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Objective To investigate whether menaquinone-4 （MK-4） can exert a protective effect against carbon tetrachloride （CCl4）-induced acute liver injury （ALI） in mice by alleviating ferroptosis. Methods After adaptive feeding， adult male ICR mice， aged 8 weeks， were divided into Control group， MK-4 group， CCl4 model group （6-hour， 12-hour， and 24-hour）， and MK-4+CCl4 group （6-hour， 12-hour， and 24-hour）， with 6 mice in each group. The mice in the Control group were given intraperitoneal injection of an equal dose of corn oil； the mice in the MK-4 group were given intraperitoneal injection of 40 mg/kg MK-4 solution， followed by an equal dose of corn oil after 1 hour； the mice in the MK-4+CCl4 group （6-hour， 12-hour， and 24-hour） were given intraperitoneal injection of 40 mg/kg MK-4 solution， and after 1 hour， the mice in this group and the CCl4 model group （6-hour， 12-hour， and 24-hour） were given intraperitoneal injection of 0.3 mL/kg CCl4 solution， with samples collected at 6， 12， and 24 hours. HE staining was used to observe the pathological changes of mouse liver； Prussian blue staining was used to observe iron accumulation in liver tissue； a biochemical analyzer was used to measure the serum levels of aspartate aminotransferase （AST） and alanine aminotransferase （ALT）； related kits were used to measure the levels of tissue iron content and the oxidative stress indices malondialdehyde （MDA） and glutathione （GSH） in liver homogenate； RT-PCR was used to measure the expression levels of ferroptosis marker genes （acyl-CoA synthetase long-chain family member 4 ［ACSL4］， prostaglandin-endoperoxide synthase 2 ［PTGS2］， and glutathione peroxidase 4 ［GPX4］） and iron metabolism-related genes （hemojuvelin ［HJV］， transferrin receptor 1 ［TFR1］， and ferroportin ［FPN］）， and Western blot was used to measure the protein expression level of GPX4. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. Results In the aging study， compared with the Control group， the CCl4 model group （6-hour， 12-hour， and 24-hour） had significant increases in liver weight coefficient and the serum levels of ALT and AST （all P<0.05）， and HE staining also showed that liver injury gradually aggravated over time. Meanwhile， compared with the CCl4 model group （6-hour， 12-hour， and 24-hour）， the MK-4+CCl4 （12-hour） group had significant reductions in liver weight coefficient and the serum levels of ALT and AST （all P<0.05）， with a reduction in the necrotic area of liver tissue， and therefore， 12-hour mouse tissue samples were used for detection in the following study. Compared with the Control group， the CCl4 group had a significant increase in MDA and a significant reduction in GSH （both P<0.05）， and compared with the CCl4 group， the MK-4+CCl4 group had a significant reduction in MDA and a significant increase in GSH （both P<0.05）. Compared with the Control group， the CCl4 group had significant increases in the key ferroptosis indices ASCL4 and PTGS2 and a significant reduction in GPX4 （all P<0.05）； compared with the CCl4 group， the MK-4+CCl4 group had significant reductions in the mRNA expression levels of ASCL4 and PTGS2 and a significant increase in the mRNA expression level of GPX4 （all P<0.05）. Western blotting showed that compared with the Control group， the CCl4 group had a significant reduction in the protein expression level of GPX4 （P<0.05）， and compared with the CCl4 group， the MK-4+CCl4 group had a significant increase in the protein expression level of GPX4 （P<0.05）. Prussian blue staining showed that compared with the Control group， the CCl4 group had a significant increase in iron accumulation； after MK-4 intervention， compared with the CCl4 group， the MK-4+CCl4 group had a significant reduction in iron accumulation. As for the measurement of iron metabolism genes in mouse liver， compared with the Control group， the CCl4 group had a significant increase in iron content， significant reductions in the mRNA expression levels of FPN and HJV， and a significant increase in the mRNA expression level of TFR1 （all P<0.05）； after protection with MK-4， there was a significant reduction in iron content， significant increases in the mRNA expression levels of FPN and HJV， and a significant reduction in the mRNA expression level of TFR1 （all P<0.05）. Conclusion MK-4 intervention in advance can alleviate CCl4-induced ALI in mice， possibly by inhibiting ferroptosis and improving the expression of iron metabolism-related genes in mouse liver. [ABSTRACT FROM AUTHOR]

Osteoporotic fragility fractures substantially impact aging societies, necessitating long-term care and increasing healthcare costs. Myokine irisin, secreted by skeletal muscle, influences bone metabolism; however, a comprehensive understanding of the mechanisms by which irisin affects bone metabolism is still lacking. Therefore, this study aimed to explore the effects of irisin on osteogenesis and osteoblast differentiation triggered by bone morphogenetic protein-2 (BMP-2). We used 4-week-old male ICR mice and implanted polyethylene glycol pellets containing recombinant human BMP-2 (rh-BMP-2) into the left dorsal muscle pouch. Mice received weekly intraperitoneal injections of either phosphate-buffered saline or recombinant irisin (re-irisin). Ectopic bone formation was evaluated 3 weeks post-surgery using micro-computed tomography (μ-CT) and histological analysis. In vitro experiments, C2C12 cells were treated with or without rh-BMP-2 and re-irisin, and we assessed osteoblast differentiation markers, e.g., runt-related transcription factor 2, alkaline phosphatase, osteocalcin, and osteopontin, using real-time reverse transcription-polymerase chain reaction. The μ-CT analyses showed that re-irisin significantly increased bone mineral content and bone volume of ectopic bones newly formed by rh-BMP-2. The gene expressions of the osteoblast markers were significantly increased by rh-BMP-2 and further upregulated by re-irisin. The treatment of cyclic AMP response element-binding protein (CREB) small interfering RNA attenuated these effects, suggesting that CREB signaling pathway was involved in rh-BMP-2/re-irisin-induced osteoblastic differentiation. This study demonstrates the potential of irisin to enhance osteogenesis through BMP signaling, offering insights for osteoporosis treatment and highlighting irisin as a promising therapeutic target for improving bone health and extending a healthy lifespan., 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.)

The cytoskeleton of mammal oocytes provides structural support to the plasma membrane and contributes to critical cellular dynamic processes such as nuclear positioning, germinal vesicle breakdown, spindle orientation, chromosome segregation, polar body extrusion, and transmembrane signaling pathways. The ERM family (ezrin, radixin and moesin) well known as membrane-cytoskeletal crosslinkers play a crucial role in organizing plasma membrane domains through their capacity to interact with transmembrane proteins and the underlying cytoskeleton. Recent works mainly focused on the structural analysis of the ERM family members and their binding partners, together with multiple functions in cell mitosis, have significantly advanced our understanding of the importance of membrane-cytoskeletal interactions. In the present study, we documented that p-ERM was expressed and localized at cortical and nucleus during mouse oocyte meiosis. p-ERM and microfilaments were colocalized from GV to MII during mouse oocyte maturation. After being treated with cytochalasin B (CB), the F-actin was disassembled. Meanwhile, p-ERM exhibited a diffuse cytoplasmic distribution and no special staining was detected in either the oocyte membrane or condensed chromosomes. p-ERM depletion by trim-away caused the meiotic procedure arrest with a significantly lower polar body extrusion rate. Collectively, these data demonstrate that the subcellular distribution of p-ERM is correlated with microfilaments. Meanwhile, the p-ERM contributes to the first polar extrusion but does not regulate the microfilament assembly., 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. Published by Elsevier Inc.)

Ethnopharmacological Relevance: Angelica sinensis (AS) and Chuanxiong rhizoma (CR) are frequently prescribed in clinical settings for their ability to enrich blood, regulate menstrual cycles, and alleviate pain. Despite their widespread use, there is a relative dearth of studies exploring their anti-inflammatory properties., Aim of the Study: To evaluate the antioxidant and anti-inflammatory effects of Angelica sinensis-Chuanxiong rhizoma (ASCR) extracts and investigate its anti-inflammatory mechanisms., Materials and Methods: AS and CR were combined in six ratios and extracted using five solvents. The quality of the resulting ASCR extracts was assessed by determining the content of ferulic acid (FA) using HPLC. The antioxidant effects of the ASCR extracts were evaluated in vitro using the DPPH and ABTS assays, as well as in HUVECs exposed to H 2 O 2 -induced oxidative damage. Additionally, the anti-inflammatory effects of the extracts were investigated in vivo through the assays of ear edema in mice and paw edema in rats. Biochemical markers including NO, MDA, and SOD in paw tissues, as well as PGE2, TNF-α, and COX-2 in rat serum, were measured to further elucidate the anti-inflammatory mechanisms of ASCR extracts., Results: The WA-2-1 was obtained by combining AS and CR in a 2:1 ratio through first water then ethanol extraction, and showed favorable antioxidant and anti-inflammatory activities. The extract demonstrated effective scavenging abilities against DPPH• and ABTS + • radicals while also protecting against H 2 O 2 -induced oxidative damage. Furthermore, in vivo studies revealed that WA-2-1 had significant inhibitory effects on ear and paw edema as well as the ability to decrease NO and MDA levels, enhance SOD activity, and downregulate the expression of COX-2, PGE2, and TNF-α., Conclusions: The combination of AS and CR exhibits favorable anti-inflammatory effects, attributed to its dual actions of mitigating oxidative stress and suppressing the production of inflammatory mediators in serum or tissues during the inflammatory process., 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.)

Reactive oxygen species production might be prevented by xanthine oxidoreductase (XOR) inhibitors, which can cause glomerulosclerosis. We aimed to investigate whether topiroxostat, an XOR inhibitor, prevents diabetic kidney disease development in mice. Six-week-old control Institute of Cancer Research (ICR) mice and type 2 diabetic Nagoya Shibata Yasuda (NSY) mice were divided into the ICR group (ICR mice which received a lard-containing high-fat diet [HFD] based on the AIN-93G diet), NSY control group (NSY mice which received the same aforementioned diet), and NSY + topiroxostat group (NSY mice which received the same aforementioned diet with addition of 0.0012% topiroxostat). After 20 weeks, plasma biomarkers, XOR activity and oxidative stress levels, which were assessed using malondialdehyde (MDA), were measured through enzyme-linked immunosorbent assay or enzymatic methods. Renal pathology was evaluated using periodic acid-Schiff staining. Redox gene and protein expression were determined using RT-qPCR and western blotting, respectively. Plasma XOR activity was lower in NSY mice treated with topiroxostat than those without. Plasma cystatin C and creatinine levels did not differ between the ICR and NSY control groups or between the NSY control and NSY + topiroxostat groups. The NSY + topiroxostat group showed a smaller mesangial area than the NSY control group. The mRNA expression of Sod3, Prdx1, Gpx2, and Gpx3 was higher in the NSY + topiroxostat group than in the NSY control group. Renal MDA levels were lower in the NSY + topiroxostat group than in the NSY control group. Topiroxostat can reduce glomerulosclerosis, and the reduction is associated with renal oxidative markers., Competing Interests: Declaration of competing interest T. Nakmura is an employee of Pharmacological Study Group Pharmaceutical Research Laboratories, and he contributed to providing topiroxostat and determining XOR activity. Commercial organizations, including Pharmacological Study Group Pharmaceutical Research Laboratories, did not fund the study. None of the other authors have conflicts of interest or financial disclosures to the present study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Coenzyme Q10 (CoQ10) plays an important role in improving mitochondrial function and has many beneficial effects on the kidney. However, whether CoQ10 protects against diquat (DQ)-induced acute kidney injury (AKI) remains unclear. In this study, we investigated the protective effects and mechanism of action of CoQ10 against DQ-induced AKI. Institute of Cancer Research (ICR) mice were intraperitoneally injected with DQ to induce AKI. The expression levels of serum creatinine (Cr), urea, and kidney injury molecule-1 (KIM-1) increased, those of aquaporin 1 (AQP-1) decreased, and those of mitochondrial reactive oxygen species (ROS) increased with increased depolarization of mitochondrial membranes and mitochondrial rupture. In contrast, treatment with CoQ10 significantly improved DQ-induced AKI. CoQ10 treatment reduced serum Cr, urea, and KIM-1 contents, increased the AQP-1 expression, and reduced ROS contents in mice with DQ poisoning. Our results suggest that AKI caused by DQ poisoning may be related to the disruption of mitochondrial homeostasis and that CoQ10 treatment protects against AKI caused by DQ poisoning by improving mitochondrial kinetic homeostasis. Thus, CoQ10 represents a new therapeutic option for the prevention and treatment of AKI caused by DQ poisoning., (© 2024 The Author(s). Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC.)

This study investigated the protective effect of Vitamin U on liver injury induced by aflatoxin B 1 (AFB 1 ) in maternal mice. 25 pregnant ICR mice were randomly divided into five groups: the AFB 1 group (AF, 0.3 mg AFB 1 /kg b.w.), the Vitamin U group (U, 50 mg Vitamin U/kg b.w.), the AFB 1  + Vitamin U group (AU, 50 mg Vitamin U /kg b.w. + 0.3 mg AFB 1 /kg b.w.), the control group (DMSO), and the MOCK group (distilled water). They were administered substances by gavage every day for 28 days. Results indicated that exposure to AFB 1 increased the liver index and caused histological disruptions. Elevated serum levels of ALT and ALP were observed, along with a significant increase in liver MDA content and a decrease in GSH-Px and T-SOD levels. Moreover, the Keap1 and Hmox1 gene was downregulated with statistical significance, while the IL1β and TNFα gene were significantly upregulated. Vitamin U was demonstrated by the organized structure of liver cells in tissue slices, effectively reducing liver cell necrosis. This intervention was associated with a significant decrease in serum ALT and ALP activities, as well as a significant decrease in liver MDA content. Additionally, there were significant increases in liver T-SOD and GSH-Px levels, along with upregulation of mRNA and protein expression of Nfr2, Hmox1 and Keap1, and downregulation of mRNA expression of the IL1β gene. In summary, Vitamin U mitigated oxidative stress-induced liver injury by modulating the Nrf2/Hmox1 signaling pathway and inflammatory factors affected by AFB 1 ., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Endothelial dysfunction plays an important role in the pathogenesis of chronic kidney disease. Prostacyclin (PGI 2 ), an endothelial cell-produced endogenous prostaglandin, plays a crucial role in maintaining endothelial function. However, its effects on intestinal microcirculation and barrier function are not fully understood. We hypothesized that PGI 2 improves intestinal microcirculation and barrier function via endothelial protective effects., Methods: ICR and ICGN (a spontaneous nephrotic model) mice were used in this study. Intestinal microcirculation was visualized in vivo to investigate PGI 2 effects. Beraprost served as PGI 2 . PGI 2 administration spanned 4 weeks, following which we assessed its influence on intestinal endothelial, intestinal barrier, and renal functions., Results: We visualized intestinal microcirculation and endothelial glycocalyx in the intestinal blood vessels. Beraprost administration induced a 1.2-fold dilatation of the vascular diameter of the small intestine. Intestinal blood flow in ICGN mice was significantly reduced compared that in ICR mice but improved with beraprost administration. ICGN mice exhibited reduced serum albumin levels, decreased ambulation, an imbalance in intestinal reactive oxygen species (ROS)/nitric oxide (NO), and impaired tight junctions; all were ameliorated by beraprost administration., Conclusions: Beraprost improves intestinal microcirculation and barrier function by ameliorating ROS/NO imbalances, thereby reducing physical inactivity during renal failure., (© 2024 The Author(s). Microcirculation published by John Wiley & Sons Ltd.)

Ovarian aging is a serious clinical concern. Few safe and effective methods are currently available to improve ovarian functions. Photobiomodulation (PBM) is a safe and noninvasive physical therapy that can modulate a series of biological processes. Recently, several studies have noted its potential to improve the function of ovary and reproductive cells. However, the effects of PBM treatment on natural ovarian aging remain unclear. In this study, we used a naturally reproductive aging mouse model to observe the effect of PBM on ovarian function. Young and aged female ICR mice were treated with or without PBM for 2 months. PBM was performed using a semiconductor InGaAlP laser emitting at 650 nm (80 mW, 6.7 mW/cm 2 for 5 or 10 min, resulting in a dose of 2 or 4 J/cm 2 , respectively). After treatment, the effects of PBM and its role in oxidative stress, inflammation, and mitochondrial function were investigated. We found that PBM (4 J/cm 2 ) effectively recovered the levels of sex hormones, increased the number of primordial and growing follicles, improved angiogenesis, and decreased cell apoptosis in naturally aged mice. Moreover, PBM reduced oxidative stress, inhibited chronic ovarian inflammation, and improved mitochondrial function in aged ovaries. Similar protective effects of PBM were observed in a hydrogen peroxide-induced oxidative stress model of human granulosa cell line (KGN) in vitro. Increased cell viability, cell proliferation, hormone secretion, mitochondrial membrane potential, and adenosine triphosphate levels and decreased apoptosis and oxidative stress were detected in KGN cells after PBM treatment. Collectively, this study suggest that PBM treatment is beneficial for restoring ovarian function in naturally reproductive aging mice and has a significant protective effect against oxidative stress damage in KGN cells. The mechanisms underlying the benefits of PBM in ovarian aging include antioxidant stress, reduction of inflammation, and preservation of mitochondrial function. Therefore, this study emphasizes the potential of PBM as a therapeutic intervention to ameliorate ovarian aging., 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. Published by Elsevier B.V.)

Many chemotherapeutic and molecular targeted drugs have been used to treat brain metastases, e.g., anti-angiogenic vandetanib. However, the blood-brain barrier and brain-specific resistance mechanisms make these systemic therapeutic approaches inefficacious. Brain metastatic cancer cells could mimic neurons to upregulate multiple serpins and secrete them into the extracellular environment to reduce local plasmin production to promote L1CAM-mediated vessel co-option and resist anti-angiogenesis therapy. Here, we developed brain-tumor-seeking and serpin-inhibiting outer membrane vesicles (DE@OMVs) to traverse across the blood-brain barrier, bypass neurons, and specially enter metastatic cancer cells via targeting GRP94 and vimentin. Through specific delivery of dexamethasone and embelin, reduced serpin secretion, restored plasmin production, significant L1CAM inactivation and tumor cell apoptosis were specially found in intracranial metastatic regions, leading to delayed tumor growth and prolonged survival in mice with brain metastases. By combining the brain-tumor-seeking properties with the regulation of the serpin/plasminogen activator/plasmin/L1CAM axis, this study provides a potent and highly-selective systemic therapeutic option for brain metastases., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Hexavalent chromium (Cr(VI)) causes testicular damage and reduces testosterone secretion. Testosterone synthesis relies on cholesterol as a raw material, and its availability can be affected by lipophagy. However, the role of lipophagy in Cr(VI)-induced testicular damage and reduced testosterone secretion remains unclear. In this study, we investigated the effect of Cr(VI) on lipid metabolism and lipophagy in the testes of ICR mice. Forty mice were randomly divided into four groups and exposed to different doses of Cr(VI) (0, 75, 100, 125 mg/kg) for thirty days. Cr(VI) increased the rate of sperm abnormalities, decreased testosterone level, and decreased the levels of testosterone synthesis-related proteins, namely steroidogenic acute regulatory (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) proteins. Through metabolomic analysis, Oil Red O staining, and biochemical indicator (triglyceride and total cholesterol) analysis, Cr(VI) was found to disrupt testicular lipid metabolism. Further investigation revealed that Cr(VI) inhibited the AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein 1 (SREBP1) pathway, elevated levels of the autophagy-related proteins microtubule-associated protein 1 light chain 3B (LC3B) and sequestosome 1 (SQSTM1)/P62 and lipophagy-related proteins Rab7 and Rab10, while increasing colocalization of LC3B and Perilipin2. These findings suggest that Cr(VI) exposure leads to abnormal lipid metabolism in the testes by suppressing the AMPK/SREBP1 pathway and disrupting lipophagy, ultimately reducing testosterone level and inducing testicular damage., 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.)

Atmospheric particulate matter (PM) exacerbates the risk factor for Alzheimer's and Parkinson's diseases (PD) by promoting the alpha-synuclein (α-syn) pathology in the brain. However, the molecular mechanisms of astrocytes involvement in α-syn pathology underlying the process remain unclear. This study investigated PM with particle size <200 nm (PM 0.2 ) exposure-induced α-syn pathology in ICR mice and primary astrocytes, then assessed the effects of mammalian target of rapamycin inhibitor (PP242) in vitro studies. We observed the α-syn pathology in the brains of exposed mice. Meanwhile, PM 0.2 -exposed mice also exhibited the activation of glial cell and the inhibition of autophagy. In vitro study, PM 0.2 (3, 10 and 30 µg/mL) induced inflammatory response and the disorders of α-syn degradation in primary astrocytes, and lysosomal-associated membrane protein 2 (LAMP2)-mediated autophagy underlies α-syn pathology. The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3 (LC3II), cathepsin B (CTSB) and lysosomal abundance increased first and then decreased, which might both be a compensatory mechanism to toxic α-syn accumulation induced by PM 0.2 . Moreover, with the transcription factor EB (TFEB) subcellular localization and the increase in LC3II, LAMP2, CTSB, and cathepsin D proteins were identified, leading to the restoration of the degradation of α-syn after the intervention of PP242. Our results identified that PM 0.2 exposure could promote the α-syn pathological dysregulation in astrocytes, providing mechanistic insights into how PM 0.2 increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM 0.2 toxicity., Competing Interests: Declaration of Competing Interests 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 © 2023. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Realgar (As 2 S 2 or As 4 S 4 ) is a traditional Chinese medicine (TCM) containing arsenic. Existing studies have shown that it has genotoxicity under long-term use with large doses. Niuhuang Jiedu (NHJD) is a Chinese medicine prescription containing realgar and seven other TCMs. Whether the multiple TCMs combination in NHJD can reduce the genotoxicity induced by realgar in equivalent doses is still unknown., Aim of the Study: To research the effect of NHJD on realgar's genotoxicity and the possible mechanism involved based on the arsenic methylation metabolic pathway., Material and Methods: Six groups (control, realgar (0.8 g/kg), NHJD (12.48 g/kg), as well as Glycyrrhiza uralensis Fisch (GU), Scutellaria baicalensis Georg (SB), Rheum palmatum L (RP) plus equivalent doses of realgar, respectively) were set up. ICR mice were intragastric administered for 12 weeks. First, genotoxicology tests were conducted to evaluate the effect of NHJD, GU, SB, and RP on reducing realgar's genotoxicity. The inorganic arsenic (iAs), dimethyl arsenic acid (DMA), and monomethyl arsenic acid (MMA) were determined by HPLC-AFS, and the iAs%, MMA%, DMA%, primary methylation index (PMI), etc. Were calculated. Meanwhile, the S-adenosyl methionine (SAM) and arsenate reductase (ARR) levels, the arsenic (+3)methyltransferase (As 3 MT), purine-nucleoside phosphorylase (PNP), glutathione S-transfer omega1 (GSTO1) gene expression were detected, aimed to explore the possible alleviation mechanisms of NHJD., Results: The combination of multiple TCMs in NHJD decreased the levels of MN‰, SPA%, and DNA damage caused by realgar, with similar effects observed when SB, RP, and GU were used separately with realgar. Notably, the iAs% significantly decreased, while DMA% and PMI notably increased in the NHJD and realgar + SB (or RP) groups compared to the realgar-only group (P < 0.05). Increases in SAM and ARR levels were observed across various groups, but only the ARR increase in the NHJD group was statistically significant. Moreover, significant increases in As 3 MT mRNA and GSTO1 mRNA were noted in the NHJD group, and PNP mRNA levels significantly rose in the realgar + SB group., Conclusions: This study revealed that NHJD could attenuate the genotoxic effects of realgar. The botanicals SB, RP, and GU within NHJD may be key contributors to this effect. Enhancements in arsenic methylation capabilities through increased levels of SAM and ARR and elevated gene expressions of As 3 MT, PNP, and GSTO1 suggest potential mechanisms behind these findings., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: In recent years, in addition to hypertension, hyperglycemia, and hyperlipidemia, the prevalence of hyperuricemia (HUA) has increased considerably. Being the fourth major health risk factor, HUA can affect the kidneys and cardiovascular system. Chrysanthemi Indici Flos is a flavonoid-containing traditional Chinese patent medicine that exhibits a uric acid (UA)-lowering effect. However, the mechanisms underlying Chrysanthemi Indici Flos-enriched flavonoid part (CYM.E) mediated alleviation of HUA remain unelucidated., Aim of the Study: This study aimed to elucidate the efficacy of CYM.E in preventing and treating HUA and its specific effects on UA-related transport proteins, to explore possible mechanism., Methods: The buddleoside content in CYM.E was determined through high-performance liquid chromatography. HUA was induced in mice models using adenine and potassium oxonate. Subsequently, mice were administered 10 mg/kg allopurinol, and 30, 60, and 90 mg/kg CYM.E to evaluate the effects of CYM.E on the of HUA mice model. Herein, plasma uric acid (UA), creatinine (CR), blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) contents, along with serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities were measured. Additionally, xanthine oxidase (XOD) and adenosine deaminase (ADA) activities in the liver were determined. The histomorphologies of the liver and kidney tissues were examined through hematoxylin and eosin staining. The messenger RNA (mRNA) expression of facilitated glucose transporter 9 (GLUT9), organic anion transporter (OAT)1, OAT3, and adenosine triphosphate binding cassette subfamily G2 (ABCG2) in the kidney was assessed by real-time quantitative polymerase chain reaction. Furthermore, the expression of urate transporter 1 (URAT1), GLUT9, OAT1, and OAT3 in the kidney, OAT4, and ABCG2 proteins was determined by immunohistochemistry and western blotting., Results: The buddleoside content in CYM.E was approximately 32.77%. CYM.E improved body weight and autonomous activity in HUA mice. Additionally, it reduced plasma UA, BUN, and CR levels and serum ALT and AST activities, thus improving hepatic and renal functions, which further reduced the plasma UA content. CYM.E reduced histopathological damage to the kidneys. Furthermore, it lowered plasma TC, TG, and LDL-c levels, thereby improving lipid metabolism disorder. CYM.E administration inhibited hepatic XOD and ADA activities and reduced the mRNA expression of renal GLUT9. CYM.E inhibited the protein expression of renal URAT1, GLUT9, and OAT4, and increased the mRNA and protein expression of renal OAT1, OAT3, and ABCG2. Altogether, these results show that CYM.E could inhibit the production and promote reabsorption of UA and its excretion., 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 (DM) is a common metabolic disease that poses a severe threat to human health. Despite a range of therapeutic approaches, there remains a lack of effective and safe therapies with the existing drugs. Therefore, there is an urgent need to develop novel, effective, and safe therapeutic strategies for DM. Free fatty acid receptor 4 (FFAR4), also known as GPR120, is a member of the G protein-coupled receptor family, which has received considerable attention as an attractive new therapeutic target for treating DM. In the present study, based on the structure of TUG-891, which has excellent activity and selectivity, a series of novel FFAR4 agonists was designed by replacing the phenylpropanoic acid β position carbon atom with an oxygen atom, while replacing the linking oxymethylene with an amide-linking group. The target compounds were evaluated for FFAR4 agonistic activity, and the preferred compounds were evaluated for selectivity, oral glucose tolerance in normal ICR mice, antidiabetic activity in diet-induced obese (DIO) mice, pharmacokinetic properties in ICR mice and molecular modeling studies. The results showed that compound 10f possessed excellent FFAR4 agonistic activity and selectivity, significantly improved glucose tolerance in normal ICR mice, lowered blood glucose and promoted insulin secretion in a dose-dependent manner in DIO mice, and showed favorable pharmacokinetic properties. These results indicate that compound 10f may be a promising compound that deserves further structure-activity relationship and pharmacological studies for the development of antidiabetic drugs.

The present study investigated the neural health benefit of beta-sitosterol (BSS) against trimethyltin (TMT)-induced neurodegeneration in mice. Forty male Institute of Cancer Research (ICR) mice were randomly divided into Sham-veh, TMT-veh, TMT-BSS50, and TMT-BSS100. A one-time intraperitoneal injection of 2.6 mg/kg of TMT was given to mice in TMT groups. Vehicle (veh), BSS 50 mg/kg or BSS 100 mg/kg were orally given for 2 weeks. Spatial learning and memory were evaluated. Brain oxidative status, hippocampal neuropathology, and reactive astrocytes were done. White matter pathology was also evaluated. The results indicated the massy effect of TMT on induced motor ability and spatial memory deficits in accordance with increased neuronal degeneration in Cornus ammonis (CA) 1, CA3, and dentate gyrus (DG) and internal capsule white matter damage. TMT also induced the reduction of reactive astrocytes in CA1 and DG. Brain's catalase activity was significantly reduced by TMT, but not in mice with BSS treatments. Both doses of BSS treatment exhibited improvement in motor ability and spatial memory deficits in accordance with the activation of reactive astrocytes in CA1, CA3, and DG. However, they successfully prevented the increase of neuronal degeneration in CA1 found only with the BSS dose of 100 mg/kg, and it was indicated as the effective dose for neuroprotection in the vulnerable brain area. This study demonstrated mitigative effects of BSS against motor ability and memory deficits with neural health benefits, including a protective effect against CA1 neurodegeneration and a nurturing effect on hippocampal reactive astrocytes.

Background: Acetaminophen (APAP)-induced hepatotoxicity is a potentially life-threatening condition. Gardenia jasminoides fruit extract (GJE), which contains geniposide (Gen) as its major active constituent, possesses anti-inflammatory and antioxidant properties and may help address the underlying pathogenesis of APAP-induced hepatotoxicity. This study aimed to evaluate the effects of GJE in a mouse model of APAP-induced hepatotoxicity., Methods: Twenty-four male ICR mice were divided into 4 groups (n = 6/group): [1] Control group, mice were given distilled water; [2] APAP group, mice received a single dose of 600 mg/kg APAP; [3] APAP + low-dose GJE group, mice received APAP followed 30 min later by 2 doses of low-dose GJE (0.44 g/kg/dose, containing Gen 100 mg/kg/dose) 8 h apart; [4] APAP + high-dose GJE group, mice received APAP followed by 2 doses of high-dose GJE (0.88 g/kg/dose, containing Gen 200 mg/kg/dose). All mice were euthanized 24 h after APAP administration. Liver tissue was used for histological examination and to measure glutathione (GSH) and malondialdehyde (MDA) levels. Serum was used to determine levels of ALT and inflammatory cytokines (tumor necrosis factor- α (TNF-α) and interleukin-6 (IL-6))., Results: Liver histopathology showed moderate to severe hepatic necroinflammation in the APAP group, whereas only mild necroinflammation was observed in both treatment groups. Serum ALT levels were significantly elevated in the APAP group compared to the control group but were significantly reduced after low- and high-dose GJE treatment. Serum TNF- α levels were significantly higher in the APAP group than in the control group and were significantly lower after high-dose GJE treatment (135.5 ± 477.2 vs. 35.5 ± 25.8 vs. 74.7 ± 47.2 vs. 41.4 ± 50.8 pg/mL, respectively). Serum IL-6 followed a similar pattern. Hepatic GSH levels were significantly lower in the APAP group compared to the control group but significantly increased after both low- and high-dose GJE treatment (19.9 ± 4.5 vs. 81.5 ± 12.4 vs. 71.4 ± 7.8 vs. 82.6 ± 6.6 nmol/mg protein, respectively). Conversely, hepatic MDA levels were significantly elevated in the APAP group compared with the control group but significantly decreased after high-dose GJE treatment (108.6 ± 201.5 vs. 40.5 ± 18.0 vs. 40.5 ± 16.8 nmol/mg protein, respectively)., Conclusions: Treatment with G. jasminoides fruit extract can alleviate APAP-induced hepatotoxicity, likely through its anti-inflammatory and antioxidant properties., (© 2024. The Author(s).)

Antimony (Sb) is a metalloid, widely presents in the environment and associates with human health. In this study, we aimed to decipher whether Sb exposure is harmful to female reproduction and explore the underlying mechanisms. The ICR mice were exposed to 0, 5, 10, and 20 mg/kg acetate potassium Sb tartrate trihydrate by intraperitoneal injection for 10 days, then mouse oocytes were collected for further analysis. We first found a significant decrease in the proportion of MII-stage oocytes obtained from supernumerary ovulation in the fallopian tubes and early embryo development under Sb treatment. Then a series of tests showed Sb affects oocyte maturation by damaging the cytoskeleton of microtubule and actin. Moreover, the abnormal distribution of cortical granules and their component Ovastacin in oocytes, combined with reduced expression levels of Juno, affected sperm-oocyte binding and led to fertilization failure. Based on the sequencing results and experimental validation, it was demonstrated that Sb exposure impairs mitochondrial distribution and membrane potential, elevated levels of mitochondrial superoxide, finally caused energy supply deficits. Mitochondrial damage in oocytes after Sb exposure results in the excessive oxidative stress and early apoptosis. Taken together, these data suggest that Sb exposure decreases oocyte quality and female fertilization ability by impairing mitochondrial function and redox perturbation., 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.)

Statins are well-tolerated and widely available lipid-lowering medications with neuroprotective effects against traumatic brain injury (TBI). However, whether delayed statin therapy starting in the subacute phase promotes recovery after TBI is unknown. Elongation of the very long-chain fatty acid protein 1 (ELOVL1) is involved in astrocyte-mediated neurotoxicity, but its role in TBI and the relationship between ELOVL1 and statins are unclear. We hypothesized that delayed simvastatin treatment promotes neurological functional recovery after TBI by regulating the ELOVL1-mediated production of very long-chain fatty acids (VLCFAs). ICR male mice received daily intragastric administration of 1, 2 or 5 mg/kg simvastatin on Days 1-14, 3-14, 5-14, or 7-14 after cryogenic TBI (cTBI). The results showed that simvastatin promoted motor functional recovery in a dose-dependent manner, with a wide therapeutic window of at least 7 days postinjury. Meanwhile, simvastatin inhibited astrocyte and microglial overactivation and glial scar formation, and increased total dendritic length, neuronal complexity and spine density on day 14 after cTBI. The up-regulation of ELOVL1 expression and saturated VLCFAs concentrations in the cortex surrounding the lesion caused by cTBI was inhibited by simvastatin, which was related to the inhibition of the mTOR signaling. Overexpression of ELOVL1 in astrocytes surrounding the lesion using HBAAV2/9-GFAP-m-ELOVL1-3xFlag-EGFP partially attenuated the benefits of simvastatin. These results showed that delayed simvastatin treatment promoted functional recovery and brain tissue repair after TBI through the downregulation of ELOVL1 expression by inhibiting mTOR signaling. Astrocytic ELOVL1 may be a potential target for rehabilitation after TBI., Competing Interests: Declaration of Competing Interest None. The authors declare no competing interest!, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Toxoplasma gondii ( T. gondii ) is a zoonotic disease that poses great harm to humans and animals. So far, no effective T. gondii vaccine has been developed to provide fully protection against such parasites. Recently, numerous researches have focused on the use of poly-lactic-co-glycolic acid (PLGA) and chitosan (CS) for the vaccines against T. gondii infections. In this study, we employed PLGA and CS as the vehicles for T. gondii ribosome protein (TgRPS2) delivery. TgRPS2-PLGA and TgRPS2-CS nanospheres were synthesized by double emulsion solvent evaporation and ionic gelation technique as the nano vaccines. Before immunization in animals, the release efficacy and toxicity of the synthesized nanospheres were evaluated in vitro . Then, ICR mice were immunized intramuscularly, and immune protections of the synthesized nanospheres were assessed. The results showed that TgRPS2-PLGA and TgRPS2-CS nanospheres could induce higher levels of IgG and cytokines, activate dendritic cells, and promote the expression of histocompatibility complexes. The splenic lymphocyte proliferation and the enhancement in the proportion of CD4 + and CD8 + T lymphocytes were also observed in immunized animals. In addition, two types of nanospheres could significantly inhabit the replications of T. gondii in cardiac muscles and spleen tissues. All these obtained results in this study demonstrated that the TgRPS2 protein delivered by PLGA or CS nanospheres provided satisfactory immunoprotective effects in resisting T. gondii , and such formulations illustrated potential as prospective preventive agents for toxoplasmosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qi, Yu, Yang, Wang, Jiang, Zhang and Yu.)

The interest in transporter-mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion-transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration-dependent manner for both CP I and CP III in human hepatocytes (PXB-cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild-type ICR mice. Plasma concentrations (AUC 0-8h ) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC 50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24-h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP-mediated drug interactions in PXB mice., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Polyphenols have been well-established to exert sedative-hypnotic effects in psychopharmacology. Lime (Citrus aurantifolia) peel is rich in biologically active polyphenols; however, the effects of lime peel extract on sleep have not yet been demonstrated. A comparison was conducted in mice, between the sleep-promoting effects of a standardized lime peel supplement (SLPS) and a well-known hypnotic drug, zolpidem, and its hypnotic mechanism was investigated using in vivo and in vitro assays. The effects of SLPS on sleep were assessed using a pentobarbital-induced sleep test and sleep architecture analysis based on recording electroencephalograms and electromyograms. Additionally, a GABA A receptor binding assay, electrophysiological measurements, and in vivo animal models were used to elucidate the hypnotic mechanism. SLPS (200 and 400 mg/kg) was found to significantly decrease sleep latency and increase the amount of non-rapid eye movement sleep without altering delta activity. The hypnotic effects of SLPS were attributed to its flavonoid-rich ethyl acetate fraction. SLPS had a binding affinity to the GABA-binding site of the GABA A receptor and directly activated the GABA A receptors. The hypnotic effects and GABA A receptor activity of SLPS were completely blocked by bicuculline, a competitive antagonist of the GABA A receptor, in both in vitro and in vivo assays. To the best of our knowledge, this study is the first to demonstrate the hypnotic effects of SLPS, which acts via the GABA-binding site of the GABA A receptor. Our results suggest that lime peel, a by-product abundantly generated during juice processing, can potentially be used as a novel sedative-hypnotic., 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 Masson SAS.. All rights reserved.)

Streptococcus agalactiae (S. agalactiae) is an opportunistic pathogen, and to date, studies have mainly focused on S. agalactiae strains isolated from humans, dairy cows, and fish. We reported one S. agalactiae strain, named CFFB, which was isolated from a healthy Sichuan golden snub-nosed monkey. Classical bacteriological approaches, as well as, next-generation sequencing, comparative genomics, and mice challenge test were used to characterize this strain. CFFB was identified as serotype III, ST19 combination which is a common type found in human strains. Phylogenetic analysis showed that the genome of CFFB was closely related to human clinical isolates, rather far away from animal strains. In total, CFFB contained fewer virulence-associated genes and antibiotic resistance genes than human isolates that were close to CFFB in evolutionary relationships. In the mice challenge test, CFFB had a relative weak virulence that just caused death in 33 % of ICR mice at a dose of 10 8  CFU by intraperitoneal injection, and CFFB was reisolated from the cardiac blood of the dead mice. Meanwhile, two intact prophages (prophage 1 and 2) were identified in the CFFB genome and shared high similarities with phage Javan52 and Javan29 which from human S. agalactiae isolate Gottschalk 1002A and RBH03, respectively. Moreover, the type II-A CRISPR-Cas system was detected in the CFFB genome, and the spacers from CFFB were the same to the streptococci isolates from human. These results suggest that CFFB isolated from healthy Sichuan golden snub-nosed monkeys may have its origin in human S. agalactiae. Our results suggested some genomic similarities between the S. agalactiae colonized in Sichuan golden snub-nosed monkey and those in infected humans., 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.)

Peritoneal immune cell function is a reliable indicator of aging and longevity in mice and inflammaging is associated with a shorter lifespan. Nevertheless, it is unknown if the content of cytokines in these immune cells is linked to individual differences in lifespan. Therefore, this work aimed to investigate different peritoneal leukocyte populations and their content in intracellular pro-inflammatory (TNF and IL-6) and anti-inflammatory (IL-10) cytokines by flow cytometry in adult (10 months-old, n = 8) and old (18 months-old, n = 20) female Swiss/ICR mice. In addition, old mice were monitored longitudinally throughout their aging process, and the same markers were analyzed at the very old (24 months-old, n = 8) and long-lived (30 months-old, n = 4) ages. The longitudinal follow-up allowed us to relate the investigated parameters to individual lifespans. The results show that long-lived female mice exhibit an adult-like profile in most parameters investigated but also display specific immune adaptations, such as increased CD4+ and CD8+ T cells containing the pro-inflammatory TNF cytokine and CD4+ T cells and macrophages containing the anti-inflammatory cytokine IL-10. These adaptations may underlie their exceptional longevity. In addition, a negative correlation was obtained between the percentage of cytotoxic T cells, KLRG-1/CD4, large peritoneal macrophages, and the percentage of CD4+ T cells containing IL-6 and macrophages containing IL-10 in old age and lifespan, whereas a positive correlation was found between the CD4/CD8 ratio and the longevity of the animals at the same age. These results highlight the crucial role of peritoneal leukocytes in inflammaging and longevity., (© 2024. The Author(s).)

Selenium supplements are beneficial to human health, however, concerns regarding the toxicity of inorganic selenium have stimulated research on safer organic compounds. The main objective of this study was to develop a novel glucosamine-selenium compound (Se-GlcN), clarify its structure, and subsequently investigate its oral toxicity and in vitro anti-hepatitis B virus (HBV) activity. Electron microscopy, infrared, ultraviolet spectroscopy, nuclear magnetic resonance and thermogravimetric analyses revealed a unique binding mode of Se-GlcN, with the introduction of the Se-O bond at the C6 position, resulting in the formation of two carboxyl groups. In acute toxicity studies, the median lethal dose (LD 50 ) of Se-GlcN in ICR mice was 92.31 mg/kg body weight (BW), with a 95 % confidence interval of 81.88-104.07 mg/kg BW. A 30-day subchronic toxicity study showed that 46.16 mg/kg BW Se-GlcN caused livers and kidneys damage in mice, whereas doses of 9.23 mg/kg BW and lower were safe for the livers and kidneys. In vitro studies, Se-GlcN at 1.25 μg/mL exhibited good anti-HBV activity, significantly reducing HBsAg, HBeAg, 3.5 kb HBV RNA and total HBV RNA by 45 %, 54 %, 84 %, 87 %, respectively. In conclusion, the Se-GlcN synthesized in this study provides potential possibilities and theoretical references for its use as an organic selenium supplement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The TRPV1 channel is actively involved in various neuronal processes and is found in various structures of the nervous system, including peripheral and central neurons, sensory ganglia, spinal cord, and various parts of the brain. Due to its ability to respond to various stimuli, TRPV1 can have a significant impact on the body's responses to stress. Studies indicate the involvement of TRPV1 in the regulation of anxiety behavior. Suppression of TRPV1 activity leads to a decrease in the level of anxiety in animals, which indicates the importance of this channel in psychoemotional regulation. A promising compound for inhibiting this channel is the APHC3 peptide, which is a selective receptor antagonist. The results obtained this study show that this peptide has a pronounced anxiolytic effect, reducing the level of anxiety in the studied animals., (© 2024. Pleiades Publishing, Ltd.)

In the present study, the effects of levamlodipine benzenesulfonate on the development of fertile Sprague-Dawley (SD) rats, their embryos, and littermates were assessed using an embryo-fetal developmental toxicity test. Maternal body weight reduction was observed at a dose of 20 mg/kg, but it recovered after treatment cessation. The 20 mg/kg dose group showed a skewed sex ratio in fetal rats, with a higher proportion of males. While some effects on fetal sternum development were observed at 20 mg/kg, no skeletal malformations were observed. No significant gross morphological abnormalities were detected in the dams (mothers), no significant embryotoxicity or foetotoxicity in fetal rats and no significant effects on fetal length and weight development at doses of 5 and 10 mg/kg. Genotoxicity was evaluated using a combination of the Ames test, the Chinese hamster ovary (CHO) cell chromosome aberration assay, and the ICR mouse bone marrow micronucleus test. The Ames test results indicated substantial bacteriostatic effects at doses of 500 and 5000 mg/dish, with no mutagenicity observed at doses of 0.5, 5, and 50 mg/dish. No significant effect on the aberration rate of CHO cell chromosomes was found at doses of 2.8, 5.6, and 11.2 mg/mL. In the ICR mouse micronucleus test, no micronucleus-inducing effect was observed at doses of 3.125, 6.25, and 12.5 mg/kg in each treatment group. In conclusion, under the conditions of this experiment, the no-observed-adverse-effect level (NOAEL) for developmental toxicity of levamlodipine benzenesulfonate in fertile SD rats, their embryos, and littermates was established to be 10 mg/kg/day. Levamlodipine benzenesulfonate did not exhibit significant genotoxicity., 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. Published by Elsevier Inc.)

Background: Hand, foot and mouth disease (HFMD) is a common infectious disease caused by viral infection by a variety of enteroviruses, with coxsackievirus A 10 (CA10) having become more prevalent in recent years., Methods: In this study, models of CA10 infection were established in 7-day-old Institute of Cancer Research (ICR) mice by intraperitoneal injection to analyze the pathogenicity of the virus. RNA sequencing analysis was used to screen the differentially expressed genes (DEGs) after CA10 infection. Coxsackievirus A 16 (CA16) and enterovirus 71 (EV71) infections were also compared with CA10., Results: After CA10 virus infection, the mice showed paralysis of the hind limbs at 3 days post infection and weight loss at 5 days post infection. We observed viral replication in various tissues and severe inflammatory cell infiltration in skeletal muscle. The RNA-sequencing analysis showed that the DEGs in blood, muscle, thymus and spleen showed heterogeneity after CA10 infection and the most up-regulated DEGs in muscle were enriched in immune-related pathways. Compared with CA16 and EV71 infection, CA10 may have an inhibitory effect on T helper (Th) cell differentiation and cell growth. Additionally, the common DEGs in the three viruses were most enriched in the immune system response, including the Toll-like receptor pathway and the nucleotide-binding and oligomerization domain (NOD)-like pathway., Conclusions: Our findings revealed a group of genes that coordinate in response to CA10 infection, which increases our understanding of the pathological mechanism of HFMD., (© 2024 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

We explored the effect of Ninjinyoeito (NYT) on cisplatin-induced anorexia, which reduces cancer patient survival. Both gastrointestinal motility and plasma concentrations of gastrointestinal peptides were assessed. Nine-week-old ICR female mice received intraperitoneal cisplatin injections (10 mg/kg) and daily oral NYT doses of 300 mg/kg (NYT300) or 1000 mg/kg (NYT1000). Plasma levels of gastrointestinal peptides were measured at 3 and 6 days after cisplatin injection. Gastrointestinal motility was assessed by analyzing the concentration of phenol red marker within sections of the gastrointestinal tract. Cisplatin-injected mice showed a decrease in daily food intake, but this effect was attenuated on day 5 with NYT1000 administration. Although plasma ghrelin levels were reduced on day 3 in cisplatin-treated mice, NYT1000 administration ameliorated this decrease. However, there were no differences in ghrelin levels among all groups on day 6. Levels of peptide YY (PYY) were elevated in the plasma of cisplatin-injected mice on days 3 and 6. Administration of NYT300 and NYT1000 suppressed the increase in PYY levels on day 6 but not on day 3. Gastrointestinal motility was impaired on day 6 in cisplatin-treated mice, but NYT1000 administration attenuated this effect. Our results suggest that NYT improves cisplatin-induced anorexia by suppressing alterations in ghrelin and PYY levels and by increasing gastrointestinal motility. Therefore, NYT may be a promising candidate for alleviating cisplatin-induced anorexia., Competing Interests: Declaration of competing interest Authors declare that there is no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Neohesperidin, a citrus flavonoid, shows potential for activating the mechanistic target of rapamycin complex 1 (mTORC1). Here, the antidepressant-like effect of neohesperidin was examined in male ICR mice (naïve mice and mice treated repeatedly with prednisolone, a synthetic glucocorticoid, which induces depression-like behavior). Oral neohesperidin administration exerted an antidepressant-like effect in the forced swim test 1 h post-treatment, in naïve mice; this effect was no longer observed at 24 h. Neohesperidin also reversed prednisolone-induced depression-like behavior. This effect was blocked by infusing rapamycin, an mTORC1 inhibitor, into the medial prefrontal cortex. Neohesperidin may rapidly produce an antidepressant-like effect., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Type-1 diabetes mellitus (T1DM) is associated with numerous health problems, including peripheral neuropathy, osteoporosis, and bone denervation, all of which diminish quality of life. However, there are relatively few therapies to treat these T1DM-related complications. Recent studies have shown that Janus kinase (JAK) inhibitors reverse aging- and rheumatoid arthritis-induced bone loss and reduce pain associated with peripheral nerve injuries, and rheumatoid arthritis. Thus, we assessed whether a JAK1/JAK2 inhibitor, baricitinib, ameliorates mechanical pain sensitivity (a measure of peripheral neuropathy), osteoporosis, and bone denervation in the femur of mice with T1DM., Methods: Female ICR mice (13 weeks old) received five daily administrations of streptozotocin (ip, 50 mg/kg) to induce T1DM. At thirty-one weeks of age, mice were treated with baricitinib (po; 40 mg/kg/bid; for 28 days) or vehicle. Mechanical sensitivity was evaluated at 30, 33, and 35 weeks of age on the plantar surface of the right hind paw. At the end of the treatment, mice were sacrificed, and lower extremities were harvested for microcomputed tomography and immunohistochemistry analyses., Results: Mice with T1DM exhibited greater blood glucose levels, hind paw mechanical hypersensitivity, trabecular bone loss, and decreased density of calcitonin gene-related peptide-positive and tyrosine hydroxylase-positive axons within the marrow of the femoral neck compared to control mice. Baricitinib treatment significantly reduced mechanical hypersensitivity and ameliorated sensory and sympathetic denervation at the femoral neck, but it did not reverse trabecular bone loss., Conclusions: Our findings suggest that baricitinib may represent a new therapeutic alternative to treat T1DM-induced peripheral neuropathy and bone denervation., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Bisphenol M (BPM), an alternative to bisphenol A (BPA), is commonly utilized in various industrial applications. However, BPM does not represent a safe substitute for BPA due to its detrimental effects on living beings. This research aimed to assess the influence of BPM exposure on the in vitro maturation of mouse oocytes. The findings revealed that BPM exposure had a notable impact on the germinal vesicle breakdown (GVBD) rate and polar body extrusion (PBE) rate throughout the meiotic progression of mouse oocytes, ultimately resulting in meiotic arrest. Investigations demonstrated that oocytes exposure to BPM led to continued activation of spindle assembly checkpoint. Further studies revealed that securin and cyclin B1 could not be degraded in BPM-exposed oocytes, and meiosis could not realize the transition from the MI to the AI stage. Mechanistically, BPM exposure resulted in abnormal spindle assembly and disrupted chromosome alignment of oocytes. Additionally, abnormal positioning of microtubule organizing center-associated proteins implied that MTOC may be dysfunctional. Furthermore, an elevation in the acetylation level of α-tubulin in oocytes was observed after BPM treatment, leading to decreased microtubule stability. In addition to its impact on microtubules, BPM exposure led to a reduction in the expression of the actin, signifying the disruption of actin assembly. Further research indicated a heightened incidence of DNA damage in oocytes following BPM exposure. Besides, BPM exposure induced alterations in histone modifications. The outcomes of this experiment demonstrate that BPM exposure impairs oocyte quality and inhibits meiotic maturation of mouse oocytes., 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.)

Aim: The binding of integrin αvβ3 with endometrial fibronectin (FN) promotes the migration of preimplantation embryos in mice. We have previously shown that cyclosporine A (CsA) improves the adhesion and invasion of mouse preimplantation embryos. In this study, we evaluated the roles of calcium ions and downstream signaling factors in the binding of integrin αvβ3 to FN., Methods: Female Institute of Cancer Research (ICR) mice were superovulated and mated, and two-cell embryos were harvested from the oviducts and cultured to the blastocyst stage The adhesion and stretching growth of hatched embryos in laminin-coated dishes were evaluated, and integrinβ3 expression was determined using qPCR. Blastocytes were cultured with 0 or 1  μM cyclosporine A (CsA) and the attachment of embryonic integrin αvβ3 to FN120 was observed using a fluorescent bead. To further determine the mechanism, the cells were also incubated with calcium ions and protein kinase C and calmodulin antagonists. The binding of integrin αvβ3 to FN120 was examined via confocal laser scanning microscopy., Results: The adhesion and stretching growth of peri-implantation embryos were greater and integrinβ3 expression was higher in the 1 μM CsA group than in the 0 μM CsA group (p < 0.05). When incubated with calcium ions and protein kinase C and calmodulin antagonists, the ability of peri-implantation embryos to bind to FN decreased; CsA treatment promoted this binding., Conclusion: This study revealed that CsA up - regulates integrinβ3 expression in peri - implantation embryos and promotes binding to FN via calcium ions, and protein kinase C, and calmodulin. These findings provide evidence supporting the beneficial effect of CsA on the peri - implantation embryo adhesion., (© 2024 The Author(s). Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Sheng-ma is recorded in the Compendium of Materia Medica and mainly originates from the rhizomes of Cimicifuga dahurica (Turcz.) Maxim. (CD), Cimicifuga heracleifolia Kom. and Cimicifuga foetida L. The alcoholic extract of Cimicifuga foetida L. (Brand name: Ximingting®) has been approved for the treatment of perimenopausal symptoms accompanying hot flash, depression and anxiety in China. However, there's no further study about the antidepressant-like effects of C. dahurica (CD). The aim of this study is to investigate the antidepressant-like effect of CD extracted by 75% ethanol and its possible mechanisms.The neuro-protective effects of CD on injured PC12 cells induced by corticosterone was measured firstly. Then, forced swim test (FST), tail suspension test (TST), reserpine-induced hypothermia, 5-hydroxytryptophan (5-HTP) induced head twitch response in mice and chronic unpredictable mild stress (CUMS) on sucrose preference tests were executed. Moreover, the potential mechanisms were explored by measuring levels of monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme A (MAO-A) activities in the brains of CUMS-exposed mice. Results showed that CD (60, 120 mg/kg) can significantly decreased the immobility period in FST and TST in mice without affecting locomotor activity. CD (30 mg/kg, 60 mg/kg, 120 mg/kg) could significantly counteracted reserpine-induced hypothermia and increased the number of head-twitches in 5-HTP induced head twitch response. It was also found that the monoamine neurotransmitter levels in the hippocampus and frontal cortex were significantly increased in 60 mg/kg and 120 mg/kg CD treated mice. In addition, CD (60 and 120 mg/kg) significantly inhibited MAO-A after 6-week CUMS exposure. CD can effectively produce an antidepressant-like effect, which involved with modulation of monoamine regulatory pathways., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Our previous studies have demonstrated a strong relationship betweenCutibacterium acnes(C. acnes), oxidative stress, and acne inflammation. Syringic acid (SA) is a plant widely used for its antimicrobial, anti-inflammatory, and antioxidant activities, but lacking data on acne. This study aims to investigate the effect and mechanism of SA on acne inflammation induced by C. acnes in vitro and in vivo., Methods: After using the SA to expose HaCaT keratinocytes, we reevaluated the effect of the SA on cell viability, cell apoptosis, ROS, CAT, SOD, and other inflammatory variables in the heat-killed C. acnes-treated HaCaT cells. Next, to induce mice with acne inflammation, ICR mice were given an intradermal injection of live C. acnes into their right ears. The effect of SA on this inflammation was then examined. Moreover, we explored the mechanism of SA on PPARγ/Nrf2 and NLRP3/caspase-1/IL-1β pathways by ELISA, immunofluorescence microscopy, and western blot assay., Results: Heat-killed C. acnes triggered remarkable cell apoptosis, ROS production, interleukin (IL)-1β, IL-18, IL-6, and TNF-α release, reduced SOD and CAT activity, and upregulated the expression of proteins in HaCaT cells, including up-regulating IL-1β, PPARγ, Nrf2, HO-1, NQO1, NLRP3, and caspase-1, whereas SA inhibited these effects by partially impairing PPARγ activation. In addition, PPARγ silencing decreased C. acnes-induced IL-1β secretion and the production of intracellular ROS, down-regulating the expression of Nrf2. Nrf2 activator (SFN) enhanced anti-inflammatory activity through antioxidant mechanisms, boosting intracellular ROS production, reducing SOD and CAT activity, and promoting the increase in ROS, HO-1, NQO1, and IL-1β levels, while PPARγ inhibitor (GW662) effectively inhibited this effect in heat-killed C. acnes-treated cells. Finally, SA also exhibited notable improvements in ear redness, swelling, and the expression of PPARγ, NLRP3, and IL-1β in vivo., Conclusions: SA inhibited C. acnes-induced inflammation via regulating the NLRP3/caspase-1/IL-1β signaling axis by activating the PPARγ/Nrf2-antioxidant pathway, suggesting a new treatment possibility for acne vulgaris., 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: 18KHT01 is a novel synergistic composition of Quercus acutissima , Camellia sinensis , Geranium thunbergii , and a small portion of Citrus limon . Our previous report demonstrated that the 18KHT01 exhibits potent antiobesity effects, with synergistic antioxidant, antiadipogenic, and antiobesity activities in diet-induced obese mice. This study explores the toxicity profile and quality control parameters of the 18KHT01 formulation. Methods: Broad-spectrum acute and subacute oral toxicity studies were performed using male and female ICR mice. In order to simultaneous analysis of the 18KHT01 formulation, an ultraperformance liquid chromatography coupled with a diode array detector (UPLC-DAD) method was developed and validated using six marker compounds. Results: Acute oral toxicity evaluation of 18KHT01, administered at single high doses of 2, 2.5, 3, and 5 g/kg, identified 2 g/kg as the no-observed adverse effect level (NOAEL). The LD50 (50% lethal dose) and LD100 (100% lethal dose) of 18KHT01 for male ICR mice were 3.99 and 7.77 g/kg, and those for the female mice were 2.94 and 4.70 g/kg, respectively. In addition, a 30-day repeated dose oral subacute toxicity evaluation indicated that 18KHT01 is safe below 500 mg/kg/day for long-term administration in ICR mice of either sex. UPLC-DAD method validation revealed that each calibration curve for the marker compounds showed good linearity, as well as the validation parameters such as precision, specificity, and accuracy met the acceptance criteria. Conclusion: The present study evidenced the toxicological profile of 18KHT01 polyherbal formulation in mice as well as developed a simple, rapid, and accurate chromatographic method for quality control., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Prakash Raj Pandeya et al.)

The neurotoxicity of bisphenol A (BPA) exposure has been confirmed in vitro and in vivo , and inflammatory response is considered the main pathway. Green tea is a healthy life habit as it is rich in various anti-inflammatory components. To confirm that green tea diet is an effective measure to antagonize BPA-induced neurotoxicity, mice were treated with 0.5 and 5000 μg/kg/day of BPA from postnatal days (PNDs) 10-50 and supplemented with green tea on PND 21. From PND 51, behavioral tests were conducted on mice to assess their emotional, cognitive, and spatial learning memory capabilities. The open field test and elevated plus maze test indicated anxiety-like behaviors induced by BPA. Interestingly, green tea diet significantly alleviated BPA-induced anxiety-like behaviors. Meanwhile, the green tea diet effectively reversed BPA-induced microglia activation and morphological changes in the hippocampus of mice. Molecularly, green tea inhibited hippocampal neuroinflammation of mice by reducing BPA-induced expressions of NLRP3, ASC, cleaved-caspase-1, GSDMD-N, IL-6, and IL-1β, as well as significantly reducing the expression of Bak1, Bax, caspase-9, and Cytc c genes ( p < 0.05). Molecular docking suggests that various anti-inflammatory components of green tea can competitively bind to the estrogen receptors with BPA. In general, a green tea diet alleviates BPA-induced emotional disorders by inhibiting microglial polarization and hippocampal pyroptosis, indicating its effective antagonistic ability against the neurotoxicity induced by environmental BPA exposure.

As organophosphorus flame retardants (OPFRs) are constantly detected in human samples, the neurotoxicity of OPFRs is of concern. In this study, pregnant ICR mice were exposed to 2-ethylhexyl diphenyl phosphate (EHDPP) in drinking water from gestation to lactation to investigate its effects on autism spectrum disorder-like (ASD-like) behaviors in offspring. Serum EHDPP concentrations in dams in the 0.4, 2, and 10 mg/kg groups were 0.282 ± 0.051, 0.713 ± 0.115, and 0.974 ± 0.048 ng/mL, respectively, within the concentration range in humans. At the highest dose, EHDPP exposure induced ASD-like behaviors in both female and male offspring. Significant reductions in mature dendritic spines and structural damage to the postsynaptic density zone were noted in all but the lowest exposure groups, indicating postsynaptic membrane impairment. Mechanistically, EHDPP significantly downregulated disc large MAGUK scaffold protein 4 expression by inhibiting protein kinase B and type 1 insulin-like growth factor receptor phosphorylation. In the heterologous synapse formation assay in vivo , EHDPP significantly reduced the levels of postsynaptic density protein 95 expression in neurons at 1 μM. Overall, the study utilized in vitro and in vivo experiments to confirm that EHDPP damaged postsynaptic membrane formation and might increase the incidence of ASD in offspring.

The etiology and pathological complexity of acute kidney injury (AKI) pose great challenges for early diagnosis, typing, and personalized treatment. It is an important reason for poor prognosis and high mortality of AKI. In order to provide a relatively noninvasive diagnostic and typing method for AKI, we proposed the pathological changes of albumin permeability after glomerular injury and reabsorption efficiency after tubular injury as potential entry points. Thus, a renal tubule labeling fluorescent dye which features albumin concentration-related fluorescence intensity was used to fit these pathological changes. Utilizing this fluorescence assay, we realized urinary tract obstruction imaging as early as 12 h after morbidity. For glomerular and tubular injury discrimination, compared to a healthy control, membranous nephropathy as a representative glomerular injury resulted in enhanced fluorescence intensity of the kidney due to increased albumin penetration, while renal tubular injury caused insufficient dye reabsorption to exhibit weakened fluorescence intensity. The significant differences demonstrated the feasibility of this approach for fluorescence imaging-based AKI typing in vivo.

Cisplatin (CDDP) is a platinum-based anticancer drug widely prescribed for its effectiveness in treating various forms of cancer. However, its major side effect is nephrotoxicity. Although several methods have been developed to mitigate CDDP-induced nephrotoxicity, an optimal approach has yet to be established. This study aimed to investigate the "chronotoxicity" of CDDP as a potential strategy to reduce its side effects. Male ICR mice were treated with CDDP (20 mg/kg, intraperitoneal injection, one shot) at zeitgeber time (ZT) 2 or ZT14 (light or dark phase). After 72 h, we collected plasma and kidney and evaluated several markers. We found that body weight change between ZT2 and ZT14 by CDDP was comparable. In contrast, many toxicological factors, such as plasma blood urine nitrogen, plasma creatinine, renal oxidative stress (malondialdehyde), DNA damage (γH2AX), acute kidney injury biomarker (KIM-1), and inflammation (Tnfα), were significantly induced at ZT14 compared to than that of ZT2. Our present data suggested that chronotoxicology might provide beneficial information on the importance of administration timings for toxic evaluations and unacceptable side effects., 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.)

Lactation women, a highly concerned demographic in society, face health risks that deserve attention. Zinc oxide nanoparticles (ZnO NPs) are widely utilized in food and daily products due to their excellent physicochemical properties, leading to the potential exposure of lactating women to ZnO NPs. Hence, assessing the potential risks associated with ZnO NP exposure during lactation is critical. While studies have confirmed that exposure to ZnO NPs during lactation can induce toxic responses in multiple organs through blood circulation, the effects of lactational exposure on mammary tissue remain unclear. This research investigated the impairment of mammary tissue induced by ZnO NPs and its potential mechanisms. Through administering multiple injections of ZnO NPs into the tail vein of lactating ICR mice, our study revealed that ZnO NPs can deposit in the mammary tissues, downregulating key components of mammary epithelial barrier such as ZO-1, occludin, and claudin-3. In vivo, we also found that ZnO NPs can simultaneously induce apoptosis, necroptosis, and pyroptosis, called PANoptosis. Additionally, using EpH4-Ev cells to simulate an in vitro mammary epithelial barrier model, we observed that ZnO NPs effectively disrupted the integrity of mammary epithelial barrier and induced PANoptosis. Furthermore, we confirmed that PANoptosis was responsible for the mammary epithelial barrier disruption induced by ZnO NPs. Moreover, we identified that ZBP1 was the primary mechanism of ZnO NPs inducing PANoptosis. These discoveries are designed to enhance our comprehension of the mechanisms underlying mammary epithelial barrier disruption caused by ZnO NPs, and we aim to highlight the potential hazards associated with daily usage and therapeutic exposure to ZnO NPs during lactation., 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.)

Propylparaben (PrPB) is a known endocrine disrupting chemicals that is widely applied as preservative in pharmaceuticals, food and cosmetics. PrPB has been detected in human urine samples and human serum and has been proven to cause functional decline in reproduction. However, the direct effects of PrPB on mammalian oocyte are still unknown. Here, we demonstrationed that exposure to PrPB disturbed mouse oocyte maturation in vitro, causing meiotic resumption arrest and first polar body extrusion failure. Our results indicated that 600 μM PrPB reduced the rate of oocyte germinal vesicle breakdown (GVBD). Further research revealed that PrPB caused mitochondrial dysfunction and oxidative stress, which led to oocyte DNA damage. This damage further disturbed the activity of the maturation promoting factor (MPF) complex Cyclin B1/ Cyclin-dependent kinase 1 (CDK1) and induced G2/M arrest. Subsequent experiments revealed that PrPB exposure can lead to spindle morphology disorder and chromosome misalignment due to unstable microtubules. In addition, PrPB adversely affected the attachment between microtubules and kinetochore, resulting in persistent activation of BUB3 amd BubR1, which are two spindle-assembly checkpoint (SAC) protein. Taken together, our studies indicated that PrPB damaged mouse oocyte maturation via disrupting MPF related G2/M transition and SAC depended metaphase-anaphase transition., 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.)

Long-term exposure to ultraviolet (UV) radiation induces skin photoaging, which manifests as oxidative stress, inflammation, and collagen degradation. Multiple approaches (topical or systemic retinoids, antioxidants, alpha-hydroxy acids, laser, surgery) are used in the treatment of photoaged skin, and the use of topical retinoids is currently a primary clinical treatment. Previous studies revealed that retinoic acid promotes keratinocyte proliferation and reduces melanin deposition and matrix metalloproteinase (MMP) secretion; it also causes potential allergic and inflammatory damage to the skin. This study aimed to investigate the therapeutic effects and mechanisms of trifarotene, a functional retinoic acid analog, on UV-irradiated photoaging ICR and BALB/c nude mice and UVB photodamaged human epidermal keratinocyte (HaCaT) cells by examining indicators such as collagen, oxidoreductase, and inflammatory factor presence through histochemical staining, Western blot, and ELISA. Results suggested that trifarotene significantly reduced UV-induced photoaging in mouse skin tissue, potentially by reducing oxidative stress damage and inflammatory factor release, and inhibiting melanin deposition and collagen degradation by downregulating MMP expression. Concentrations of malondialdehyde, tyrosinase, interleukin-6, interleukin- 12, and tumor necrosis factor-alpha in photoaged skin decreased, while SOD content in photodamaged HaCaT cells significantly increased. Trifarotene (3.3 μmol L-1) inhibited phosphorylated JNK and c-Jun expression both independently and collaboratively with the JNK activator anisomycin, demonstrating that trifarotene mitigates UV-induced collagen degradation and apoptosis through inhibition of the JNK/c-Jun/MMPs signaling pathway., (© 2024 Xuan Fei et al., published by Sciendo.)

Microplastics (MPs), a brand-new class of worldwide environmental pollutant, have received a lot of attention. MPs are consumed by both humans and animals through water, food chain and other ways, which may cause potential health risks. However, the effects of MPs on embryonic development, especially placental function, and its related mechanisms still need to be further studied. We investigated the impact on fetal development and placental physiological function of pregnant mice by consecutive gavages of MPs at 0, 25, 50, 100 mg/kg body weight during gestational days (GDs 0-14). The results showed that continuous exposure to high concentrations of MP significantly reduced daily weight gain and impaired reproductive performance of pregnant mice. In addition, MPs could significantly induce oxidative stress and placental dysfunction in pregnant mice. On the other hand, MPs exposure significantly decreased placental barrier function and induced placental inflammation. Specifically, MPs treatment significantly reduced the expression of tight junction proteins in placentas, accompanied by inflammatory cell infiltration and increased mRNA levels of pro-inflammatory cytokines and chemokines in placentas. Finally, we found that MPs induced placental apoptosis and endoplasmic reticulum (ER) stress through the GRP78/IRE1α/JNK axis, leading to placental dysfunction and decreased reproductive performance in pregnant mice. We revealed for the first time that the effects of MPs on placental dysfunction in pregnant animals. Blocking the targets of MPs mediated ER stress will provide potential therapeutic ideas for the toxic effects of MPs on maternal pregnancy., (© 2024. The Author(s).)

Introduction: Photoaging-induced skin damage leads to appearance issues and dermatoma. Selenium nanoparticles (SeNPs) possess high antioxidant properties but are prone to inactivation. In this study, human serum albumin/SeNPs (HSA-SeNPs) were synthesized for enhanced stability., Methods: HSA-SeNPs were prepared by self-assembling denatured human serum albumin and inorganic selenite. The cytotoxicity of HSA-SeNPs was assessed using the MTT method. Cell survival and proliferation rates were tested to observe the protective effect of HSA-SeNPs on human skin keratinocytes against photoaging. Simultaneously, ICR mice were used for animal experiments. H&E and Masson trichromatic staining were employed to observe morphological changes in skin structure and collagen fiber disorders after UVB irradiation. Quantitative RT-PCR was utilized to measure changes in mRNA expression levels of factors related to collagen metabolism, inflammation, oxidative stress regulation, and senescence markers., Results: The HSA-SeNPs group exhibited significantly higher survival and proliferation rates of UVB-irradiated keratinocytes than the control group. Following UVB irradiation, the back skin of ICR mice displayed severe sunburn with disrupted collagen fibers. However, HSA-SeNPs demonstrated superior efficacy in alleviating these symptoms compared to SeNPs alone. In a UVB-irradiated mice model, mRNA expression of collagen type I and III was dysregulated while MMP1, inflammatory factors, and p21 mRNA expression were upregulated; concurrently Nrf2 and Gpx1 mRNA expression were downregulated. In contrast, HSA-SeNPs maintained the mRNA expression of those factors to be stable In addition, the level of SOD decreased, and MDA elevated significantly in the skin after UVB irradiation, but no significant differences in SOD and MDA levels between the HSA-SeNPs group with UVB irradiation and the UVB-free untreated group., Discussion: HSA-SeNPs have more anti-photoaging effects on the skin than SeNPs, including the protective effects on skin cell proliferation, cell survival, and structure under photoaging conditions. HSA-SeNPs can be used to protect skin from photoaging and repair skin injury caused by UVB exposure., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Yao et al.)

The impairment of the immune system by fluoride is a public health concern worldwide, yet the underlying mechanism is unclear. Both riboflavin and IL-17A are closely related to immune function and regulate the testicular toxicity of fluoride. However, whether riboflavin or IL-17A is involved in fluoride-induced immunotoxicity is unknown. Here, we first established a male ICR mouse model by treating mice with sodium fluoride (NaF) (100 mg/L) via the drinking water for 91 days. The results showed that fluoride increased the expression of the proinflammatory factors IL-1β and IL-17A, which led to splenic inflammation and morphological injury. Moreover, the expression levels of the riboflavin transporters SLC52A2 and SLC52A3; the transformation-related enzymes RFK and FLAD1; and the key mitochondrial functional determinants SDH, COX, and ATP in the spleen were measured via real-time PCR, Western blotting, and ELISA. The results revealed that fluoride disrupted riboflavin transport, transformation, metabolism, and mitochondrial function. Furthermore, wild-type (WT) and IL-17A knockout (IL-17A -/- ) C57BL/6 J male mice of the same age were treated with NaF (24 mg/kg·bw, equivalent to 100 mg/L) and/or riboflavin sodium phosphate (5 mg/kg·bw) via gavage for 91 days. Similar parameters were evaluated as above. The results confirmed that fluoride increased riboflavin metabolism through RFK but not through FLAD1. Fluoride also affected mitochondrial function and activated neutrophils (marked with Ly6g) and macrophages (marked with CD68) in the spleen. Interestingly, IL-17A partly mediated fluoride-induced riboflavin metabolism disorder and immunotoxicity in the spleen. This work not only reveals a novel toxic mechanism for fluoride but also provides new clues for exploring the physiological function of riboflavin and for diagnosing and treating the toxic effects of fluoride in the environment., 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: A broad suite of bisphenol S (BPS) derivatives as alternatives for BPS have been identified in various human biological samples, including 4-hydroxyphenyl 4-isopropoxyphenylsulfone (BPSIP) detected in human umbilical cord plasma and breast milk. However, very little is known about the health outcomes of prenatal BPS derivative exposure to offspring., Objectives: Our study aimed to investigate the response of hepatic cholesterol metabolism by sex in offspring of dams exposed to BPSIP., Methods: Pregnant ICR mice were exposed to 5 μ g / kg body weight (BW)/day of BPSIP, BPS, or E2 through drinking water from gestational day one until the pups were weaned. The concentration of BPSIP, BPS, or E2 in the plasma and liver of pups was determined by liquid chromatography-tandem mass spectrometry. Metabolic phenotypes were recorded, and histopathology was examined for liver impairment. Transcriptome analysis was employed to characterize the distribution and expression patterns of differentially expressed genes across sexes. The metabolic regulation was validated by quantitative real-time PCR, immunohistochemistry, and immunoblotting. The role of estrogen receptors (ERs) in mediating sex-dependent effects was investigated using animal models and liver organoids., Results: Pups of dams exposed to BPSIP showed a higher serum cholesterol level, and liver cholesterol levels were higher in females and lower in males than in the controls. BPSIP concentration in the male liver was 1.22 ± 0.25  ng / g and 0.69 ± 0.27  ng / g in the female liver. Histopathology analysis showed steatosis and lipid deposition in both male and female offspring. Transcriptome and gene expression analyses identified sex-specific differences in cholesterol biosynthesis, absorption, disposal, and efflux between pups of dams exposed to BPSIP and those in controls. In vivo , chromatin immunoprecipitation analysis revealed that the binding of ER α protein to key genes such as Hmgcr , Pcsk9 , and Abcg5 was attenuated in BPSIP-exposed females compared to controls, while it was enhanced in males. In vitro , the liver organoid experiments demonstrated that restoration of differential expression induced by BPSIP in key genes, such as Hmgcr , Ldlr , and Cyp7a1 , to levels comparable to the controls was only achieved when treated with a combination of ER α agonist and ER β agonist., Discussion: Findings from this study suggest that perinatal exposure to BPSIP disrupted cholesterol metabolism in a sex-specific manner in a mouse model, in which ER α played a crucial role both in vivo and in vitro . Therefore, it is crucial to systematically evaluate BPS derivatives to protect maternal health during pregnancy and prevent the transmission of metabolic disorders across generations. https://doi.org/10.1289/EHP14643.

Scope: Chalcones are widely present in most plants and have various health beneficial functions. This study investigates the suppressive effect of 13 natural and synthetic chalcones on transformation of aryl hydrocarbon receptor (AhR) induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC) in a cell-free system, Hepa-1c1c7 cells, and liver of ICR mice., Methods and Results: In the cell-free system, cardamonin dose-dependently inhibits AhR transformation. Chalcones with substitution on 2' and/or 6' position is important for the suppressive effect, while the substitution on 4' position is negatively for the effect. Moreover, cardamonin and 2'-hydroxychalcone competitively inhibit the binding of [ 3 H]-3-MC to the AhR. In Hepa-1c1c7 cells, cardamonin inhibits AhR transformation and expression of cytochrome P4501A1 (CYP1A1) in a dose-dependent manner through suppressing TCDD-induced phosphorylation of both AhR and AhR nuclear translocator, heterodimerization of them, and nuclear translocation of AhR. In the liver of mice, oral administered cardamonin also inhibits 3-MC-induced AhR translocation and expression of CYP1A1., Conclusion: Among used chalcones, a natural chalcone cardamonin competitively binds to AhR and suppresses its transformation. Thus, cardamonin is an effective food factor for suppression of the dioxin-caused biochemical alterations and toxicities., (© 2024 Wiley‐VCH GmbH.)

Stressful life events contribute to the onset of major depressive disorder (MDD). We recently demonstrated abnormalities in ubiquitination in the pathophysiology of MDD. However, the underlying molecular mechanisms remain unclear. We investigated the involvement of the ubiquitination system-mediated glutamatergic dysfunction in social impairment induced by chronic social defeat stress (CSDS). Adult C57BL/6J mice were exposed to aggressor ICR male mice for 10 consecutive days. Social impairment was induced by CSDS in the social interaction test 1 days after the last stress exposure. In terms of brain microdialysis, CSDS reduced depolarization-evoked glutamate release in the prefrontal cortex (PFC), which was reversed by a glutamate transporter 1 (GLT-1) inhibitor. Interestingly, the expression of ubiquitinated, but not total GLT-1, was decreased in the PFC of mice exposed to CSDS. The expression of neural precursor cells expressing developmentally downregulated gene 4-like (Nedd4L: E3 ligase for GLT-1), and ubiquitin-conjugating enzyme E2D2 (Ube2d2: E2 ubiquitin-conjugating enzyme for Nedd4L) was also reduced in CSDS mice. Furthermore, the downregulation of the Nedd4L-GLT-1 ubiquitination pathway decreased SIT ratio, but up-regulation increased it even in non-CSDS mice. Taken together, the decrease in GLT-1 ubiquitination may reduce the release of extracellular glutamate induced by high-potassium stimulation, which may lead to social impairment, while we could not find differences in GLT-1 ubiquitination between susceptible and resistant CSDS mice. In conclusion, GLT-1 ubiquitination could play a crucial role in the pathophysiology of MDD and is an attractive target for the development of novel antidepressants., (© 2024 International Society for Neurochemistry.)

The increasing prevalence of sleep dysregulation cases has prompted the search for effective and safe sleep-enhancing agents. Numerous medications used in the treatment of sleep disorders function by enhancing γ -aminobutyric acid neurotransmitter activity. Unfortunately, these substances may induce significant adverse effects in chronic users, such as dependence and motor behavior impairments. Consequently, there is a growing interest in exploring therapeutic sleep-enhancing agents derived from natural sources, with the anticipation of causing less severe side effects. Prunella vulgaris (PV), a perennial plant indigenous to South Korea, exhibits various pharmacological effects, likely attributed to its chemical composition. Rosmarinic acid, one of its components, has previously demonstrated sleep-potentiating properties, suggesting the potential for PV to exhibit similar pharmacological effects. This study aims to investigate the potential effects of repeated administration of PV extract on the sleep behavior, brainwave activity, sleep-wake cycle, and physiological behavior of mice. Findings indicate that PV extracts exhibit sleep-enhancing effects in mice, characterized by prolonged sleep duration and a reduced onset time of pentobarbital-induced sleep. However, PV extracts only reduced alpha wave powers, with minor alterations in wakefulness and rapid-eye-movement sleep duration. In contrast to diazepam, PV extracts lack adverse effects on locomotor activity, motor coordination, or anxiety in mice. Receptor-binding assay and caffeine treatment support the potential involvement of adenosine A 2A receptors in the effects of PV, suggesting distinct mechanisms of action compared to diazepam, despite both exhibiting sleep-altering effects. Overall, our results suggest that PV holds promise as a potential source of sleep-aiding agents., Competing Interests: Three of the co-authors (Sangsu Park, Jeongin Lim, and Heejin Kang) are employees of the company that provided the PV extract used in the study. This company has plans to develop the PV extract into dietary supplements and other products in the future. Additionally, the company assisted with substance analysis such as LC (Liquid Chromatography) for this research.The others have no conflicts of interest., (Thieme. All rights reserved.)