The incidence of cutaneous squamous cell carcinoma (CSCC) is increasing rapidly. This study discussed the effects of artesunate (ART) on CSCC cell proliferation and migration via the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) pathway. MTT assessed cell viability and analyzed the IC50 value (69.26 μM). Accordingly, human CSCC cells (A431) were cultured in vitro, and treated with 70 μM ART, Ferrostatin-1, oe-SLC7A11, and C646, with cell biological behavior assessed.The potential targets of ART were predicted. p53 acetylation and protein stability and ART-p300 binding were examined. Thymusless nude mice were subcutaneously inoculated with A431 cells, and treated with ART and C646. ART-treated A431 cells showed weakened proliferation, migration, lactate dehydrogenase levels, oxidized glutathione/glutathione ratio, reactive oxygen species, malondialdehyde, and active Fe2+ levels, which could be reversed by suppressing ferroptosis. ART promoted p53 acetylation and protein stability and curbed the SLC7A11-GPX4 pathway by targeting p300. ART stimulated ferroptosis via the SLC7A11-GPX4 pathway, thereby repressing CSCC cell proliferation and migration, which were counteracted by p300 inhibition. ART regulated the SLC7A11-GPX4 pathway by up-regulating the p300-p53 axis, thereby hindering tumor growth in vivo. Collectively, ART inhibits CSCC proliferation and migration by modulating the SLC7A11-GPX4 pathway through the p300-p53 axis.

The incidence of cutaneous squamous cell carcinoma (CSCC) is increasing rapidly. This study discussed the effects of artesunate (ART) on CSCC cell proliferation and migration via the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) pathway. MTT assessed cell viability and analyzed the IC50 value (69.26 μM). Accordingly, human CSCC cells (A431) were cultured in vitro, and treated with 70 μM ART, Ferrostatin-1, oe-SLC7A11, and C646, with cell biological behavior assessed.The potential targets of ART were predicted. p53 acetylation and protein stability and ART-p300 binding were examined. Thymusless nude mice were subcutaneously inoculated with A431 cells, and treated with ART and C646. ART-treated A431 cells showed weakened proliferation, migration, lactate dehydrogenase levels, oxidized glutathione/glutathione ratio, reactive oxygen species, malondialdehyde, and active Fe2+ levels, which could be reversed by suppressing ferroptosis. ART promoted p53 acetylation and protein stability and curbed the SLC7A11-GPX4 pathway by targeting p300. ART stimulated ferroptosis via the SLC7A11-GPX4 pathway, thereby repressing CSCC cell proliferation and migration, which were counteracted by p300 inhibition. ART regulated the SLC7A11-GPX4 pathway by up-regulating the p300-p53 axis, thereby hindering tumor growth in vivo. Collectively, ART inhibits CSCC proliferation and migration by modulating the SLC7A11-GPX4 pathway through the p300-p53 axis.

The incidence of cutaneous squamous cell carcinoma (CSCC) is increasing rapidly. This study discussed the effects of artesunate (ART) on CSCC cell proliferation and migration via the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) pathway. MTT assessed cell viability and analyzed the IC50 value (69.26 μM). Accordingly, human CSCC cells (A431) were cultured in vitro, and treated with 70 μM ART, Ferrostatin-1, oe-SLC7A11, and C646, with cell biological behavior assessed.The potential targets of ART were predicted. p53 acetylation and protein stability and ART-p300 binding were examined. Thymusless nude mice were subcutaneously inoculated with A431 cells, and treated with ART and C646. ART-treated A431 cells showed weakened proliferation, migration, lactate dehydrogenase levels, oxidized glutathione/glutathione ratio, reactive oxygen species, malondialdehyde, and active Fe2+ levels, which could be reversed by suppressing ferroptosis. ART promoted p53 acetylation and protein stability and curbed the SLC7A11-GPX4 pathway by targeting p300. ART stimulated ferroptosis via the SLC7A11-GPX4 pathway, thereby repressing CSCC cell proliferation and migration, which were counteracted by p300 inhibition. ART regulated the SLC7A11-GPX4 pathway by up-regulating the p300-p53 axis, thereby hindering tumor growth in vivo. Collectively, ART inhibits CSCC proliferation and migration by modulating the SLC7A11-GPX4 pathway through the p300-p53 axis.

ObjectiveTo explore whether fluoroethylnormemantine （FENM）， an NMDA receptor antagonist， could improve compulsive-like behaviors and to investigate its underlying mechanisms in the RU24969-induced obsessive-compulsive disorder （OCD） mouse model. MethodsThirty-two mice were randomly assigned to four groups： Saline （n=8）， RU24969 （n=8）， RU+FENM （n=8）， and FENM （n=8）. Mice received FENM or an equivalent volume of saline for pre-treatment， followed by RU24969 or saline for model induction 30 minutes later. Behavioral tests were performed 1 hour after modeling， and serum samples were collected to measure the level of brain-derived neurotrophic factor （BDNF）. Evans Blue dye was intravenously injected to assess dye content in brain tissue， thereby evaluating potential blood-brain barrier damage. ResultsFENM treatment significantly improved repetitive stereotyped circling behavior （F=39.850， P＜0.001） and alleviated persistent motor activity （F=50.200， P＜0.001） in RU24969 model mice. Additionally， FENM treatment significantly increased serum BDNF level in RU24969-induced OCD mice （F=18.930， P＜0.001）. ConclusionsFENM ， an NMDA receptor antagonist， may alleviate compulsive behaviors in OCD mice by modulating BDNF levels ， thereby exerting anti-compulsive effects. Neither the RU24969 model nor FENM treatment significantly affectes blood-brain barrier integrity.

Metabolic reprogramming plays a central role in tumors. However, the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood. Here, we try to identify the mechanism by which histone acetyltransferase 1 (HAT1) confers reprogramming of gluconeogenesis/lipogenesis in liver cancer. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl₄)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice. Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver. Protein phosphatase 2 scaffold subunit alpha (PPP2R1A) promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1 (PCK1) serine 90 dephosphorylation to suppress the tumor growth. HAT1 succinylated PPP2R1A at lysine 541 (K541) to block the assembly of protein phosphatase 2A (PP2A) holoenzyme and interaction with PCK1, resulting in the depression of dephosphorylation of PCK1. HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation, leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1 (SREBP1) nuclear accumulation-induced lipogenesis gene expression, which enhanced the tumor growth. In conclusion, succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer. Our finding provides new insights into the mechanism by which post-translational modifications (PTMs) confer the conversion of tumor suppressor function to oncogene.

Seven novel acylphloroglucinol-sesquiterpenoid adducts, designated as dryatraols J-P (1-7), were isolated from the rhizomes of Dryopteris atrata (Wall. ex Kunze) Ching. The structures, including absolute configurations, were elucidated using comprehensive spectroscopic data, calculated ¹³C Nuclear Magnetic Resonance-Diastereotopic Probability Assignment Plus (¹³C NMR-DP4+) probability analysis, and ECD calculations. These structures represent a rare subclass of carbon skeleton of acylphloroglucinol-sesquiterpenoid adducts with a furan ring connecting the acylphloroglucinol and sesquiterpenoid moieties. Notably, compounds 1-6 are the first reported examples of acylphloroglucinol-sesquiterpenoid adducts with dimeric acylphloroglucinol incorporated into the aristolane- or rulepidanol-type sesquiterpene, while compound 7 features a hydroxylated monomeric acylphloroglucinol motif. A preliminary evaluation of their antiviral activities revealed that compounds 1-6 exhibited more potent activities against respiratory syncytial virus (RSV) with IC₅₀ values ranging from 0.75 to 3.12 μmol·L^-1 compared to the positive control (ribavirin).
Antiviral Agents/isolation & purification* ; Phloroglucinol/isolation & purification* ; Sesquiterpenes/isolation & purification* ; Molecular Structure ; Dryopteris/chemistry* ; Respiratory Syncytial Viruses/drug effects* ; Humans ; Rhizome/chemistry* ; Drugs, Chinese Herbal/pharmacology*

Pancreatic cancer is one of the most malignant tumors with a 5-year survival rate of 13%. Difficulty in early diagnosis,high tumor heterogeneity,high rate of drug resistance,and lack of effective new drugs are the main reasons for the poor therapeutic effect. Traditional cell line models cannot simulate the tumor environment in vitro and cannot reflect the heterogeneity of pancreatic cancer,while animal models have a long culture process and cannot be used for high-throughput screening. Pancreatic cancer organoids can be continuously expanded and cultured in vitro,which can realistically reflect the heterogeneity of pancreatic cancer and allow high-throughput drug screening,making it an ideal tool for individualized precision diagnosis and treatment of pancreatic cancer. According to recent studies on the evaluation of clinical drug efficacy using pancreatic cancer organoids,the drug sensitivity of pancreatic cancer organoids is highly consistent with the clinical efficacy,demonstrating the feasibility of drug sensitivity of pancreatic cancer organoids in guiding clinical therapy,comfirming the ability to discover potential therapeutic drugs through high-throughput drug screening of pancreatic cancer organoids. At the same time,this review reveals the importance of pancreatic cancer organoids as a model of the pancreatic cancer microenvironment for the development of new drugs and tumor microenvironment research. and the role of pancreatic cancer organoids as a model that can reflect the specific microenvironment of pancreatic cancer for new drug discovery and microenvironmental evaluation. Pancreatic cancer organoids and organ-on-chips are powerful tools for precision companion therapy and new drug discovery.

Objective To explore whether the environmental pollutant triclosan(TCS)has negative effects on the various biological characteristics of dental pulp stem cells(DPSCs),as well as the distribution and hazards of TCS in rat dental pulp tissue in vivo,which will provide a basis for the clinical application of DPSCs and the safety of TCS.Methods Tooth collection was approved by the Ethics Committee of Tianyou Hospital Affiliated to Wuhan University of Science and Technology.Human DPSCs were extracted,cultured,and identified.Up to 0.08 mmol/L of TCS was added to the in vitro culture medium of DPSCs.The proliferation ability of DPSCs was detected by CCK-8.The migration ability of DPSCs was detected via scratch assay.The differentiation ability of DPSCs was detected by inducing trilineage differenti-ation.The gene or protein expression levels of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6),interleukin-10(IL-10),inducible nitric oxide synthase(iNOS),and transforming growth factor-β(TGF-β)in DPSCs were detected.The level of reactive oxygen species(ROS)generated by DPSCs was analyzed using fluorescence staining.Changes in mitochondrial membrane potential of DPSCs were detected using a fluorescent probe.The activity of PI3K/Akt/mTOR,p38,and JNK pathways of DPSCs were detected.Animal experiments were approved by the Animal Ethics Committee of Wuhan University of Science and Technology.A rat model of short-term oral exposure to 50 mg/kg/d of TCS for 2 months was established,and the TCS concentration in the liver,brain,and dental pulp tissues of rats was detected through liquid chromatography-mass spectrometry.Results TCS at 0.02 mmol/L,0.04 mmol/L,and 0.08 mmol/L significantly inhibited the proliferation ability of human-derived DPSCs on the 5th and 7th days of contact.TCS at 0.04 mmol/L and 0.08 mmol/L significantly inhibited the migration ability and tri-lineage differentiation ability of DPSCs on the 3rd day of contact.TCS induced the gene or protein expression of proinflammatory factors including TNF-α,IL-1β,IL-6,and iNOS,induced the gene or protein expression of TGF-β,and inhibited the protein expression of anti-inflammatory factor IL-10.On day 1,TCS at 0.04 mmol/L and 0.08 mmol/L induced the production of ROS in DPSCs and reduced the mitochondrial membrane potential of DPSCs.On day 3,TCS at these levels inhibited PI3K/Akt/mTOR pathway activity and enhanced p38 pathway activity of DPSCs,without affecting the pathway activity of JNK.After short-term intragastric exposure of rats to TCS,TCS was detected in liver(430 ng/mL)and brain(41.4 ng/mL)tissues but not in the dental pulp.The TCS concentration was highest in the liver,but no obvious histopathological changes were observed.Conclusion TCS inhibits a variety of biological characteristics of DPSCs and poses a potential risk to the organism.No TCS exists in the dental pulp tissue of rats exposed to TCS for a brief period of time,and the health of the rats is not damaged.

Objective:To investigate the techniques of digit-tip replantation with anastomosis of superior digital arch artery in children and to evaluate the clinical effects.Methods:From January 2020 to September 2022, 62 children (62 digits) with completely severed digit-tips were admitted to the Department of Paediatric Orthopaedics, Suzhou Ruihua Orthopaedic Hospital. All the injury planes were distal to the nail root. All arterial dissections were distal to the digital arterial arch with the vessel calibre from 0.15 mm to 0.35 mm. The superior arch arteries of the digital arterial arch were successfully anastomosed. After surgery, a significant blood flux to the replanted digit body were observed. Postoperative necroses or failures were analysed for the causes. All children with survived digit-tips were entered into scheduled follow-ups through a combination of visit of outpatient clinics or via WeChat and telephone reviews. Postoperative follow-up included digit body fullness, motion of distal interphalangeal joint, nail growth, scarring, and response of the replanted digit-tips to needling. Clinical outcomes were evaluated according to the evaluation criteria for finger replantation function.Results:Of the 62 replanted digit-tips, 56 survived after replantation. Two digits had wound infection after surgery, and survived by dressing change and applying sensitive antibiotics. Necrosis occurred in 6 replanted digit-tips, of which 2 necrotic digit bodies were amputated, and the stumps at the distal interphalangeal joint were repaired. The other 4 necrotic digits were healed after dressing change under the scab due to a smaller digit body. A total of 52 children (including 2 survivals from postoperative infection after dressing changes and 4 survivals with healing underneath-eschar after necrosis) and with 10 lost during follow-up (including 2 with stump repairs after necrosis). The follow-up period ranged from 2 to 30 months, with an average of 6 months. The shape and function of replanted digit-tips recovered well. According to the evaluation criteria for finger replantation function, 44 digits were of excellent, 6 of good, and 2 of fair.Conclusion:In children, the superior arch arteries of digital arterial arches of the digit-tips are small in diameter. However, the vessels in smaller calibres can be anastomosed, should proper surgical techniques are applied. Therefore, due to the satisfactory outcomes, microsurgeons should try the best efforts to replant a digit severed at the plane of digit-tip.

Background::Prenatal and postnatal factors may have joint effects on cardiovascular health, and we aimed to assess the joint association of birth weight and ideal cardiovascular health metrics (ICVHMs) prospectively in adulthood with incident cardiovascular disease (CVD).Methods::In the UK Biobank, 227,833 participants with data on ICVHM components and birth weight and without CVD at baseline were included. The ICVHMs included smoking, body mass index, physical activity, diet information, total cholesterol, blood pressure, and hemoglobin A1c. The Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) in men and women.Results::Over a median follow-up period of 13.0 years (2,831,236 person-years), we documented 17,477 patients with incident CVD. Compared with participants with birth weights of 2.5-4.0 kg, the HRs (95% CIs) of CVD among those with low birth weights was 1.08 (1.00-1.16) in men and 1.23 (1.16-1.31) in women. The association between having a birth weight <2.5 kg and CVD risk in men was more prominent for those aged <50 years than for those of older age ( P for interaction = 0.026). Lower birth weight and non-ideal cardiovascular health metrics were jointly related to an increased risk of CVD. Participants with birth weights <2.5 kg and ICVHMs score 0-1 had the highest risk of incident CVD (HR [95% CI]: 3.93 [3.01-5.13] in men; 4.24 [3.33-5.40] in women). The joint effect (HR [95% CI]: 1.36 [1.17-1.58]) could be decomposed into 24.7% (95% CI: 15.0%-34.4%) for a lower birth weight, 64.7% (95% CI: 56.7%-72.6%) for a lower ICVHM score, and 10.6% (95% CI: 2.7%-18.6%) for their additive interaction in women. Conclusions::Birth weight and ICVHMs were jointly related to CVD risk. Attaining a normal birth weight and ideal ICVHMs may reduce the risk of CVD, and a simultaneous improvement of both prenatal and postnatal factors could further prevent additional cases in women.