ZnS Nanoseeds Sealed in N, P, S Co-Doped Carbon Hollow Rhombic Dodecahedra as a Superlithiophilic Host for Dendrite-Free Lithium Metal Anodes.

Lithium (Li) metal is considered a hopeful anode for next-generation Li-ion batteries thanks to its ultra-high theoretical specific capacity, extra-low theoretical density, and low negative potential. However, the uncontrolled growth of Li dendrites and volume fluctuation during plating/stripping processes severely hamper its commercial application. Herein, ZnS seeds sealed in N, P, S co-doped carbon hollow rhombic dodecahedra (ZnS@NPS-C HRD) is fabricated as a superlithiophilic host for Li metal anodes (LMAs) to solve the above problems. In addition, the Li nucleation and deposition mechanism on ZnS@NPS-C HRD is investigated by in situ optical microscopy, ex-situ X-ray diffraction, scanning electron microscopy, and theoretical calculations. Owing to the synergistic strategy of ZnS seeds-inducing nucleation and Li-limited growth, the as-prepared composite exhibits stability for 300 cycles in asymmetric cells and a long lifespan over 1100 h in symmetric cells. Moreover, the ZnS@NPS-C HRD@Li|LiFePO4 full cell demonstrates a reversible capacity of 100.91 mAh g-1 after 400 cycles at 1 C.

Integrative analysis of transcriptomic and metabolomic profiles reveals abnormal phosphatidylinositol metabolism in follicles from endometriosis-associated infertility patients.

Endometriosis is a common gynecological disorder that causes female infertility. Our recent research found that excessive oxidative stress in ovaries of endometriosis patients induced senescence of cumulus granulosa cells. Here, we analyzed the transcriptomic and metabolomics profiles of follicles in a mouse model of endometriosis and in patients with endometriosis and investigated the potential function of changed metabolites in granulosa cells. RNA-sequencing indicated that both endometriosis lesions and oxidative stress in mice induced abnormalities of reactive oxidative stress, steroid hormone biosynthesis, and lipid metabolism. The mouse model and women with endometriosis showed altered lipid metabolism. Nontargeted metabolite profiling of follicular fluid from endometriosis and male-factor infertility patients by liquid chromatography mass spectrometry identified 55 upregulated and 67 downregulated metabolites. These differential metabolites were mainly involved in steroid hormone biosynthesis and glycerophospholipid metabolism. Phosphatidylinositol (PI 16:0/18:2) was significantly elevated in follicular fluid from endometriosis patients compared with controls (p < 0.05), while lysophosphatidylinositol (LPI 18:2, 20:2, 18:1, 20:3 and 18:3) was reduced (p < 0.05). Upregulated PI and downregulated LPI correlated with oocyte retrieval number and mature oocyte number. LPI inhibited cellular reactive oxidative stress induced by hemin in granulosa cells. Cell proliferation inhibition, senescence, and apoptosis induced by hemin were partially reversed by LPI. Moreover, LPI administration rescued hemin blocking of cumulus-oocyte complex expansion and stimulated expression of ovulation-related genes. Transcriptomic Switching mechanism at 5' end of the RNA transcript sequencing and western blot revealed that LPI effects on granulosa cells were associated with its regulation of MAPK-ERK1/2 signaling, which was suppressed in the presence of hemin. In conclusion, our results revealed the dysregulation of lipid metabolism in endometriotic follicles. LPI may represent a novel agent for in vitro follicular culture that reverses the excessive oxidative stress from endometriotic lesions. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Clinical data, survival, and prognosis of 426 cases of oropharyngeal cancer: a retrospective analysis.

OBJECTIVE: To determine factors influencing survival and prognosis of HPV-related and non-related oropharyngeal cancer. METHODS: Subjects were determined from the three hospitals in Anhui province of China between 2015 and 2020. Paraffin-embedded specimens from participants' tissues were analyzed, and the subjects were classified as P16 + and P16 - cases using immunohistochemical staining for P16 protein. RESULTS: A total of 426 patients with oropharyngeal cancer were recruited in this study; 108 cases were found to be P16 + . The subjects were treated with the three regimens: surgery/radiotherapy/chemotherapy (SRCT), radiotherapy/chemotherapy (RCT), and surgery/chemotherapy (SCT). There were no statistically significant differences in the survival rates within the P16 + or P16 - groups between the three treatment regimens (P > 0.05). The 1-, 3-, and 5-year survival rates for P16 + and P16 - groups were statistically different (P < 0.05). Multivariate analysis showed that age, physical health status, smoking, and alcohol abuse were independent risk factors affecting the prognosis of P16 + cases, while pathological grading and TNM staging were independent risk factors affecting the P16 - cases. CONCLUSION: The etiology, pathogenesis, survival status, and prognostic factors of HPV-related oropharyngeal cancer are very different from those of traditional oropharyngeal cancer. Thus, HPV-related oropharyngeal cancer could be classified as a separate type of disease. This distinction could be of great significance for treatment, prevention, and prognostication of oropharyngeal cancer.

Platelet-rich plasma alleviates knee arthritis in rats by inhibiting p65.

Knee osteoarthritis (KOA) is a chronic joint disease characterized by the degeneration of articular cartilage. In this study, we explored the potential therapeutic effects of platelet-rich plasma (PRP) and identified molecular targets for treating KOA. A rat model of KOA was established via the Hulth method and primary knee joint chondrocytes were isolated to evaluate the effects of PRP and shRNA targeting p65 (sh-p65). ELISA was used to detect inflammatory factors, including IL-6, IL-1ß, and TNF-α. HE staining, Safranin O/Fast Green staining and Masson staining were performed to evaluate the morphology of articular cartilage, followed by detection of p65, COL2A1, ACAN, MMP13, and ADAMTS5 expression. The proliferation and apoptosis of primary knee chondrocytes were detected by the CCK-8 assay and TUNEL staining, respectively. Treatment with either PRP or sh-p65 decreased IL-6, IL-1ß, and TNF-α levels in the peripheral blood of KOA rats and chondrocyte culture supernatants, increased COL2A1 and ACAN levels, and decreased MMP13 and ADAMTS5 expression. Furthermore, administration of PRP or sh-p65 exerted protective effects on articular cartilage, enhanced the vitality of knee joint chondrocytes, and inhibited apoptosis. Collectively, PRP inhibited inflammation, promoted chondrocyte proliferation and cartilage matrix secretion, and induced cartilage regeneration by suppressing p65 expression; these effects allow PRP to alleviate KOA progression. P65-based targeted therapy administered in combination with PRP might be a promising strategy for treating KOA.

The effect of arbuscular mycorrhizal fungi and biochar on the growth and Cd/Pb accumulation in Zea mays.

A greenhouse pot experiment was conducted to assess the effects of biochar (BC) and arbuscular mycorrhizal fungus (AMF)-Funneliformis mosseae (Fm), Glomus versiforme (Gv) and Rhizophagus intraradices (Ri) on the plant growth and Cd/Pb accumulation by corn grown in the soils artificially contaminated with 5 mg Cd and 300 mg Pb kg-1 soil. The single AMF inoculation and combined usage of AMF and BC evidently improved the P contents of maize. Furthermore, the combined use of AMF and BC produced pronounced positive effect on corn growth, and the shoot biomass in Gv + BC group was 9.85-fold higher than that of the control. Meanwhile, the single BC addition and combined utilization of AMF and BC significantly reduced Cd and Pb concentrations in maize, and the greater reduces were found in the combined utilization, and the lowest Cd concentration of shoot was appeared in Gv + BC group. The single BC addition and combined application of AMF and BC significantly increased soil pH, and reduced soil diethylenetriaminepentaacetic acid (DTPA)-extractable Cd/Pb. This study demonstrated a synergistic effect between AMF (Gv, Fm, Ri) and BC on improving maize growth and decreasing Cd/Pb accumulation in maize, and the combined use of Gv and BC brought the most pronounced effect, which could provide a feasible strategy for safe production of maize from Cd/Pb-polluted soils.

Germacrone alleviates collagen-induced arthritis via regulating Th1/Th2 balance and NF-κB activation.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. The imbalance of T helper type 1 (Th1) and Th2 immune responses contributes to the pathogenesis of this disease. Germacrone is a major bioactive component isolated from Rhizoma Curcuma with multiple bioactivities including anti-inflammation. However, the role and mechanism of germacrone in RA are still unknown. Collagen-induced arthritis (CIA) model was established in male DBA/1 J mice by two immunizations with chicken collagen II. Germacrone was orally administered once per day starting on the day of second immunization for 3 weeks. Arthritis scoring was evaluated every 3 days after second immunization. H&E staining was used for histopathological examination. Levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-4 in serum and synovial tissues of mice were detected by ELISA. Th1 and Th2 cell percentage in mouse spleens was analyzed by flow cytometry. IκB and phosphorylation of NF-κB p65 (p-p65) expression in mouse synovial tissues was assayed by Western blot. We found germacrone treatment significantly reduced arthritis score and inflammation in CIA mice. Levels of TNF-α and IFN-γ were elevated, and IL-4 reduced, in the serum and synovial tissues of CIA mice. Germacrone partially reversed levels of these cytokines. Moreover, germacrone decreased the ratio of Th1 to Th2 cells in mouse spleens. Additionally, germacrone remarkably enhanced IκB expression, but suppressed p-p65 level in CIA mice. Taken together, these results suggest that germacrone alleviated the progression of arthritis that might be related to the regulation of Th1/Th2 balance and inactivation of NF-κB pathway.

Shared and Study-specific Dietary Patterns and Head and Neck Cancer Risk in an International Consortium.

BACKGROUND: A few papers have considered reproducibility of a posteriori dietary patterns across populations, as well as pattern associations with head and neck cancer risk when multiple populations are available. METHODS: We used individual-level pooled data from seven case-control studies (3844 cases; 6824 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We simultaneously derived shared and study-specific a posteriori patterns with a novel approach called multi-study factor analysis applied to 23 nutrients. We derived odds ratios (ORs) and 95% confidence intervals (CIs) for cancers of the oral cavity and pharynx combined, and larynx, from logistic regression models. RESULTS: We identified three shared patterns that were reproducible across studies (75% variance explained): the Antioxidant vitamins and fiber (OR = 0.57, 95% CI = 0.41, 0.78, highest versus lowest score quintile) and the Fats (OR = 0.80, 95% CI = 0.67, 0.95) patterns were inversely associated with oral and pharyngeal cancer risk. The Animal products and cereals (OR = 1.5, 95% CI = 1.1, 2.1) and the Fats (OR = 1.8, 95% CI = 1.4, 2.3) patterns were positively associated with laryngeal cancer risk, whereas a linear inverse trend in laryngeal cancer risk was evident for the Antioxidant vitamins and fiber pattern. We also identified four additional study-specific patterns, one for each of the four US studies examined. We named them all as Dairy products and breakfast cereals, and two were associated with oral and pharyngeal cancer risk. CONCLUSION: Multi-study factor analysis provides insight into pattern reproducibility and supports previous evidence on cross-country reproducibility of dietary patterns and on their association with head and neck cancer risk. See video abstract at, http://links.lww.com/EDE/B430.

Combined application of arbuscular mycorrhizal fungi and steel slag improves plant growth and reduces Cd, Pb accumulation in Zea mays.

Little attention has been paid to the combined use of arbuscular mycorrhizal fungus (AMF) and steel slag (SS) for ameliorating heavy metal polluted soils. A greenhouse pot experiment was conducted to study the effects of SS and AMF-Funneliformis mosseae (Fm), Glomus versiforme (Gv) and Rhizophagus intraradices (Ri) on plant growth and Cd, Pb uptake by maize grown in soils added with 5 mg Cd kg-1 and 300 mg Pb kg-1 soil. The combined usage of AMF and SS (AMF + SS) promoted maize growth, and Gv + SS had the most obvious effect. Meanwhile, single SS addition and AMF + SS decreased Cd, Pb concentrations in maize, and the greater reductions were found in combined utilization, and the lowest Cd, Pb concentrations of maize appeared in Gv + SS. Single SS amendment and AMF + SS enhanced soil pH and decreased soil diethylenetriaminepentaacetic acid (DTPA)-extractable Cd, Pb concentrations. Furthermore, alone and combined usage of AMF and SS increased contents of soil total glomalin. Our research indicated a synergistic effect between AMF and SS on enhancing plant growth and reducing Cd, Pb accumulation in maize, and Gv + SS exerted the most pronounced effect. This work suggests that AMF inoculation in combination with SS addition may be a potential method for not only phytostabilization of Pb-Cd-contaminated soil but maize safety production.

A Highly Selective and Robust Co(II)-Based Homogeneous Catalyst for Reduction of CO2 to CO in CH3CN/H2O Solution Driven by Visible Light.

Visible-light driven reduction of CO2 into chemical fuels has attracted enormous interest in the production of sustainable energy and reversal of the global warming trend. The main challenge in this field is the development of efficient, selective, and economic photocatalysts. Herein, we report a Co(II)-based homogeneous catalyst, [Co(NTB)CH3CN](ClO4)2 (1, NTB = tris(benzimidazolyl-2-methyl)amine), which shows high selectivity and stability for the catalytic reduction of CO2 to CO in a water-containing system driven by visible light, with turnover number (TON) and turnover frequency (TOF) values of 1179 and 0.032 s-1, respectively, and selectivity to CO of 97%. The high catalytic activity of 1 for photochemical CO2-to-CO conversion is supported by the results of electrochemical investigations and DFT calculations.

0D/2D Heterojunctions of Vanadate Quantum Dots/Graphitic Carbon Nitride Nanosheets for Enhanced Visible-Light-Driven Photocatalysis.

0D/2D heterojunctions, especially quantum dots (QDs)/nanosheets (NSs) have attracted significant attention for use of photoexcited electrons/holes due to their high charge mobility. Herein, unprecedent heterojunctions of vanadate (AgVO3 , BiVO4 , InVO4 and CuV2 O6 ) QDs/graphitic carbon nitride (g-C3 N4 ) NSs exhibiting multiple unique advances beyond traditional 0D/2D composites have been developed. The photoactive contribution, up-conversion absorption, and nitrogen coordinating sites of g-C3 N4 NSs, highly dispersed vanadate nanocrystals, as well as the strong coupling and band alignment between them lead to superior visible-light-driven photoelectrochemical (PEC) and photocatalytic performance, competing with the best reported photocatalysts. This work is expected to provide a new concept to construct multifunctional 0D/2D nanocomposites for a large variety of opto-electronic applications, not limited in photocatalysis.

Design and discovery of Novel Thiazole acetamide derivatives as anticholinesterase agent for possible role in the management of Alzheimer's.

A novel series of thiazole acetamides was synthesized in excellent yields and characterized with the aid of various spectroscopic and elemental analysis. These compounds were evaluated for in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities for possible benefit in Alzheimers disease (AD). Among the synthesized compound, 6d was identified as the most potent compound of AChE (IC50=3.14±0.16 µM) with a selectivity index (SI) of 2.94 against BuChE. These compounds were further tested for inhibition of Aß aggregation and ß-secretase, where it showed potent inhibition which confirmed its multifactorial benefits in AD. The toxicity and docking study were also carried out to exemplify the pharmacological profile of compound 6d as prospective lead molecule against AD.

2,6-Bis(benzimidazol-2-yl)pyridine as a potent transmembrane anion transporter.

2,6-Bis(benzimidazol-2-yl)pyridine was shown to exhibit potent anionophoric activity via a process of both Cl(-)/NO3(-) antiport and H(+)/Cl(-) symport. This is in sharp contrast to the finding that its corresponding N-methylated analog exhibited negligible activity and reveals the importance of the imidazolyl-NH fragments in the anion-transport process.

Prognostic value of microRNA-10b overexpression in peripheral blood mononuclear cells of nonsmall-cell lung cancer patients.

We examined microRNA (miRNA)-10b expression in peripheral blood mononuclear cells (PBMCs) of nonsmall-cell lung cancer (NSCLC) patients for its clinical value. A group of 74 patients confirmed with NSCLC were recruited as case group and 52 healthy volunteers as control group. PBMCs were isolated from all subjects, and miRNA-10b expression level in these cells was measured by reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between miRNA-10b expression levels and the clinical and pathological characteristics of NSCLC was obtained. The miRNA-10b expression level in NSCLS patients is markedly higher than control subjects (P < 0.01). Analysis of receiver operating characteristic (ROC) curve estimated the peak diagnostic sensitivity of miRNA-10b at 86.5 % and specificity at 76.9 %. NSCLC patients were divided into high expression group (64 patients) and low expression group (10 patients). Further analysis showed that miRNA-10b expression levels in PBMCs correlated with lymph node metastasis, distant metastasis, and TNM classification (all P < 0.05). The 5-year survival rate in high expression group was significantly lower than low expression group (P = 0.017). Multivariate analysis by Cox regression model showed that high miRNA-10b expression, age >60 years, lymph node and distant metastases, and stage III-IV carcinoma were risk factors for poor prognosis in NSCLC patients (all P < 0.05). MiRNA-10b expression levels in PBMCs can distinguish NSCLC patients from cancer-free subjects with a high sensitivity and specificity, suggesting that miRNA-10b expression in PBMCs is a valuable diagnostic and prognostic marker in NSCLC.

Homogeneous electrocatalytic water oxidation at neutral pH by a robust macrocyclic nickel(II) complex.

The development of an earth-abundant, first-row water oxidation catalyst that operates at neutral pH and low overpotential remains a fundamental chemical challenge. Herein, we report the first nickel-based robust homogeneous water oxidation catalyst, which can electrocatalyze water oxidation at neutral pH and low overpotential in phosphate buffer. The results of DFT calculations verify that the O-O bond formation in catalytic water oxidation prefers a HO-OH coupling mechanism from a cis-isomer of the catalyst.

[Clinical application of free peroneal artery leaflet perforator flap in postoperative complex defect of oral cancer].

Objective:To investigate the clinical effect of a segmented perforator flap of free peroneal artery to repair a complex defect after oral cancer. Methods:Forty-eight patients with oral cancer admitted to the Department of Oral and Maxillofacial Surgery of the First Affiliated Hospital of Bengbu Medical College from January 2018 to January 2022, including 8 of buccal cancer, 7 of floor cancer, 14 of tongue cancer, 5 of retromolar cancet, 9 of maxillary gingival cancer and 5 of mandibular gingival cancer. After lesion resection, 24 patients in the experimental group used the partial perforator flap to repair the defect, and 24 patients in the control group used the single flap to repair the defect. Compared with the general data of the two groups, the difference was not statistically significant（P>0.05）, which was comparable. The flap cutting range of the experimental group was 38.5-74.5 cm², and tension-reduced suture for the donor area. In the control group, the myocutaneous flap incision range was 61.0-76.5 cm², and skin graft suture for the donor area. Flap survival and patient survival were recorded and compared. The patients were followed up at 6 and 12 months after surgery, and their swallowing function and speech function, including the drinking water test, functional oral food intake scale and the Chinese language clarity test word table, were evaluated respectively, and their subjective satisfaction with the repair appearance was recorded. Patients in both groups were followed up for 12 to 60 months. Kaplan-Meier method was used to calculate the cumulative survival rate of patients, and survival curves were plotted. log-rank test was used to compare the survival curves between groups. Results:The survival rate of the two groups was 100%. The 5-year survival rate was 62.5% in the experimental group and 54.2% in the control group. There was no significant difference between the two groups （P>0.05）. According to the results of the functional recovery evaluation, the groups in swallowing and speech function and subjective satisfaction（P>0.05）, and at 12 months after surgery（P<0.05）. Conclusion:The segmented perforator flap of free peroneal artery is flexible and can repair different anatomical structures of postoperative composite defect of oral cancer, which can effectively improve postoperative functional recovery and patient satisfaction. Therefore, the peroneal artery segmented perforator flap is the ideal flap for reconstructing postoperative composite defect of oral cancer.

The involvement of RNA N6-methyladenosine and histone methylation modification in decidualization and endometriosis-associated infertility.

Defective decidualization of endometrial stromal cells (ESCs) in endometriosis (EM) patients leads to inadequate endometrial receptivity and EM-associated infertility. Hypoxia is an inevitable pathological process of EM and participates in deficient decidualization of the eutopic secretory endometrium. Enhancer of zeste homology 2 (EZH2) is a methyltransferase which catalyses H3K27Me3, leading to decreased expression levels of target genes. Although EZH2 expression is low under normal decidualization, it is abundantly increased in the eutopic secretory endometrium of EM and is induced by hypoxia. Chromatin immunoprecipitation-PCR results revealed that decidua marker IGFBP1 is a direct target of EZH2, partially explaining the increased levels of histone methylation modification in defected decidualization of EM. To mechanism controlling this, we examined the effects of hypoxia on EZH2 and decidualization. EZH2 mRNA showed decreased m6 A modification and increased expression levels under hypoxia and decidualization combined treatment. Increased EZH2 expression was due to the increased expression of m6 A demethylase ALKBH5 and decreased expression of the m6 A reader protein YTHDF2. YTHDF2 directly bind to the m6 A modification site of EZH2 to promote EZH2 mRNA degradation in ESCs. Moreover, selective Ezh2 depletion in mouse ESCs increased endometrial receptivity and improved mouse fertility by up-regulating decidua marker IGFBP1 expression. This is the first report showing that YTHDF2 can act as a m6 A reader to promote decidualization by decreasing the stability of EZH2 mRNA and further increasing the expression of IGFBP1 in ESCs. Taken together, our findings highlight the critical role of EZH2/H3K27Me3 in decidualization and reveal a novel epigenetic mechanism by which hypoxia can suppress EM decidualization by decreasing the m6 A modification of EZH2 mRNA.

Fatigue behavior of freestanding nickel-molybdenum-tungsten thin films with high-density planar faults.

This research addresses the fatigue behavior of freestanding nickel-molybdenum-tungsten (Ni-Mo-W) thin films with high-density planar faults. The as-deposited Ni-Mo-W thin films demonstrate an unprecedented fatigue life, withstanding over a million cycles at a Goodman stress amplitude (Sa,Goodman) of 2190 MPa - nearly 80% of the tensile strength. The texture, columnar grain width, planar fault configuration (spacing and orientation), and tensile strength were unchanged after annealing at 500 °C for 24 hours, and the film endured over 2 × 105 cycles at Sa,Goodman of 1050 MPa. The fatigue life of annealed Ni-Mo-W thin films is comparable to those of nanocrystalline Ni-based alloys, but has deteriorated significantly compared to that of the as-deposited films. The high fatigue strength of Ni-Mo-W thin films is ascribed to extremely dense planar faults suppressing fatigue crack initiation, and planar fault-dislocation interaction and grain boundary plasticity are proposed as mechanisms responsible for the fatigue failure. Provisionally the latter is a more convincing account of the experimental results, in which changes in the grain boundary characteristics after annealing cause higher susceptibility to stress concentration during cyclic loading. The fatigue behavior revealed in this work consolidates the thermal and mechanical reliability of Ni-Mo-W thin films for potential nano-structural applications.

Low-frequency rTMS Plays a Neuroprotective role in Pilocarpine-induced Status Epilepticus Rat Models Through the AMPAR GluA1-STIM-Ca2+ Pathway.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) refers to the stimulation of the brain using repetitive magnetic field pulses at a low frequency (≤ 1 Hz) to reduce seizures. Currently, the mechanism is not well understood. Male Sprague-Dawley rats underwent pilocarpine-induced status epilepticus (SE) and were then stimulated with low-frequency rTMS. An epilepsy cell model was then established by incubating rat hippocampal neurons with Mg2+-free extracellular fluids. The effects of the low-frequency rTMS on epileptogenesis and hippocampal neuron injury were evaluated using a video electroencephalogram (vEEG) and Nissl staining, and the expression of AMPAR GluA1 and STIM in the hippocampus and hippocampal neurons was assessed using western blot and immunofluorescence. Additionally, the intracellular Ca2+ concentration and reactive oxygen species (ROS) were measured using flow cytometry. Low-frequency rTMS attenuated spontaneous recurrent seizures in rats with epilepsy, with the SE group exhibiting a higher incidence (100%) and frequency (3.00 ± 0.18 times/day) than the SE + 0.3 (50% incidence, 0.06 ± 0.03 times/day), SE + 0.5 (0.20 ± 0.02 times/day) and SE + 1 Hz (1.02 ± 0.05 times/day) groups. Additionally, rTMS reduced the damage and apoptosis of hippocampal pyramidal neurons, increasing their numbers in the CA1 and CA3 regions. Furthermore, AMPAR GluA1 and STIM expression were upregulated in the hippocampus when using rTMS, reversing the downregulation caused by seizures. Immunofluorescence verified the increased fluorescence intensity of AMPAR GluA1 and STIM. Moreover, rTMS inhibited Ca2+ overload and ROS in epileptic neuron models. Low-frequency rTMS may exert neuroprotective effects through the AMPAR GluA1-STIM-Ca2+ pathway.

Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ. Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.

Histone-deacetylase-targeted fluorescent ruthenium(II) polypyridyl complexes as potent anticancer agents.

Histone deacetylases inhibitors (HDACis) have gained much attention as a new class of anticancer agents in recent years. Herein, we report a series of fluorescent ruthenium(II) complexes containing N(1)-hydroxy-N(8)-(1,10-phenanthrolin-5-yl)octanediamide (L), a suberoylanilide hydroxamic acid (SAHA) derivative, as a ligand. As expected, these complexes show interesting chemiphysical properties, including relatively high quantum yields, large Stokes shifts, and long emission lifetimes. The in vitro inhibitory effect of the most effective drug, [Ru(DIP)2L](PF6)2 (3; DIP: 4,7-diphenyl-1,10-phenanthroline), on histone deacetylases (HDACs) is approximately equivalent in activity to that of SAHA, and treatment with complex 3 results in increased levels of the acetylated histone H3. Complex 3 is highly active against a panel of human cancer cell lines, whereas it shows relatively much lower toxicity to normal cells. Further mechanism studies show that complex 3 can elicit cell cycle arrest and induce apoptosis through mitochondria-related pathways and the production of reactive oxygen species. These data suggest that these fluorescent ruthenium(II)-HDACi conjugates may represent a promising class of anticancer agents for potential dual imaging and therapeutic applications targeting HDACs.