Blocking lactate regulation of the Grhl2/SLC31A1 axis inhibits trophoblast cuproptosis and preeclampsia development.

PURPOSE: Abnormal cell death due to superficial trophoblast dysfunction caused by placental hypoxia plays a vital role in the development of preeclampsia (PE). Lactic acid stimulates gene transcription in chromatin through lactate modification of histone lysine. Nevertheless, the content and function of lactate in PE development remains largely unclear. METHODS: The contents of lactic acid and copper in 30 PE and 30 normal placentas were determined by kit colorimetry. Real-time quantitative fluorescent PCR (qRT-PCR) and Western blot were used to detect the expression of SLC31A1 in cells and tissues. Cell proliferation, apoptosis, and invasion were detected by cell counting kit 8 (CCK-8), MTS assay, colony formation assay, and Transwell assay. The transcriptional regulation between Grhl2 and SLC31A was verified by the luciferase reporter gene method and ChIP. The H3K18la modification level was detected by ChIP-PCR. RESULTS: Herein, we detected increased lactic acid levels in the PE placental tissue, which inhibit the proliferation and invasion of trophoblasts. Interestingly, lactic acid increases intracellular copper content by enhancing the expression of SLC31A1, a key protein of copper ion transporters. Lentivirus knockdown of SLC31A1 blocked the lactate-induced proliferation and invasion of trophoblasts by inhibiting cell cuproptosis. Mechanically, we identified that Grhl2 mediated SLC31A1 expression through transcription and participated in SLC31A1-inhibited proliferation, invasion, and cuproptosis of trophoblasts. Furthermore, the high lactate content increased Grhl2 expression by enhancing lactate modification of histone H3K18 in the Grhl2 promoter region. CONCLUSIONS: Blocking the lactate-regulated Grhl2/SLC31A1 axis and trophoblastic cuproptosis may be a potential approach to prevent and treat PE.

Development, characterization and underling mechanism of 3D printable quinoa protein emulsion gels by incorporating of different polysaccharides for curcumin delivery.

Emulsion gels stabilized by food-grade polymers such as proteins and polysaccharides are edible 3D food printing inks with various applications in food industry. In this study, 3D printable quinoa protein emulsion gels with four polysaccharides incorporated were fabricated to delivery curcumin. The effect of inulin (INU), fucoidan (FU), dextran sulfate (DS), and sodium alginate (SA) on the microstructure, rheological properties, and 3D printing performance of quinoa protein emulsion gels were all investigated. The results showed that the incorporation of four polysaccharides promoted formation of tightly packed oil droplets within gel networks, along with enhanced hardness, water holding capacity, freeze-thaw stability and decreased swelling ratio of the QP emulsion gel. All samples exhibited shear thinning behavior and polysaccharides increased viscoelasticity of QP emulsion gel. The hydrophobic interactions and disulfide bond are the main chemical molecular force of emulsion gels, INU significantly increased the hydrogen bonds interactions, and anionic polysaccharide (FU, DS, and SA) significantly increased the electrostatic interactions. QP-INU exerted best printing performance as identified by preferable self-supporting capability and high line printing accuracy. The addition of polysaccharides improved the encapsulation efficiency of curcumin in QP emulsion gel. In vitro release property showed that FU increased the bioavailability of curcumin, DS and SA decreased bioavailability of curcumin with delayed digestion rate. This study demonstrated the potential of utilizing polysaccharides to improve the flexibility of QP emulsion gel for 3D printing functional food.

Distinct electrochemical and metabolic responses of anode respiring bacteria to sulfamethoxazole in microbial fuel cells coupled with constructed wetlands.

The influence of sulfamethoxazole (SMX) on the electrochemical activity, bacterial community, and metabolic state of anode respiring microbes was investigated in constructed-wetland-coupled microbial fuel cells (CW-MFCs). Results suggested that SMX shortened the acclimatisation period and enhanced the maximal power density of the CW-MFC at 0.1 mg/L. Cyclic voltammetry (CV) results indicated that SMX may trigger an electrocatalytic process related to an extra redox-active compound. Exposure to SMX significantly altered the bacterial communities, leading to decreased abundances of Desulfurivibrio and Pseudomonas, while increasing the contents of Rhodobacter and Anaerovorax. Furthermore, metabolites related to amino acids and nucleotide metabolism were suppressed at 10 mg/L SMX, while the related metabolites increased at 0.1 mg/L SMX. The upregulated pathway of biofilm formation indicated that the bacteria tended to form biofilms under the influence of SMX. This study provides valuable insights into the complex interactions between SMX and electrochemically active bacteria.

Exploring the potential mechanism of WuFuYin against hypertrophic scar using network pharmacology and molecular docking.

BACKGROUND: Hypertrophic scar (HTS) is dermal fibroproliferative disorder, which may cause physiological and psychological problems. Currently, the potential mechanism of WuFuYin (WFY) in the treatment of HTS remained to be elucidated. AIM: To explore the potential mechanism of WFY in treating HTS. METHODS: Active components and corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. HTS-related genes were obtained from the GeneCards, DisGeNET, and National Center for Biotechnology Information. The function of targets was analyzed by performing Gene Ontology and Kyoto Encyclopaedia of Genes and Genome (KEGG) enrichment analysis. A protein + IBM-protein interaction (PPI) network was developed using STRING database and Cytoscape. To confirm the high affinity between compounds and targets, molecular docking was performed. RESULTS: A total of 65 core genes, which were both related to compounds and HTS, were selected from multiple databases. PPI analysis showed that CKD2, ABCC1, MMP2, MMP9, glycogen synthase kinase 3 beta (GSK3B), PRARG, MMP3, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) were the hub targets and MOL004941, MOL004935, MOL004866, MOL004993, and MOL004989 were the key compounds of WFY against HTS. The results of KEGG enrichment analysis demonstrated that the function of most genes were enriched in the PI3K-Akt pathway. Moreover, by performing molecular docking, we confirmed that GSK3B and 8-prenylated eriodictyol shared the highest affinity. CONCLUSION: The current findings showed that the GSK3B and cyclin dependent kinase 2 were the potential targets and MOL004941, MOL004989, and MOL004993 were the main compounds of WFY in HTS treatment.

Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Novel functions of o-cymen-5-ol nanoemulsion in reversing colistin resistance in multidrug-resistant Klebsiella pneumoniae infections.

Multidrug resistance (MDR) Klebsiella pneumoniae (K. pneumoniae) is a major emerging threat to human health, and leads to very high mortality rate. The effectiveness of colistin, the last resort against MDR Gram-negative bacteria, is significantly compromised due to the widespread presence of plasmid- or chromosome-mediated resistance genes. In this study, o-cymen-5-ol has been found to greatly restore colistin sensitivity in MDR K. pneumoniae. Importantly, this compound does not impact bacterial viability, induce resistance, or cause any noticeable cell toxicity. Various routes disclosed the potential mechanism of o-cymen-5-ol potentiating colistin activity against MDR K. pneumoniae. These include inhibiting the activity of plasmid-mediated mobile colistin resistance gene (mcr-1), accelerating lipopolysaccharide (LPS) - mediated membrane damage, and promoting the ATP-binding cassette (ABC) transporter pathway. To enhance the administration and bioavailability of o-cymen-5-ol, a nanoemulsion has been designed, which significantly improves the loading efficiency and solubility of o-cymen-5-ol, resulting in antimicrobial potentiation of colistin against K. pneumoniae infection. This study has revealed a new understanding of the o-cymen-5-ol nanoemulsion as a means to enhance the effectiveness of colistin against resistant factors. The finding also suggests that o-cymen-5-ol nanoemulsion could be a promising approach in the development of potential treatments for multidrug-resistant Gram-negative bacterial infections.

Plexin domain-containing 1 may be a biomarker of poor prognosis in hepatocellular carcinoma patients, may mediate immune evasion.

BACKGROUND: For the first time, we investigated the oncological role of plexin domain-containing 1 (PLXDC1), also known as tumor endothelial marker 7 (TEM7), in hepatocellular carcinoma (HCC). AIM: To investigate the oncological profile of PLXDC1 in HCC. METHODS: Based on The Cancer Genome Atlas database, we analyzed the expression of PLXDC1 in HCC. Using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting, we validated our results. The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features, such as patient survival, methylation level, tumor immune microenvironment features, and immune cell surface checkpoint expression. Finally, to assess the immune evasion potential of PLXDC1 in HCC, we used the tumor immune dysfunction and exclusion (TIDE) website and immunohistochemical staining assays. RESULTS: Based on immunohistochemistry, qRT-PCR, and Western blot assays, overexpression of PLXDC1 in HCC was associated with poor prognosis. Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor. In HCC patients with high methylation levels, the prognosis was worse than in patients with low methylation levels. Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling, and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup. The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis, and PLXDC1-related risk scores were also associated with a poor prognosis. CONCLUSION: As a result of this study analyzing PLXDC1 from multiple biological perspectives, it was revealed that it is a biomarker of poor prognosis for HCC patients, and that it plays a role in determining immune evasion status.

Preventive effects of lactoferrin on acute alcohol-induced liver injury via iron chelation and regulation of iron metabolism.

Lactoferrin is widely found in milk and has the ability to bind iron. Previous studies have reported that lactoferrin was effective in the prevention and treatment of acute alcohol-induced liver injury (AALI). Ferroptosis is a recently discovered cell death and is involved in the development of AALI. However, the potential role of lactoferrin in acute alcohol-induced ferroptosis is still unclear. In this study, we observed that lactoferrin (10, 20, and 40 µg/mL) significantly mitigated alcohol (300 mM)-induced injury in vitro. Additionally, lactoferrin (100 and 200 mg/kg BW) significantly alleviated alcohol (4.8 g/kg BW)-induced injury in vivo. Our results showed that lactoferrin inhibited alcohol-induced upregulation of the ferroptosis marker protein ACSL4 and downregulation of GPX4. Meanwhile, lactoferrin treatment successfully reversed the elevated malondialdehyde (MDA) levels and the reduced glutathione (GSH) levels caused by alcohol treatment. These results may indicate that lactoferrin significantly decreased ferroptosis in vivo and in vitro. Lactoferrin has the potential to chelate iron, and our results showed that lactoferrin (20 µg/mL) significantly reduced iron ions and the expression of the ferritin heavy chain (FTH) under FeCl3 (100 µM) treatment. It was demonstrated that lactoferrin had a significant iron-chelating effect and reduced iron overload caused by FeCl3 in AML12 cells. Next, we examined iron content and the expression of iron metabolism marker proteins transferrin receptor (TFR), divalent metal transporter 1 (DMT1), FTH, and ferroportin (FPN). Our results showed that lactoferrin alleviated iron overload induced by acute alcohol. The expression of TFR and DMT1 was downregulated, and FPN and FTH were upregulated after lactoferrin treatment in vivo and in vitro. Above all, the study suggested that lactoferrin can alleviate AALI by mitigating acute alcohol-induced ferroptosis. Lactoferrin may offer new strategies for the prevention or treatment of AALI.

Plant growth regulators mitigate oxidative damage to rice seedling roots by NaCl stress.

The aim of this experiment was to investigate the effects of exogenous sprays of 5-aminolevulinic acid (5-ALA) and 2-Diethylaminoethyl hexanoate (DTA-6) on the growth and salt tolerance of rice (Oryza sativa L.) seedlings. This study was conducted in a solar greenhouse at Guangdong Ocean University, where 'Huanghuazhan' was selected as the test material, and 40 mg/L 5-ALA and 30 mg/L DTA-6 were applied as foliar sprays at the three-leaf-one-heart stage of rice, followed by treatment with 0.3% NaCl (W/W) 24 h later. A total of six treatments were set up as follows: (1) CK: control, (2) A: 40 mg⋅ L-1 5-ALA, (3) D: 30 mg⋅ L-1 DTA-6, (4) S: 0.3% NaCl, (5) AS: 40 mg⋅ L-1 5-ALA + 0.3% NaCl, and (6) DS: 30 mg⋅ L-1 DTA-6+0.3% NaCl. Samples were taken at 1, 4, 7, 10, and 13 d after NaCl treatment to determine the morphology and physiological and biochemical indices of rice roots. The results showed that NaCl stress significantly inhibited rice growth; disrupted the antioxidant system; increased the rates of malondialdehyde, hydrogen peroxide, and superoxide anion production; and affected the content of related hormones. Malondialdehyde content, hydrogen peroxide content, and superoxide anion production rate significantly increased from 12.57% to 21.82%, 18.12% to 63.10%, and 7.17% to 56.20%, respectively, in the S treatment group compared to the CK group. Under salt stress, foliar sprays of both 5-ALA and DTA-6 increased antioxidant enzyme activities and osmoregulatory substance content; expanded non-enzymatic antioxidant AsA and GSH content; reduced reactive oxygen species (ROS) accumulation; lowered malondialdehyde content; increased endogenous hormones GA3, JA, IAA, SA, and ZR content; and lowered ABA content in the rice root system. The MDA, H2O2, and O2- contents were reduced from 35.64% to 56.92%, 22.30% to 53.47%, and 7.06% to 20.01%, respectively, in the AS treatment group compared with the S treatment group. In the DS treatment group, the MDA, H2O2, and O2- contents were reduced from 24.60% to 51.09%, 12.14% to 59.05%, and 12.70% to 45.20%. In summary, NaCl stress exerted an inhibitory effect on the rice root system, both foliar sprays of 5-ALA and DTA-6 alleviated damage from NaCl stress on the rice root system, and the effect of 5-ALA was better than that of DTA-6.

Associations of global biomarkers of oxidative stress with osteoporosis, bone microstructure and bone turnover: Evidence from human and animal studies.

PURPOSE: Human evidence on the association between oxidative stress and osteoporosis is inconsistent. Fluorescent Oxidation Products (FlOPs) are global biomarkers of oxidative stress. We examined the associations of FlOPs (excitation/emission wavelengths 320/420 nm for FlOP_320, 360/420 nm for FlOP_360, and 400/475 nm for FlOP_400) with osteoporosis, bone microstructure, and bone turnover markers in humans and rats. METHODS: In humans, we conducted a 1:2 age, sex, hospital, and specimen-matched case-control study to test the association between FlOPs and osteoporosis diagnosed from dual-energy X-ray absorptiometry. In eight-week-old male Wistar rats, we administrated D-galactose and 0.9 % saline for 90 days in treatment and control groups (n = 8/group); micro-CT was used to determine bone microstructure. RESULTS: In humans, higher levels of FlOP_320 (OR for per 1 SD increase = 1.49, 95 % CI: 1.01-2.20) and FlOP_360 (OR for per 1 SD increase = 1.59, 95 % CI: 1.07-2.37) were associated with increased odds of osteoporosis. FlOP_400 were not associated with osteoporosis. D-galactose treated rats, as compared with control rats, showed higher levels of FlOP_320 and MDA, and lower P1NP levels during 90 days of experiment (all P < 0.05). The D-galactose group had lower trabecular bone volume fraction (0.07 ± 0.03 vs. 0.13 ± 0.05; P = 0.008) and volumetric BMD (225.4 ± 13.8 vs. 279.1 ± 33.2 mg HA/cm3; P = 0.001) than the control group. CONCLUSION: In conclusion, higher FlOP_320 levels were associated with increased odds of osteoporosis, impaired bone microstructure and decreased bone formation.

Compositional effects on structural, electronic, elastic, piezoelectric and dielectric properties of GaInN alloys: a first-principles study.

We conduct a comprehensive theoretical analysis of wurtzite GaxIn1-xN ternary alloys, focusing on their structural, electronic, elastic, piezoelectric, and dielectric properties through rigorous first-principles calculations. Our investigation systematically explores the influence of varying Ga composition (x = 0%, 25%, 50%, 75%, 100%) on the alloy properties. Remarkably, we observe a distinctive non-linear correlation between the band gap and Ga concentration, attributable to unique slopes in the absolute positions of the valence band maximum and conduction band minimum with respect to Ga concentration. Our effective band structure analysis reveals the meticulous preservation of Bloch characters near band extrema, minimizing charge carrier scattering. Furthermore, we scrutinize deviations from linear Vegard-like dependence in elastic, piezoelectric, and dielectric constants. Additionally, our calculations encompass various optical properties, including absorption coefficient, reflectivity, refractive index, energy loss function, and extinction coefficient. We analyze their trends with photon energy, providing valuable insights into the optical behavior of GaxIn1-xN alloys. Our results, in excellent agreement with available experimental data, significantly contribute to a deeper understanding of the alloys' electronic properties. This study offers valuable insights that may illuminate potential applications of GaxIn1-xN alloys in diverse technological fields.

NTPDase1-ATP-P2Y2Rs axis in the sciatic nerve contributes to acupuncture at "Zusanli" (ST36)-induced analgesia in ankle arthritis rats.

BACKGROUND: The efficacy of acupuncture at Zusanli (ST36) in alleviating lower-limb pain is widely acknowledged in clinical practice, while its underlying mechanism remains incompletely elucidated. Our previous research had revealed that the prompt analgesia induced by needling-ST36 was accompanied by expression alterations in certain exco-nucleotidases within the sciatic nerve. Building upon this finding, the current work focused on NTPDase1, the primary ecto-nucleotidase in the human body, which converts ATP into AMP. METHODS: A 20-min acupuncture was administered unilaterally at the ST36 on rats with acute ankle arthritis. The pain thresholds of the injured hind paws were determined. Pharmacological interference was carried out by introducing the corresponding reagents to the sciatic nerve. ATP levels around the excised nerve were measured using a luciferase-luciferin assay. Live calcium imaging, utilizing the Fura 2-related-F340/F380 ratio, was conducted on Schwann cells in excised nerves and cultured rat SCs line, RSC96 cells. RESULTS: The analgesic effect induced by needling-ST36 was impaired when preventing ATP degradation via inhibiting NTPDase1 activities with ARL67156 or Ticlopidine. Conversely, increasing NTPDase1 activities with Apyrase duplicated the acupuncture effect. Similarly, preventing the conversion of AMP to adenosine via suppression of NT5E with AMP-CP hindered the acupuncture effect. Unexpectedly, impeded ATP hydrolysis ability and diminished NTPDase1 expression were observed in the treated group. Agonism at P2Y2Rs with ATP, UTP, or INS365 resulted in anti-nociception. Contrarily, antagonism at P2Y2Rs with Suramin or AR-C 118925xx prevented acupuncture analgesia. Immunofluorescent labeling demonstrated that the treated rats expressed more P2Y2Rs that were predominant in Schwann cells. Suppression of Schwann cells by inhibiting ErbB receptors also prevented acupuncture analgesia. Finally, living imaging on the excised nerves or RSC96 cells showed that agonism at P2Y2Rs indeed led to [Ca2+]i rise. CONCLUSION: These findings strongly suggest that the analgesic mechanism of needling-ST36 on the hypersensation in the lower limb partially relies on NTPDase1 activities in the sciatic nerve. In addition to facilitating adenosine signaling in conjunction with NT5E, most importantly, NTPDase1 may provide an appropriate low-level ATP milieu for the activation of P2Y2R in the sciatic nerve, particularly in Schwann cells.

Coordination-Polymer-Derived Cu-CoO/C Nanocomposite Used in Fenton-like Reaction to Achieve Efficient Degradation of Organic Compounds.

In this paper, carbon-matrix-supported copper (Cu) and cobaltous oxide (CoO) nanoparticles were obtained by using coordination polymers (CPs) as a precursor. The aqueous solutions of copper methacrylate (CuMA) and cobalt methacrylate (CoMA) were preferentially prepared, which were then mixed with anhydrous ethanol to fabricate dual metal ion coordination polymers (CuMA/CoMA). After calcination under an argon atmosphere, the Cu-CoO/C nanocomposite was obtained. Scanning electron microscope (SEM) and transmission electron microscope (TEM) showed that the material has banded morphology, and the dual functional nanoparticles were highly dispersed in the carbon matrix. The prepared material was used in a heterogeneous Fenton-like reaction, with the aim of replacing traditional ferric catalysts to solve pH constraints and the mass production of ferric slime. The obtained nanocomposite showed excellent catalytic performance on the degradation of methylene blue (MB) at near-neutral conditions; the discoloration efficiency is about 98.5% within 50 min in the presence of 0.15 mmol/mL H2O2 and 0.5 mg/mL catalyst. And good reusability was verified via eight cycles. The plausible pathway for MB discoloration and the possible catalytic mechanism was also proposed.

Transcatheter arterial chemoembolisation combined with lenvatinib plus camrelizumab as conversion therapy for unresectable hepatocellular carcinoma: a single-arm, multicentre, prospective study.

Background: The synergistic effect of locoregional therapy in combination with systemic therapy as a conversion therapy for unresectable hepatocellular carcinoma (uHCC) is unclear. The purpose of this study was to evaluate the efficacy and safety of transcatheter arterial chemoembolisation (TACE) combined with lenvatinib and camrelizumab (TACE + LEN + CAM) as conversion therapy for uHCC. Methods: This single-arm, multicentre, prospective study was conducted at nine hospitals in China. Patients (aged 18-75 years) diagnosed with uHCC, an Eastern Cooperative Oncology Group performance score (ECOG-PS) of 0-1 and Child-Pugh class A received camrelizumab (200 mg, every 3 weeks) and lenvatinib (bodyweight ≥60 kg: 12 mg/day; <60 kg: 8 mg/day) after TACE treatment. Surgery was performed after tumour was assessed as meeting the criteria for resection. Patients who did not meet the criteria for surgery continued to receive triple therapy until disease progression or intolerable toxicity. Primary endpoints were objective response rate (ORR) according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) and safety. Secondary endpoints included the surgical conversion rate, radical (R0) resection rate, and disease control rate (DCR). This study was registered with Chinese Clinical Trial Registry (ChiCTR2100050410). Findings: Between Oct 25, 2021, and July 20, 2022, 55 patients were enrolled. As of the data cutoff on June 1, 2023, the median follow-up was 13.3 months (IQR 10.6-15.9 months). The best tumour response to triple therapy was complete response (CR) in 9 (16.4%) patients, partial response (PR) in 33 (60.0%) patients, stable disease (SD) in 5 (9.1%) patients, or progressive disease (PD) in 7 (12.7%) patients. The ORR was 76.4% (42/55, 95% CI, 65.2-87.6%), and the DCR was 85.5% (47/55, 95% CI, 76.2-94.8%) per mRECIST. Twenty-four (43.6%) of the 55 patients suffered from grade 3-4 treatment-related adverse events (TRAEs). No grade 5 TRAEs occurred. A total of 30 (30/55, 54.5%) patients were converted to resectable HCC and 29 (29/55, 52.7%) patients underwent resection. The R0 resection rate was 96.6% (28/29). The major pathologic response (MPR) and pathologic complete response (pCR) rates in the surgery population were 65.5% (19/29) and 20.7% (6/29), respectively. Only one patient developed a Clavien-Dindo IIIa complication (abdominal infection). No Clavien-Dindo IIIb-V complications occurred. The median OS and median PFS were not reached. Interpretation: The triple therapy (TACE + LEN + CAM) is promising active for uHCC with a manageable safety. Moreover, triple therapy has good conversion efficiency and the surgery after conversion therapy is feasible and safe. To elucidate whether patients with uHCC accepting surgical treatment after the triple therapy can achieve better survival benefits than those who receive triple therapy only, well-designed randomised controlled trials are needed. Funding: This study was funded by the Natural Science Foundation of Fujian Province, China (2022J01691) and the Youth Foundation of Fujian Province Health Science and Technology Project, China (2022QNA035).

Electroacupuncture at Sensitized Acupoints Relieves Somatic Referred Pain in Colitis Rats by Inhibiting Sympathetic-Sensory Coupling to Interfere with 5-HT Signaling Pathway.

OBJECTIVE: To investigate whether electroacupuncture (EA) at sensitized acupoints could reduce sympathetic-sensory coupling (SSC) and neurogenic inflammatory response by interfering with 5-hydroxytryptamine (5-HT)ergic neural pathways to relieve colitis and somatic referred pain, and explore the underlying mechanisms. METHODS: Rats were treated with 5% dextran sodium sulfate (DSS) solution for 7 days to establish a colitis model. Twelve rats were randomly divided into the control and model groups according to a random number table (n=6). According to the "Research on Rat Acupoint Atlas", sensitized acupoints and non-sensitized acupoints were determined. Rats were randomly divided into the control, model, Zusanli-EA (ST 36), Dachangshu-EA (BL 25), and Xinshu (BL 15) groups (n=6), as well as the control, model, EA, and EA + GR113808 (a 5-HT inhibitor) groups (n=6). The rats in the control group received no treatment. Acupuncture was administered on 2 days after modeling using the stimulation pavameters: 1 mA, 2 Hz, for 30 min, with sparse and dense waves, for 14 consecutive days. GR113808 was injected into the tail vein at 5 mg/kg before EA for 10 min for 7 consecutive days. Mechanical sensitivity was assessed with von Frey filaments. Body weight and disease activity index (DAI) scores of rats were determined. Hematoxylin and eosin staining was performed to observe colon histopathology. SSC was analyzed by immunofluorescence staining. Immunohistochemical staining was performed to detect 5-HT and substance P (SP) expressions. The calcitonin gene-related peptide (CGRP) in skin tissue and tyrosine hydroxylase (TH) protein levels in DRG were detected by Western blot. The levels of hyaluronic acid (HA), bradykinin (BK), prostaglandin I2 (PGI2) in skin tissue, 5-HT, tryptophan hydroxylase 1 (TPH1), serotonin transporters (SERT), 5-HT 3 receptor (5-HT3R), and 5-HT 4 receptor (5-HT4R) in colon tissue were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: BL 25 and ST 36 acupoints were determined as sensitized acupoints, and BL 15 acupoint was used as a non-sensitized acupoint. EA at sensitized acupoints improved the DAI score, increased mechanical withdrawal thresholds, and alleviated colonic pathological damage of rats. EA at sensitized acupoints reduced SSC structures and decreased TH and CGRP expression levels (P<0.05). Furthermore, EA at sensitized acupoints reduced BK, PGI2, 5-HT, 5-HT3R and TPH1 levels, and increased HA, 5-HT4R and SERT levels in colitis rats (P<0.05). GR113808 treatment diminished the protective effect of EA at sensitized acupoints in colitis rats (P<0.05). CONCLUSION: EA at sensitized acupoints alleviated DSS-induced somatic referred pain in colitis rats by interfering with 5-HTergic neural pathway, and reducing SSC inflammatory response.

Co-assembled whey protein and proanthocyanidins as a promising biocarrier for hydrophobic pterostilbene: Fabrication, characterization, and cellular antioxidant potential.

The usage of food-derived polyphenols with different polarities has been limited by their instability and incompatibility. Therefore, a biocarrier was developed by co-assembly of whey protein isolate (WPI) and hydrophilic proanthocyanidin (PC) for loading hydrophobic pterostilbene (PTE). Such biocarrier has superior affinity for PTE than WPI alone, as determined by encapsulation efficiency and loading capacity assay, fluorescence quenching analysis, and molecular docking, whereas the assembly process was characterized by particle size and zeta potential, 3-dimensional fluorescence, and scanning electron microscopy. Circular dichroism and Fourier transform infrared spectroscopy spectra confirmed the α-helix to ß-sheet and random coil transition of proteins during the formation of nanocomplexes. Whey protein isolate acted as a mediator through altering the binding mode of PC and PTE, allowing them to perform significant synergistic effects in enhancing 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl radical scavenging and reducing H2O2-induced cell damage. This research may serve to develop new protein/polyphenol co-loading systems and offer a reliable nutritional fortification.

Blocking the interaction between circTNRC18 and LIN28A promotes trophoblast epithelial-mesenchymal transformation and alleviates preeclampsia.

Defects in migration and invasion caused by dysregulation of trophoblastic epithelial-mesenchymal transformation (EMT) play a vital role in preeclampsia (PE). We have previously shown that circTNRC18 inhibits the migration and EMT of trophoblasts; however, its role in PE remains unknown. Herein, we demonstrate that circTNRC18 interacts with an RNA-binding protein, lin-28 homolog A (LIN28A), and this interaction is enhanced in PE placental tissue. LIN28A overexpression suppresses circTNRC18-mediated inhibition of trophoblast migration, invasion, and EMT, whereas LIN28A knockdown promotes them. The intracellular distribution of LIN28A is regulated by circTNRC18, where it promotes the expression of insulin-like growth factor II by stabilizing its mRNA. circTNRC18 also promotes complex formation between GATA-binding factor 1 (GATA1) and sine oculis homeobox 1 (SIX1) by inhibiting LIN28A-GATA1 interaction. GATA1-SIX1 promotes transcription of grainyhead-like protein 2 homolog and circTNRC18-mediated regulation of cell migration and invasion. Moreover, blocking circTNRC18-LIN28A interaction with antisense nucleotides alleviates PE in a mouse model of reduced uterine perfusion pressure. Thus, targeting the circTNRC18-LIN28A regulatory axis may be a novel PE treatment method.

Experience in the management of sigmoid sinus thrombophlebitis secondary to middle ear cholesteatoma.

OBJECTIVE: To discuss the management of sigmoid sinus thrombophlebitis secondary to middle ear cholesteatoma. METHODS: We retrospectively analyzed all cases of sigmoid sinus thrombophlebitis caused by middle ear cholesteatoma over a period of 7 years. 7 male and 2 female patients, ranging in age from 9 to 66 years, were diagnosed with sigmoid sinus thrombophlebitis by clinical presentation and radiological examination. By executing a modified mastoidectomy and tympanoplasty (canal wall-down tympanoplasty) to entirely remove the cholesteatoma-like mastoid epithelium, all patients were effectively treated surgically without opening the sigmoid sinus. All patients were treated with broad-spectrum antibiotics, but no anticoagulants were used. RESULTS: 9 patients had otogenic symptoms such as ear pus, tympanic membrane perforation, and hearing loss. In the initial stage of the surgery, modified mastoidectomy and tympanoplasty were performed on 8 of the 9 patients. 1 patient with a brain abscess underwent puncturing (drainage of the abscess) to relieve cranial pressure, and 4 months later, a modified mastoidectomy and tympanoplasty were carried out. Following surgery and medication, the clinical symptoms of every patient improved. After the follow-up of 6 months to 7 years, 3 patients were re-examined for MRV and showed partial sigmoid sinus recovery with recanalization. 4 months following middle ear surgery, the extent of a patient's brain abscess lesions was significantly reduced. 1 patient experienced facial paralysis after surgery and recovered in 3 months. None of the patients had a secondary illness, an infection, or an abscess in a distant organ. CONCLUSION: The key to a better prognosis is an adequate course of perioperative antibiotic medication coupled with surgical treatment. A stable sigmoid sinus thrombus can remain for a long time after middle ear lesions have been removed, and it is less likely to cause infection and abscesses in the distant organs. The restoration of middle ear ventilation is facilitated by tympanoplasty. It is important to work more closely with multidisciplinary teams such as neurology and neurosurgery when deciding whether to perform lateral sinusotomies to remove thrombus or whether to administer anticoagulation.

Exploring the links among peripheral immunity, biomarkers, cognition, and neuroimaging in Alzheimer's disease.

INTRODUCTION: We analyzed relationships among peripheral immunity markers, cognition, Alzheimer's disease (AD)-related biomarkers, and neuroimaging to understand peripheral immunity involvement in AD. METHODS: Peripheral immunity markers were assessed in AD, non-AD neurodegenerative disorders, and controls, examining their connections with cognition, AD-related biomarkers, and neuroimaging using multiple regression models. RESULTS: The study included 1579 participants. Higher levels of white blood cell, neutrophil, monocyte, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and lower lymphocyte-to-monocyte ratio (LMR) were associated with cognitive decline and more severe anxiety and depression. The impact of lower LMR, lymphocyte count, and higher NLR on cognitive decline is mediated through cerebrospinal fluid amyloid beta (Aß) levels. Additionally, increased PLR, NLR, and SII were associated with brain atrophy and hippocampal Aß deposition (amyloid positron emission tomography). DISCUSSION: Peripheral immunity markers offer a non-invasive and cost-effective means of studying AD-related pathophysiological changes, providing valuable insights into its pathogenesis and treatment. Highlights: Peripheral immunity markers linked to cognitive decline and anxiety/depression.Low LMR, LYM, and high NLR linked to reduced CSF Aß, impacting cognition.High PLR, NLR, SII associated with brain atrophy and hippocampal Aß deposition.

Different equations for estimating age-related changes of glomerular filtration rate in the healthy population.

BACKGROUND: Identifying age-related trend of estimated glomerular filtration rate (eGFR) is necessary to assess whether kidney function is healthily aging. This study aimed to investigate the application of CKD-EPI, FAS, and Xiangya equations for the aging estimation of eGFR in the healthy Chinese individuals. METHODS: A total of 36,911 healthy individuals were enrolled in this study. We grouped every ten years to observe the trend of eGFR with aging and investigated decline rate of it by general linear regression analysis in each age-groups. Agreement between equations was determined by intraclass correlation coefficient (ICC) and Bland-Altman plot. We calculated reference interval in each age-group. We further analyzed above statistical indicators in males and females. RESULTS: The eGFR by CKD-EPI, and Xiangya equation started to decline from the age of 18. Whereas eGFR by FAS equation remained stable under 40 years, then decreased more rapidly. Compared with males, the females had a higher level but a faster decline rate of eGFR with aging. Agreement analysis revealed good agreement between CKD-EPI and FAS equations (ICC 0.818-0.920). Agreement between Xiangya and CKD-EPI or FAS equations was poor to moderate in most of the population under 70 years old (ICC 0.282-0.786), but good in individuals above 70 years (ICC 0.769-0.881). CONCLUSIONS: The trend of eGFR with aging was different by CKD-EPI, FAS, and Xiangya equations in the healthy Chinese. It may be necessary to take these equations- or age-related differences into consideration when assessing kidney function in primary health care and clinical practice.