2 , O 2 •- , and •OH levels decreasing by 19.1%, 42.8%, and 17.9% in root tips, thus protecting the plasma membrane from oxidative damage. Although Al stress increased the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX) in wheat roots, cyclo(-Phe-Pro) application reduced these enzyme activities. However, compared to the Al treatment, cyclo(-Phe-Pro) application increased DPPH and FRAP activities by 16.8% and 14.9%, indicating increased non-enzymatic antioxidant capacity in wheat roots. We observed that Al caused the oxidation of ascorbate (AsA) and glutathione (GSH) to dehydroascorbate (DHA) and glutathione disulfide (GSSG), respectively. Under Al stress, cyclo(-Phe-Pro) treatment maintained reduced AsA and GSH levels, as well as high AsA/DHA and GSH/GSSG redox pair ratios in wheat roots. High AsA/DHA and GSH/GSSG ratios can reduce Al toxicity by neutralizing free radicals and restoring redox homeostasis via antioxidant properties. These results suggest that cyclo(-Phe-Pro) maintains ASA- and GSH-dependent redox homeostasis to alleviate oxidative and Al stress in wheat roots. Findings of this study establishes a theoretical foundation for using microbial metabolites to mitigate Al toxicity in acidic soils, highlighting their potential in sustainable agriculture., 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 Ltd. All rights reserved.)

The use of pesticides in integrated rice-fish farming could have an impact on fish health. The present study aimed to evaluate, for the first time, the biological effects of the insecticide bifenthrin on fish (Piaractus mesopotamicus and Hoplosternum littorale) using a caging experiment. Fish were divided into two sites: control (C) and bifenthrin exposure (BF). Two cages (n = 8 fish/cage) per species were placed separately at each site. The BF application (Seizer ®) was carried out with a coastal sprayer according to the BF recommended dose for rice cultivation (0.1 L/ha). After 72 h, fish were collected, and gills, liver, brain, and muscle were dissected for the analysis of biomarkers of accumulation, oxidative stress, and neurotoxicity. In P. mesopotamicus, the main changes were observed in the muscle, where BF accumulated and induced neurotoxicity (inhibition of cholinesterase activity) and oxidative stress (activation of antioxidant enzymes, decreased glutathione levels, increased lipid peroxidation). The gills and liver also showed changes in some markers of the antioxidant system. In H. littorale, BF exposure induced changes in oxidative stress biomarkers in liver (activation of antioxidant enzymes and lipid peroxidation) and gill tissues (alteration in antioxidant markers). These results show that the use of bifenthrin in rice fields poses a risk to fish farming under current pesticide management practices. Furthermore, its use could affect other species in these agroecosystems, highlighting the need for further studies to assess the ecological and productive consequences in a context of increasing pyrethroid use worldwide., 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 Inc. All rights reserved.)

Aflatoxin B1 (AFB1) is a widespread food contaminant with toxic effects on female reproductive system. This concerns the human public health and the development of the livestock industry. Effective and feasible measures against reproductive toxicity of AFB1 are also unknown. Curcumin has been shown to improve animal production performance and alleviate toxicity of AFB1 in other tissues. The study aimed to reveal the potential mechanism of curcumin in alleviating AFB1 exposure-triggered reproductive toxicity in porcine. Porcine GCs and matured oocytes in vitro and mouse ovary in vivo were cultured as model and then exposed to AFB1 and curcumin. The transcriptomics for porcine GCs was performed. The apoptosis, cell cycle, ROS content and mitochondrial membrane potential level analysis were determined using probe staining and flow cytometry. QRT-PCR and western blotting were analyzed for the genes expression. Oocytes maturation and parthenogenetic activation were performed to evaluate the quality of oocytes. The data showed that AFB1 exposure significantly inhibited porcine GCs viability and exhibited concentration-dependent relationship from 1 to 16 μM. Curcumin supplementation efficiently reversed the inhibition of cell viability. Further analysis indicated that curcumin application alleviated AFB1-exposed porcine GCs and mouse ovary mitochondria dysfunction, oxidative stress, cell cycle arrest, and apoptosis. We found that PI3K/Akt signaling pathway plays a vital role in AFB1-induced porcine GCs toxicity through bioinformatic analysis. The data not only confirmed the correlation of PI3K/Akt signaling pathway and oxidative stress, cell cycle arrest and apoptosis, but also consistent with the results that curcumin supplementation could markedly activate the PI3K/Akt signal inhibited by AFB1. Moreover, curcumin reversed AFB1-impaired cumulus-oocyte complex expansion, oocytes maturation rate, blastocyst rate and formation. Our study demonstrated that curcumin supplementation can protect porcine GCs and mouse ovary from toxicity of AFB1 by targeting the PI3K/AKT signaling pathway and provides a viable treatment approach for AFB1-induced female reproductive toxicity., 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 Ltd. All rights reserved.)

To study the intricate toxicological mechanisms triggered by exposure to mixed pollutants, we exposed zebrafish embryos to legacy and emerging pollutants through binary mixtures of benzo[a]pyrene (B[a]P) and diclofenac (DFC). The combination of next-generation transcriptomics and toxicopathology disclosed instances where exposure to mixtures did not attain the expected sum of acute effects of individual toxicants, indicating potential antagonism. Despite overall higher mortality in DFC treatments, the same antagonistic trend was noted in genotoxicity and molecular pathways related to RNA turnover, cell proliferation, apoptosis and cell-cycle control. The formation of oedemas in the heart cavity and yolk sac can be an adverse outcome (AO) resulting from exposure to DFC isolated or combined, whose potential key events (KEs) may involve cell cycle arrest and apoptosis via p53 and MAPK pathways. From the findings it can be hypothesised that, rather than genotoxicity, the molecular initiating event (MIE) maybe inflammation triggered by oxidative stress. Nonetheless, the exact role of ROS in the process needs further clarification. Impaired eye function by action of DFC and B[a]P combined may be another AO, in the case caused by ocular degeneration following the suppression of biologic processes and molecular functions involved in eye development and its functionalities, possibly linked to hindered regulation of the expression of hsf4 and cryaa. Altogether, toxicopathology suggests predominance of antagonistic effects, but its integration with mechanism suggests that interactions between DFC and B[a]P in environmentally-relevant concentrations that may lead to hindrance of key functions such as the control of inflammation and cell cycle. These outcomes suggest potentially severe implications for health and survival, in case of prolonged chronic exposure to combined toxicants., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The occurrence of microplastics (MPs) in aquaculture environments is a growing concern due to their potential negative effects on fish health and, ultimately, on seafood safety. Earthen pond aquaculture, a prevalent aquaculture system worldwide, is typically located in coastal and estuarine areas thus vulnerable to MP contamination. The present study investigated the possible relation between MP levels of European seabass (Dicentrarchus labrax) farmed in an earthen pond and its health status. More precisely, two groups of fish were established based on the lowest and highest number of MPs found collectively in their gastrointestinal tract (GIT), liver, and dorsal muscle: fish with ≤2 MP/g and fish with ≥4 MP/g. The intestinal integrity and oxidative stress biomarkers in the liver and dorsal muscle were evaluated in the established groups. No significant differences in the biometric and organosomatic parameters between groups were observed. The results indicated a significant increase in the number of acid goblet cells (GC) in the rectum of fish with higher MP levels (p = 0.016). Increased acid GC number may constitute a first defence strategy against foreign particles to protect the intestinal epithelium. No significant differences in oxidative stress biomarkers between the two fish groups were observed, namely in the activity of superoxide dismutase, catalase, glutathione reductase, and glutathione S-transferase in the liver, or in lipid peroxidation levels in the liver and dorsal muscle. The overall results suggest that MP levels were possibly related to an intestinal response but its potential implications on the health status of pond-farmed seabass warrant further investigation. Monitoring MP occurrence across stages of aquaculture production could help to elucidate the potential threats of MPs to fish health., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

The implementation of advanced recycling techniques represents a key strategy for mitigating the mismanagement and the environmental impact of plastic waste. A limited array of plastic polymers can be efficiently recycled, while a notable portion of plastic waste remains unrecyclable. In Italy, this residual, heterogeneous fraction is referred to as Plasmix. Because of its complexity and non-homogeneous composition, Plasmix is primarily directed towards low-value applications. However, recent developments in laboratory-scale mechanical recycling have enabled the creation of new plastic materials from Plasmix. Prior to their application, these materials must undergo rigorous eco-safety evaluation. The present study aims to assess the potential toxicity of microplastics (MPs) from Plasmix-based materials on the freshwater crustacean Daphnia magna. Specifically, this study investigated sub-individual and individual effects induced by a 21-day exposure to different concentrations of MPs generated from the grinding of naïve and Additivated Plasmix-based materials (hereafter referred to as Px-MPs and APx-MPs, respectively). Sub-individual endpoints focused on changes in oxidative status, including the modulation of antioxidant and detoxifying enzyme activities, as well as oxidative damage, such as lipid peroxidation. Individual level endpoints included alterations in survival and reproduction. Microscopy analyses confirmed the ingestion of both Px-MPs and APx-MPs by D. magna individuals. An oxidative stress condition raised in organisms exposed to Px-MPs, whereas no effect was observed in individuals exposed to APx-MPs. Although survival was not affected, a significant impairment in reproductive output was detected at the end of exposure to all the concentrations of both MP types. These findings suggest that even low concentrations of Px-MPs and APx-MPs could negatively affect the health status of D. magna, underscoring the need for further research to complete the risk assessment of Plasmix-based materials prior to their use in consumer products., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Marco Parolini reports financial support was provided by University of Milan. Marco Parolini reports a relationship with University of Milan that includes: employment. If there are other authors, they 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The current research sheds light on the biological toxicity of organophosphate flame retardants (OPFRs), yet it overlooks the neurotoxicity and potential molecular mechanisms of tris(1,3-dichloro-2-propyl) phosphate (TiBP), a prominent constituent of the OPFRs. To address this, we utilized zebrafish larvae as a model to investigate TiBP's acute toxicity and neurotoxic effects, along with the associated molecular pathways. Our findings revealed that the 96 h and 120 h LC50 values for TiBP were 56.51 mg/L and 48.85 mg/L, respectively. Gradient exposure based on the 120 h LC50 demonstrated that TiBP induced developmental toxicity, characterized by elevated heart rate, reduced body length, and diminished eye distance. Additionally, a decrease in swimming activity was observed in the light test, along with the inhibition of the neuro crest cell development in Tg (HuC:eGFP) and Tg (sox10: eGFP) zebrafish larvae following TiBP exposure, as well as the alterations of neurogenesis and ACh-related genes. Expression of key neurodevelopment genes, including mbpa, gap43, nestin, ngfra, was significantly downregulated. Furthermore, heightened anxiety-like behaviors in open field and phototaxis tests were observed, concomitant with neurotransmitter imbalances. Specifically, there was an increase in DA levels, a decrease in GABA, and an upregulation of AChE activity. These disruptions were primarily mediated through transcriptional dysregulation of neurotransmitter synthesis, transport, and reception. Upon exposure to TiBP, zebrafish larvae exhibited a concentration-dependent increase in both ROS level and apoptosis. An upregulation of antioxidant enzymes and their transcription levels indicated the presence of oxidative stress in the larvae. The induction of ddit3 was congruent with the observed apoptosis, suggesting that it may be triggered by oxidative stress via the ERs-CHOP pathway. In summary, our study indicates that oxidative stress is a pivotal molecular event in the neurotoxicity induced by TiBP, implicating the disruption of the GABAergic, dopaminergic, and cholinergic systems, as well as triggering apoptosis., 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 Ltd. All rights reserved.)

Versicolorin A (VerA), a precursor of the potent carcinogen Aflatoxin B1 (AFB1), is an emerging mycotoxin. Recent research has highlighted the mutagenic and genotoxic properties of VerA, yet several facets of its pronounced toxicity remain unexplored. In the present study, we investigated early (6 h) transcriptomic changes induced by VerA in differentiated intestinal cells in non-cytotoxic conditions (1 and 3 μM) and compared its effects to those of AFB1 at 1 μM. Our findings indicated that VerA led to substantial alterations in global gene expression profiles, while AFB1 did not exhibit the same effects. As expected, both toxins caused alterations in gene expression associated with well-known aspects of their toxicity, including mutagenicity, genotoxicity, oxidative stress, and apoptosis. However, we also observed novel features of VerA toxicity, including the ability to cause mitochondrial dysfunction and to trigger a type-1 interferon response, at least partially mediated by cGAS-STING. VerA also induced changes in the expression of genes involved in the regulation of cell shape and adhesion, transcription/translation as well as genes associated with tumor biology. Our results provide new evidence of the high toxicity of VerA and underscore the importance of further assessing the risks associated with its presence in food., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Soler L reports financial support was provided by French National Research Agency. If there are other authors, they 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This article provides a comprehensive review of the toxic effects of environmental pollution on the male reproductive system, with a particular emphasis on ferroptosis, a form of programmed cell death. Research has shown that environmental pollutants, such as heavy metals, pesticide residues, and plastic additives, can disrupt oxidative stress, increasing the production of reactive oxygen species (ROS) in germ cells. This disruption damages cellular lipids, proteins, and DNA, culminating in cell dysfunction or death. Ferroptosis, a cell death pathway closely linked to oxidative stress, is characterized by the accumulation of intracellular iron ions and elevated levels of lipid ROS. This review also explores the role of ferroptosis in male reproductive disorders, including its contributions to reduced sperm count, decreased motility, and abnormal morphology. Environmental pollutants, particularly heavy metals, can induce ferroptosis by interfering with intracellular antioxidant systems, notably the NRF2, GSH, and GPX4 pathways, accumulating toxic lipid peroxides. Furthermore, the article examines the potential interplay between ferroptosis and other forms of cell death, such as apoptosis, autophagy, pyroptosis, and necrosis, in the context of male reproductive health. The review underscores the critical need for further research into the link between environmental pollutants and male fertility, particularly focusing on ferroptosis. It advocates for targeted research efforts to mitigate the adverse effects of ferroptosis and protect reproductive health, emphasizing that a deeper understanding of these mechanisms could lead to innovative preventive strategies against environmental threats to fertility., 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 Ltd. All rights reserved.)

Microplastics (MPs) are widely used and disposed of indiscriminately, posing a potential threat to aquatic life. Herein, Asian seabass (Lates calcarifer) fingerlings were exposed to various concentrations (1, 10 and 100 ppt or g/kg) of dietary polyethylene MPs for 16 days. The results indicated a significant increase in mortality among the fish fed with dietary MPs compared to the control. Furthermore, histological analysis of the liver revealed moderate-to-severe morphological alterations, hepatocyte necrosis and vacuolisation as the concentration gradient of MPs increased. The severity of the alterations was highest at a concentration of 100 ppt, indicating a direct correlation between MP and liver damage. In addition, RNA sequencing and Gene Ontology term enrichment analysis revealed that a total of 4137 genes were significantly differentially expressed, with 1958 upregulated and 2179 downregulated genes. The significantly enriched terms included 'oxidoreductase activity', 'endocytosis', 'mitochondrial', 'immune system process' and 'lipid catabolic process'. Moreover, the Kyoto Encyclopaedia of Genes and Genomes enrichment analysis demonstrated that dietary MPs triggered oxidative stress, immune response and adaptive mechanism pathways in fish. Thus, MPs can induce metabolic disorders in L. calcarifer, highlighting their potential threat to aquatic organisms., 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 Ltd. All rights reserved.)

The effects of chemical components of ambient fine particulate matter (PM 2.5 ) on human early maternal-fetal interface are unknown. We estimated the associations of PM 2.5 and component exposures with placental villi 8-hydroxy-2'-deoxyguanosine (8-OHdG) in 142 normal early pregnancy (NEP) and 142 early pregnancy loss (EPL) from December 2017 to December 2022. We used datasets accessed from the Tracking Air Pollution in China platform to estimate maternal daily PM 2.5 and component exposures. Effect of average PM 2.5 and component exposures during the post-conception period (i.e., from ovulation to villi collection) on the concentration of villi 8-OHdG were analyzed using multivariable linear regression models. Distributed lag and cumulative effects of PM 2.5 and component exposures during the periovulatory period and within ten days before villi collection on villi 8-OHdG were analyzed using distributed lag non-linear models combined with multivariable linear regression models. Per interquartile range increase in average PM 2.5 , black carbon (BC), and organic matter (OM) exposures during the post-conception period increased villi 8-OHdG in all subjects (β = 34.48% [95% CI: 9.33%, 65.42%], β = 35.73% [95% CI: 9.08%, 68.89%], and β = 54.71% [95% CI: 21.56%, 96.91%], respectively), and in EPL (β = 63.37% [95% CI: 16.00%, 130.10%], β = 47.43% [95% CI: 4.30%, 108.39%], and β = 72.32% [95% CI: 18.20%, 151.21%], respectively), but not in NEP. Specific weekly lag effects of PM 2.5 , BC, and OM exposures during the periovulatory period increased villi 8-OHdG in all subjects. Ten-day cumulative and lag effects of PM 2.5 , BC, and OM increased villi 8-OHdG in all subjects and EPL, but not in NEP; and the effects of OM were robust after adjusting for BC, ammonium, nitrate, or sulfate in two-pollutant models. In conclusion, placental oxidative DNA damage in early pregnancy was associated with maternal exposure to PM 2.5 , especially its chemical components BC and OM., 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 Inc. All rights reserved.)

Per-and polyfluoroalkyl substances (PFAS) are a group of synthetic, highly fluorinated, and emerging chemicals that are reported to be used for both industrial and domestic applications. Several PFAS have demonstrated persistent, bioaccumulative and toxic tendencies in marine organisms. Therefore, this research aims to characterize and quantify these compounds in both recreational fisheries and surface water samples, including estimating their bioaccumulation potentials. In addition, we assessed the potential contribution of biomonitoring tools such as oxidative stressors and morphological index on fish and ecological health. Finally, human health risk assessment was performed based on available toxicological data on limited PFAS. All PFAS were detected in at least one sample except for N-EtFOSAA in lobster which was below the method detection limit. ƩPFAS body burden ranged from 0.15 to 3.40 ng/g wet weight (ww) in blackfin tuna samples and 0.37-5.15 ng/g ww in lobster samples, respectively. Wilcoxon rank paired test (α = 0.05) shows that there is statistical significance (ρ < 0.05) of ƩPFAS between species. Bioaccumulation factors (BAF) suggest an increasing trend in PFAS classes (PFCAs < PFSAs < FTSs), with higher BAFs observed in tuna compared to lobster. Long-chain PFESAs and FASAA were reported at higher concentrations in lobster compared to Blackfin tuna due to their bioavailability through sediment-sorption interactions. Although Fulton's condition factor (FCF) indicates healthy fish conditions, oxidative stress biomarkers suggest that tuna and lobster might be under stress, which can weaken their immune system against exposure to emerging contaminants such as PFAS. Hazard risk (HR) suggests a low risk to human health based on the consumption of the studied species; however, the risk of contaminant exposure may be higher than estimated. This study is aimed at improving food safety by providing better understanding of how PFAS infiltrate into human diet and incorporating data on influence of contaminant exposure and environmental stressors on marine health., 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., (Published by Elsevier Inc.)

For clinically prevalent traumatic optic neuropathy (TON) and other retinal and optic nerve injuries lacking effective therapeutic agents, there is an urgent clinical demand for developing highly efficient and safe neuroprotective agents. Here, we have integrated naturally sourced chalcone with isatin through a catalyst-free green synthesis method, reporting a series of spirocyclic chalcone derivatives with significantly lower cytotoxicity than chalcone itself. Following in vitro cell protection assays in models of hydrogen peroxide and glutamic acid-induced damage, multiple active compounds capable of combating both forms of damage were identified. Among these, candidate compound X38 demonstrated promising neuroprotective prospects: in vitro, it attenuated glutamate-induced cell apoptosis, while in vivo, it effectively ameliorated retinal thinning and loss of optic nerve electrophysiological function induced by optic nerve injury. Preliminary mechanistic studies suggest that X38 exerts its neuroprotective effects by mitigating intracellular ROS accumulation, inhibiting JNK phosphorylation, and alleviating oxidative stress. Additionally, acute toxicity studies (intraperitoneal injection, 500 mg/kg) underscored the favorable in vivo safety profile of X38. Taken together, this study has designed a class of safe, neuroprotective spirocyclic chalcone derivatives that can be synthesized using green methods, offering an attractive candidate for treating retinal and optic nerve injuries., 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 Masson SAS. All rights reserved.)

Fosthiazate (FOS) is a widely used organophosphorus insecticide effective against soil root-knot nematodes. However, its ecotoxicity to non-target soil organisms, particularly in combination with microplastics (MPs), is unclear. This study explores the toxic-effects and molecular mechanisms of co-exposure to FOS and MPs on earthworms (Eisenia fetida) using multilevel toxicity endpoints and transcriptomics. Results showed that both FOS and MPs elevated the intracellular levels of reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-2-deoxyguanosine (8-OHdG) in earthworms' cells. The superoxide dismutase (SOD) and catalase (CAT) activities followed a similar trend in all treatments, with changes observed at 14 and 28 days, indicating that co-exposure to FOS and MPs increased DNA oxidative damage. Notably, the co-exposure more significantly inhibited Ca 2+ -ATPase activity and exacerbated neurotoxicity compared to individual treatments, closely associated with changes in intracellular ROS levels that mediate neuroinhibition and lead to neurotoxicity. KEGG enrichment analysis revealed that MPs and FOS disrupted pathways related to metabolism, immunity, and apoptosis, while co-exposure primarily impaired endocrine and receptor pathways, showing higher toxicity. Our study offers novel insights into the ecotoxicological effects and mechanisms of pesticides and microplastics on earthworms, providing valuable data for evaluating the soil environmental health risks associated with compound pollution., 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 Ltd. All rights reserved.)

Inorganic toxicants like arsenic, copper, lead, nickel and fluoride are notorious agro-pollutants, impeding plant-productivity due to high bioaccumulation. Consumption of such contaminated plant-parts causes irreversible health hazards. We identified a G-protein coupled receptor, serving as melatonin receptor (MelR) in Nicotiana tabacum (NtMelR), that relayed downstream-signaling after binding melatonin, a potent growth regulator and antioxidant. Using inhibitors against G-protein-α and NADPH oxidase (NOX), and by supplementing epidermal strips with exogenous melatonin and H 2 O 2 , we established that NtMelR acted upstream of reactive oxygen species (ROS) production in guard cells. Transgenic lines of N. benthamiana overexpressing NtMelR maintained constitutive melatonin-signaling via MelR, leading to efficient stomatal closure for preventing desiccation during oxidative stress. Melatonin biosynthesis was stimulated in the transgenic lines, exposed to different agro-pollutant stress, providing a steady-abundance of ligand for NtMelR binding and activating the defence machinery, comprising of enzymatic-antioxidants like superoxide dismutase, catalase, peroxidases and glyoxalases. Due to increased antioxidant capacity, the transgenics exhibited less molecular injuries (electrolyte leakage, methylglyoxal accumulation and NOX activity), generated less ROS and bioaccumulated significantly lower levels of toxicants. Unlike the wild-type counterparts, the transgenics maintained high relative water content, photosynthetic efficiency, could flower abundantly and even produce seeds. Overall, we established that overexpression of NtMelR is a single-window strategy to generate multiple-stress tolerant genotypes., Competing Interests: Declaration of competing interest Aryadeep Roychoudhury reports that financial support was provided by Science and Engineering Research Board, Government of India. If there are other authors, they 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 Ltd. All rights reserved.)

Aims: Fibromyalgia (FM) is an idiopathic syndrome with painful burdensome symptoms. Radiotherapy is one of the main therapeutic modalities for treating various malignancies and there is a probable association between FM exacerbation and exposure to ionizing radiation. Based on that nanomedicines progressively being explored for their promising applications in medicine, the aim of the current study is to assess the possible therapeutic benefits of nanoform of pregabalin (N-PG) in managing FM symptoms during being exposed to ionizing radiation., Main Methods: Rats were allocated into four groups. First group served as control, the other three groups received gamma radiation (2 Gy/day) after 1 h of reserpine administration (1 ml/kg per day, s.c.) to induce FM for three successive days. On the next day, third and fourth groups received (30 mg/kg, p.o.) of PG and N-PG, respectively once daily for ten consecutive days. Tail flick test was performed and von Frey filaments were used to assess mechanical allodynia/hyperalgesia, and then rats were sacrificed to obtain brains., Key Findings: N-PG effectively replenished reserpine effects and treated both allodynia and hyperalgesia, improved thermal allodynia, effectively recovered all neurotransmitters near to normal baseline, inhibited oxidative stress status via decreasing malondialdehyde (MDA), increasing glutathione (GSH) and superoxide dismutase (SOD), it had strong anti-inflammatory effect as verified by reducing both cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-kB) in addition to inhibition of intrinsic apoptosis through caspase-3 (casp-3) decrease and B-cell lymphoma-2 (Bcl-2) increase. Histopathological and immunohistochemical results confirmed the biochemical findings., Significance: N-PG could be a promising drug for treating FM especially when there is urgent need to expose patient to ionizing radiation., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The health risk associated with acrylamide exposure has emerged as a significant issue of public health, attracting global attention. However, epidemiologic evidence on whether and how daily acrylamide exposure increases depression risk of the general population is unclear., Methods: The study included 3991 adults from the National Health and Nutrition Examination Survey. The urinary metabolites of acrylamide (N-Acetyl-S-(2-carbamoylethyl)-L-cysteine [AAMA] and N-Acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine [GAMA]) identified as reliable indicators of acrylamide exposure were examined to determine their relationships with depressive symptoms that were evaluated using the 9-item Patient Health Questionnaire. Besides, the measurements of alkaline phosphatase (ALP) and biomarkers of inflammation (white blood cell [WBC] count) and anti-oxidative stress (albumin [ALB]) were conducted to investigate their mediation roles in above relationships., Result: AAMA, GAMA, and ΣUAAM (AAMA+GAMA) were linearly associated with increased risk of depressive symptoms. Each 2.7-fold increase in AAMA, GAMA, or ΣUAAM was associated with a 30 % (odds ratio: 1.30; 95 % confidence interval: 1.09, 1.55), 47 % (1.47; 1.16, 1.87), or 36 % (1.36; 1.13, 1.63) increment in risk of depressive symptoms, respectively. Increased WBC count (mediated proportion: 4.48-8.00 %), decreased ALB (4.88-7.78 %), and increased ALP (4.93-5.23 %) significantly mediated the associations between acrylamide metabolites and depressive symptoms., Conclusions: Acrylamide exposure of the general adult population was related to increased risk of depressive symptoms, which was mediated in part by inflammation, oxidative stress, and increased ALP. Our findings provided pivotal epidemiologic evidence for depression risk increment from exposure to acrylamide., 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.)