Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor-positive Breast Cancer.

Estrogen receptor-positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant to immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ breast cancers. However, constitutively activating mutations in the estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors resistant to endocrine therapy. Although these mutations represent a pathway of resistance, they also represent a potential source of neoepitopes that can be targeted by immunotherapy. In this study, we investigated ESR1 mutations as novel targets for breast cancer immunotherapy. Using machine learning algorithms, we identified ESR1-derived peptides predicted to form stable complexes with HLA-A*0201. We then validated the binding affinity and stability of the top predicted peptides through in vitro binding and dissociation assays and showed that these peptides bind HLA-A*0201 with high affinity and stability. Using tetramer assays, we confirmed the presence and expansion potential of antigen-specific CTLs from healthy female donors. Finally, using in vitro cytotoxicity assays, we showed the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies. SIGNIFICANCE: Estrogen receptor (ESR1) mutations have emerged as a key factor in endocrine therapy resistance. We identified and validated five novel, immunogenic ESR1-derived peptides that could be targeted through vaccine-based immunotherapy.

Exploring the contribution of the river chief system on controlling industrial water pollution under quasi-natural experimental conditions.

The innovative environmental system known as the river chief system (RCS) was developed in China to limit water pollution by appointing provincial, prefectural, county, and township officials as "river chiefs" as guardians of every river under their control. Our research project developed a quasi-natural experiment to investigate if the RCS effectively reduces the intensity of industrial water pollution. A multi-period difference-in-difference (DID) method was employed in the experiment with a total of 3808 samples from 272 prefecture-level cities. The samples gathered represented the years from 2007 to 2020. Our results demonstrated that the southern region has far more industrial water contamination than other locations, and the intensity of industrial sewage discharge decreased by 10.25% in pilot cities following the implementation of the RCS compared with what we observed in non-pilot cities. Furthermore, according to the mechanism analysis we used, cities that increased investment in technical advancement and modernized industrial structures may also account for this decreasing trend. Additionally, the results of geographical heterogeneity demonstrate that the RCS's influence on curbing industrial water pollution is greater in cities with a higher intensity of environmental regulation and higher fiscal balance pressure than in locations with low environmental regulation and low fiscal balance pressure. In summary, the Chinese government needs to continue to strengthen the RCS's implementation; this can be done by adjusting to local circumstances as needed and by carrying out the policy accurately and effectively across the country. Our research sheds light on how to prevent water pollution in China and in other countries and supports the positive effects and effectiveness of RCS.

Exposure to copper induces endoplasmic reticulum (ER) stress-mediated apoptosis in chicken (Gallus gallus) myocardium.

Copper (Cu), an omnipresent environmental pollutant, can cause potential harm to the public and ecosystems. In order to study the cardiotoxicity caused by Cu, molecular biology techniques were used to analyze the effect of Cu on ER stress-mediated cardiac apoptosis. In vivo investigation, 240 1-day-old chickens were fed with Cu (11, 110, 220, and 330 mg/kg) diet for 7 weeks. The consequence showed that high-Cu can induce ER stress and apoptosis in heart tissue. The vitro experiments, the Cu treatment for 24 h could provoke ultrastructural damage and upregulate the apoptosis rate. Meanwhile, GRP78, GRP94, eIF2α, ATF6, XBP1, CHOP, Bax, Bak1, Bcl2, Caspase-12 and Caspase-3 genes levels, and GRP78, GRP94 and Caspase-3 proteins levels were increased, which indicated that ER stress and apoptosis in cardiomyocytes. But the mRNA level of Bcl2 were decreased after Cu exposure. Conversely, Cu-induced ER stress-mediated apoptosis can be alleviated by treatment with 4-PBA. These findings generally showed that Cu exposure can contribute to ER stress-mediated apoptosis in chicken myocardium, which clarifies the important mechanism link between ER stress and apoptosis, and provides a new perspective for Cu toxicology.

Two novel Ln8 clusters bridged by CO32- effectively convert CO2 into oxazolidinones and cyclic carbonates.

It is difficult and challenging to design and construct high-nuclearity Ln(III)-based clusters due to the high coordination numbers and versatile coordination geometries of Ln(III) ions. Herein, two novel octanuclear Ln(III)-based clusters [Ln8(H2L-)4(HL2-)4(NO3)6 (CO3)2](NO3)2·2CH3CN (Ln = Nd (1) and Sm (2)) have been synthesized under solvothermal conditions. The X-ray single analysis reveals that both 1 and 2 are octanuclear structures and the eight central Ln(III) ions are bridged by two CO32- anions. Catalytic study revealed that 1 and 2 can effectively catalyze the cycloaddition reaction of CO2 and aziridines or epoxides simultaneously under mild conditions. What is more, cluster 1, as a heterogeneous catalyst, can be reused at least three times without obvious loss in catalytic activity for coupling of CO2 and epoxides. To our knowledge, cluster 1 is the first Ln(III)-based cluster catalyst used for the conversion of CO2 with aziridines or epoxides simultaneously. This work provides a successful strategy to integrate high-nuclear Ln(III)-based clusters for CO2 conversion, which may open a new space for the construction of multifunctional high-nuclear Ln(III)-based clusters as efficient catalysts for CO2 conversion.

Phase II Trial of Nelipepimut-S Peptide Vaccine in Women with Ductal Carcinoma In Situ.

NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in CTL responses between groups and between pre-vaccination and 1-month post-operation were analyzed using a two-sample t test or Wilcoxon rank sum test. The incidence and severity of adverse events were compared between groups. Overall, 45 patients were registered; 20 patients were HLA-A2 negative, 7 declined participation, 1 withdrew, and 4 failed screening for other reasons. The remaining 13 were randomized to NeuVax (n = 9) or GM-CSF alone (n = 4). Vaccination was well-tolerated with similar treatment-related toxicity between groups with the majority (>89%) of adverse events being grade 1. The percentage of NPS-specific CTLs increased in both arms between baseline (pre-vaccination) and 1-month post-operation. The increase was numerically greater in the NPS+GM-CSF arm, but the difference was not statistically significant. NPS+GM-CSF is safe and well-tolerated when given preoperatively to patients with DCIS. In patients with HLA-A2-positive DCIS, two inoculations with NPS+GM-CSF can induce in vivo immunity and a continued antigen-specific T-cell response 1-month postsurgery. PREVENTION RELEVANCE: This trial showed that vaccination of patients with HLA-A2-positive DCIS with NeuVax in the preoperative setting can induce a sustained antigen-specific T-cell response. This provides proof of principle that vaccination in the preoperative or adjuvant setting may stimulate an adaptive immune response that could potentially prevent disease recurrence.

Spatiotemporal variation pattern of production-living-ecological space and land use ecological risk and their relationship analysis: a case study of Changzhi City, China.

With the rapid development of mining, more and more cities faced the trade-off between ecological protection and large-scale mining. Assessment of production-living-ecological space transformation and land use ecological risk can provide a scientific guidance for land use management and risk control. This paper focused on a resource-based city, Changzhi City in China, using RRM model and elasticity coefficient to analyze the spatiotemporal characteristics of the production-living-ecological space evolution and land use ecological risk change, and measured the responsiveness of land use ecological risk to space transformation. The results showed the following: (1) From 2000 to 2020, production, living, and ecological spaces showed increased, decreased, and stable conditions, respectively. (2) The level of ecological risk showed an increasing trend from 2000 to 2020; the growth rate in the last 10 years was significantly lower than that in the first 10 years which was due to policy induced; the changes of ecological risk levels in each district and county were insignificant. (3) The elasticity coefficient from 2010 to 2020 became significantly less than that of the previous 10 years. The impact of the production-living-ecological space transformation on ecological risk was significantly reduced and the influencing factors of land use ecological risk were more diversified. However, Luzhou District still had a high level of land use ecological risk, which needs to pay more attention and be taken seriously. Our study provided guidance for ecological protection, rational land use, and territory development plan in Changzhi City, and also can be used as a reference in other resource-based cities.

Efficient synthesis and anticancer evaluation of spider toxin peptide LVTX-8-based analogues with enhanced stability.

Cytotoxic peptides derived from spider venoms have been considered as promising candidates for anticancer treatment. The novel cell penetrating peptide LVTX-8, which is a 25-residue amphipathic α-helical peptide isolated from spider Lycosa vittata, exhibited potent cytotoxicity and is a potential precursor for further anticancer drug development. Nevertheless, LVTX-8 may be easily degraded by multiple proteases, inducing the proteolytic stability problem and short half-life. In this study, ten LVTX-8-based analogs were rationally designed and the efficient manual synthetic method was established by the DIC/Oxyma based condensation system. The cytotoxicity of synthetic peptides was systematically evaluated against seven cancer cell lines. Seven of the derived peptides exhibited high cytotoxicity towards tested cancer in vitro, which was better than or comparable to that of natural LVTX-8. In particular, both N-acetyl and C-hydrazide modified LVTX-8 (825) and the conjugate methotrexate (MTX)-GFLG-LVTX-8 (827) possessed more durable anticancer efficiency, higher proteolytic stability, as well as lower hemolysis. Finally, we confirmed that LVTX-8 could disrupt the integrity of cell membrane, target the mitochondria and reduce the mitochondrial membrane potential to induce the cell death. Taken together, the structural modifications were conducted on LVTX-8 for the first time and the stability significantly improved derivatives 825 and 827 may provide useful references for the modifications of cytotoxic peptides.

Silk fibroin fibers-based shape memory membrane with Janus wettability for multitiered wearable protection.

Realizing breathable shape memory fiber-based material with antibacterial and waterproof performances is important for multitiered wearable protection to address the increasing concerns of air pollution. Herein, using an alternating electrospinning-electrospraying technology, we develop a fiber-based membrane with Janus wettability based on a silk fibroin nanofibers-substrate (SFNFs), a polyurethane nanospheres-top layer (PUNSs), and a middle layer of PU nanofibers-mat with in-situ grown silver nanoparticles (PUNFs-AgNPs), which serves separately for skin contact, a self-cleaning physical barrier to resist external aerosol/bacteria (PM2.5 filtration efficiency ~ 98.1%), and a bio-barrier that can sterilize harmful particles and inhibit bacteria proliferation (> 95%). This breathable Janus film (SFNFs/PUNFs-AgNPs/PUNSs, SPAP) with an antibacterial filter shows shape memory stretchability enabled by the thermoplastic PU component, which is mechanically adaptive to human body for wearable protection. This work presents a breathable wearable material for air-filtration and anti-bacteria, promising for applications such as wound dressings, medical masks, protection suits, and multifunctional filters. Graphical abstract: An alternating electrospinning-electrospraying technology was proposed to achieve a silk fibroin-based antibacterial membrane with Janus wettability, as well as good skin affinity and breathability, which serves well as physical and bio-barriers for water resistance, PM2.5 filtration (~98.1%) and bacteria inhibition (efficiency of 95%). This shape memory Janus membrane can adapt mechanically to human body curvatures for functional wearable protections. Supplementary Information: The online version contains supplementary material available at 10.1557/s43578-022-00805-w.

rs77283072 influences breast cancer susceptibility by regulating CDKN2A expression.

Breast cancer is the cancer type with the highest morbidity rates in women, and previous genome-wide association studies (GWASs) have suggested that the single nucleotide polymorphism (SNP) rs1011970 is significantly associated with this disease. An analysis of data from the 1000 Genomes Project demonstrated that there is an SNP, rs77283072, in almost complete linkage disequilibrium with rs1011970, which should therefore present the same signal in a GWAS. However, the actual causal SNP and its associated underlying mechanism have yet to be elucidated. Therefore, the present study evaluated the role of rs77283072 in terms of its association with breast cancer. A dual-luciferase assay was performed, which demonstrated that the two alleles of rs1011970 did not exhibit significantly different reporter gene activity. However, the A allele of rs77283072 exhibited a significant increase in relative luciferase activity compared with the G allele, which suggested that rs77283072 was the causal SNP for breast cancer. Chromosome conformation capture demonstrated that the enhancer containing rs77283072 interacted with the promoter of cyclin-dependent kinase inhibitor 2A (CDKN2A). Furthermore, expression quantitative trait locus analysis demonstrated that the expression of CDKN2A was dependent on the genotype of rs77283072. Taken together, the findings of the present study provided novel insights into the mechanism underlying how the genetic variation in this locus was able to influence breast cancer susceptibility and further the treatment for this disease.

The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus.

The use of oncolytic peptides with activity against a wide range of cancer entities as a new and promising cancer therapeutic strategy has drawn increasing attention. The oncolytic peptide LTX-315 derived from bovine lactoferricin (LfcinB) was found to be highly effective against suspension cancer cells, but not adherent cancer cells. In this study, we tactically fused LTX-315 with rhodamine B through a hybridization strategy to design and synthesize a series of nucleus-targeting hybrid peptides and evaluated their activity against adherent cancer cells. Thus, four hybrid peptides, NTP-212, NTP-217, NTP-223 and NTP-385, were synthesized. These hybrid peptides enhanced the anticancer activity of LTX-315 in a panel of adherent cancer cell lines by 2.4- to 37.5-fold. In model mice bearing B16-F10 melanoma xenografts, injection of NTP-385 (0.5 mg per mouse for 3 consecutive days) induced almost complete regression of melanoma, prolonged the median survival time and increased the overall survival. Notably, the administered dose of NTP-385 was only half the effective dose of LTX-315. We further revealed that unlike LTX-315, which targets the mitochondria, NTP-385 disrupted the nuclear membrane and accumulated in the nucleus, resulting in the transfer of a substantial amount of reactive oxygen species (ROS) from the cytoplasm to the nucleus through the fragmented nuclear membrane. This ultimately led to DNA double-strand break (DSB)-mediated intrinsic apoptosis. In conclusion, this study demonstrates that hybrid peptides obtained from the fusion of LTX-315 and rhodamine B enhance anti-adherent cancer cell activity by targeting the nucleus and triggering DNA DSB-mediated intrinsic apoptosis. This study also provides an advantageous reference for nucleus-targeting peptide modification.

Based on CT radiomics model for predicting the response to first-line chemotherapy of diffuse large B-cell lymphoma / 中华肿瘤杂志

Objective: To investigate the potential value of CT Radiomics model in predicting the response to first-line chemotherapy in diffuse large B-cell lymphoma (DLBCL). Methods: Pre-treatment CT images and clinical data of DLBCL patients treated at Shanxi Cancer Hospital from January 2013 to May 2018 were retrospectively analyzed and divided into refractory patients (73 cases) and non-refractory patients (57 cases) according to the Lugano 2014 efficacy evaluation criteria. The least absolute shrinkage and selection operator (LASSO) regression algorithm, univariate and multivariate logistic regression analyses were used to screen out clinical factors and CT radiomics features associated with efficacy response, followed by radiomics model and nomogram model. Receiver operating characteristic (ROC) curve, calibration curve and clinical decision curve were used to evaluate the models in terms of the diagnostic efficacy, calibration and clinical value in predicting chemotherapy response. Results: Based on pre-chemotherapy CT images, 850 CT texture features were extracted from each patient, and 6 features highly correlated with the first-line chemotherapy effect of DLBCL were selected, including 1 first order feature, 1 gray level co-occurence matrix, 3 grey level dependence matrix, 1 neighboring grey tone difference matrix. Then, the corresponding radiomics model was established, whose ROC curves showed AUC values of 0.82 (95% CI: 0.76-0.89) and 0.73 (95% CI: 0.60-0.86) in the training and validation groups, respectively. The nomogram model, built by combining validated clinical factors (Ann Arbor stage, serum LDH level) and CT radiomics features, showed an AUC of 0.95 (95% CI: 0.90-0.99) and 0.91 (95% CI: 0.82-1.00) in the training group and the validation group, respectively, with significantly better diagnostic efficacy than that of the radiomics model. In addition, the calibration curve and clinical decision curve showed that the nomogram model had good consistency and high clinical value in the assessment of DLBCL efficacy. Conclusion: The nomogram model based on clinical factors and radiomics features shows potential clinical value in predicting the response to first-line chemotherapy of DLBCL patients.

Associations of Lipoprotein(a) Level with Cerebral Small Vessel Disease in Patients with Alzheimer's Disease.

BACKGROUND: This study aimed to examine the association of lipoprotein(a) [Lp(a)] level with the burden of cerebral small vessel disease (CSVD) in patients with Alzheimer's disease (AD). METHODS: Data from 111 consecutive patients with AD admitted to Nanjing First Hospital from 2015 to 2022 were retrospectively analyzed in this study. Serum Lp(a) concentrations were grouped into tertiles (T1-T3). Brain magnetic resonance imaging (MRI) was rated for the presence of CSVD, including enlarged perivascular spaces (EPVS), lacunes, white-matter lesions, and cerebral microbleeds (CMBs). The CSVD burden was calculated by summing the scores of each MRI marker at baseline. A binary or ordinal logistic regression model was used to estimate the relationship of serum Lp(a) levels with CSVD burden and each MRI marker. RESULTS: Patients with higher tertiles of Lp(a) levels were less likely to have any CSVD (T1, 94.6%; T2, 78.4%; T3, 66.2%; p = 0.013). Multivariable analysis found that Lp(a) levels were inversely associated with the presence of CSVD (T2 vs. T1: adjusted odds ratio [aOR] 0.132, 95% confidence interval [CI] 0.018-0.946, p = 0.044; T3 vs. T1: aOR 0.109, 95% CI 0.016-0.737, p = 0.023) and CSVD burden (T3 vs. T1: aOR 0.576, 95% CI 0.362-0.915, p = 0.019). The independent relationship between Lp(a) levels and individual CSVD features was significant for moderate-to-severe EPVS in the centrum semiovale (T2 vs. T1: aOR 0.059, 95% CI 0.006-0.542, p = 0.012; T3 vs. T1: aOR 0.029, 95% CI 0.003-0.273, p = 0.002) and CMBs (T3 vs. T1: aOR 0.144, 95% CI 0.029-0.716, p = 0.018). CONCLUSIONS: In this study, serum Lp(a) level was inversely associated with CSVD in AD patients.

Deficits in ascending pain modulation pathways in breast cancer survivors with chronic neuropathic pain: A resting-state fMRI study.

Purpose: Breast cancer (BC) is the highest frequent malignancy in women globally. Approximately 25-60% of BC patients with chronic neuropathic pain (CNP) result from advances in treating BC. Since the CNP mechanism is unclear, the various treatment methods for CNP are limited. We aimed to explore the brain alternations in BC patients with CNP and the relationship between depression and CNP utilizing resting-state functional magnetic resonance imaging (rs-fMRI). Methods: To collect the data, the female BC survivors with CNP (n = 20) and healthy controls (n = 20) underwent rs-fMRI. We calculated and compared the functional connectivity (FC) between the two groups using the thalamus and periaqueductal gray (PAG) as seed regions. Results: Patients with BC showed increased depression and FC between the thalamus and primary somatosensory cortices (SI). Moreover, the Hospital Anxiety and Depression Scale-Depression (HADS-D) and pain duration were linked positively to the strength of FC from the thalamus to the SI. Furthermore, the thalamus-SI FC mediated the impact of pain duration on HADS-D. Conclusion: In BC patients with CNP, the ascending pain regulation mechanism is impaired and strongly associated with chronic pain and accompanying depression. This research increased our knowledge of the pathophysiology of CNP in patients with BC, which will aid in determining the optimal therapeutic strategy for those patients.

Self-Assembly Bifunctional Tetranuclear Ln2Ni2 Clusters: Magnetic Behaviors and Highly Efficient Conversion of CO2 under Mild Conditions.

A series of heterometallic tetranuclear clusters, Ln2Ni2(NO3)4L4(µ3-OCH3)2·2(CH3CN) (Ln = Gd(1), Tb(2), Dy(3), Ho(4), Er(5); HL = methyl 3-methoxysalicylate), were synthesized solvothermally. The intramolecular synergistic effect of two metal centers of Ln(III) and Ni(II) and the exposed multimetallic sites serving as Lewis acid activators greatly increase the efficiency of the CO2 conversion, and the yield for cluster 3 can be achieved at 96% at atmospheric pressure and low temperature. In particular, the self-assembly multimetal center with polydentate ligand shows good generality and enhanced recyclability. The design of such 3d-4f heterometallic clusters provides an effective strategy for the conversion of CO2 under greener conditions. Meanwhile, magnetic investigations indicate that cluster 1 is a good candidate for magnetic refrigerant materials with a relatively large magnetocaloric effect (MCE) (-ΔSm = 28.5 J kg-1 K-1 at 3.0 K and 7.0 T), and cluster 3 shows single-molecular magnet behavior under zero dc field. Heterometallic clusters with special magnetic properties and good catalytic behavior for the conversion of CO2 are rare. Thus, they are potential bifunctional materials applied in practice.

Self-assembly of octanuclear Ln(III)-based clusters: their large magnetocaloric effects and highly efficient conversion of CO2.

The design and construction of high-nuclear lanthanide clusters with fascinating topology and functional properties have been an active area of research, however, the development of an effective approach for obtaining high-nuclear lanthanide clusters with multifunctional properties is still extremely difficult. Up to now, a systematic approach for guiding the further expansion of Ln(III)-based clusters showing good functional properties is lacking. Herein, we design and synthesize a polydentate Schiff base ligand (HL), which reacts with ß-diketonate salts Ln(acac)3·2H2O, and a series of Ln8 clusters [Ln8(acac)6(L)2(µ3-O)6(µ2-C2H5O)4(µ2-Hacac)2]·2CH3CN (Ln(III) = Gd (1), Dy (2), and Ho (3); HL = pyridine-2-carboxylic acid (5-hydroxymethyl-furan-2-ylmethylene)-hydrazide, Hacac = acetylacetone) have been successfully synthesized. Single-crystal X-ray diffraction studies reveal that clusters 1-3 are isostructural and can be viewed as a Ln8 core bridged by eighteen µ2-O atoms, six µ3-O atoms and two µ4-O atoms. Magnetic studies show that cluster 1-Gd8 displays a large magnetocaloric effect with -ΔSm = 46.14 J kg-1 K-1 (T = 2.0 K and ΔH = 7.0 T); cluster 2-Dy8 exhibits single-molecule magnet behavior under zero-field conditions. It is worth mentioning that the -ΔSm of cluster 1-Gd8 is larger than that of most reported polynuclear Gd(III)-based clusters; the 2-Dy8 cluster is one of the rare polynuclear Lnn SMMs (n ≥ 8) under zero dc field. Importantly, these Ln(III)-based clusters (1-3) can catalyze the cycloaddition of CO2 with epoxides with high efficiency under mild conditions; and cluster 1-Gd8 as a catalyst could be reused at least three times without obvious loss of catalytic performance.

Bifunctional Metal-Organic Framework Functionalized by Dimethylamine Cations: Proton Conduction and Iodine Vapor Adsorption.

A metal-organic framework, {Zn3(BTB)2(µ3-OH)[(CH3)2NH2](H2O)}n (1), was synthesized based on H3BTB (1,3,5-tri(4-carboxyphenyl)benzene). An AC impedance test proves that 1 has a relatively high conductivity performance of 1.52 × 10-3 S·cm-1 at 338 K and 98% RH. The proton conductivity of the composite film 1@CS-9 (CS = chitosan) reaches 1.84 × 10-1 S·cm-1 at 328 K and 98% RH. In addition, 1 is discovered to have a good adsorption effect on iodine vapor, and the adsorption capacity reaches 726 mg·g-1. The multifunctionality caused by dimethylamine cations was investigated for the first time, which has implications for multifunctionality generated by host-guest molecules.

Short-Chain Fatty Acids Ameliorate Depressive-like Behaviors of High Fructose-Fed Mice by Rescuing Hippocampal Neurogenesis Decline and Blood-Brain Barrier Damage.

Excessive fructose intake is associated with the increased risk of mental illness, such as depression, but the underlying mechanisms are poorly understood. Our previous study found that high fructose diet (FruD)-fed mice exhibited neuroinflammation, hippocampal neurogenesis decline and blood-brain barrier (BBB) damage, accompanied by the reduction of gut microbiome-derived short-chain fatty acids (SCFAs). Here, we found that chronic stress aggravated these pathological changes and promoted the development of depressive-like behaviors in FruD mice. In detail, the decreased number of newborn neurons, mature neurons and neural stem cells (NSCs) in the hippocampus of FruD mice was worsened by chronic stress. Furthermore, chronic stress exacerbated the damage of BBB integrity with the decreased expression of zonula occludens-1 (ZO-1), claudin-5 and occludin in brain vasculature, overactivated microglia and increased neuroinflammation in FruD mice. These results suggest that high fructose intake combined with chronic stress leads to cumulative negative effects that promote the development of depressive-like behaviors in mice. Of note, SCFAs could rescue hippocampal neurogenesis decline, improve BBB damage and suppress microglia activation and neuroinflammation, thereby ameliorate depressive-like behaviors of FruD mice exposed to chronic stress. These results could be used to develop dietary interventions to prevent depression.

Silk Fabric Decorated with Thermo-Sensitive Hydrogel for Sustained Release of Paracetamol.

Paracetamol is a safe and widely used antipyretic and analgesic drug, however, with the drawbacks of gastrointestinal first-pass effect and short intervals of administration. Transdermal drug delivery system can effectively avoid the liver metabolism caused by excess oral ingestion of paracetamol. Herein, a silk fabric-based medical dressing decorated by a thermo-responsive hydrogel for sustained release of paracetamol is proposed. Genipin as a bio-safe cross-linker is applied to assist gelation of a thermo-responsive hydrogel system coupled with chitosan and glycerol-phosphate disodium salt around body temperature (37 °C), as well as densifying the microporous gel to improve mechanical strength. The in situ sol-gel transition enabled hydrogel well penetrate and coat the silk fabric, forming a hierarchical hydrogel structure capable of prolonging the sustained release of drug to 12 h, twice as long as a blank fabric. The silk fabric with a thin gel coating maintains a good water vapor transmission rate, compatible for skin contact application. The drug release properties can be tuned by regulating the genipin content and fabric braiding structure. The silk fabric dressing exhibits temperature-dependent instant release behavior within the first 2 h. The sustained release mechanism of paracetamol well matches with the Korsmeyer-Peppas model in a non-Fickian diffusion.

Rescuing effects of periostin in advanced glycation end-products (AGEs) caused osteogenic and oxidative damage through AGE receptor mediation and DNA methylation of the CALCA promoter.

An in vitro model was established to simulate a diabetes-type environment by treating human periodontal stem cells with advanced glycation end-products (AGEs). Periostin (POSTN) plays a crucial role in maintaining the integrity of periodontal tissues. However, the role of POSTN in human periodontal stem cells stimulated by AGEs remains unknown. Diabetes mellitus is considered a metabolic disease, and DNA methylation of CpG islands is a biomarker of metabolic syndromes. Diabetes has been found to be closely related to the DNA methylation of certain genes. Here, we investigated the protective mechanism and effect of POSTN on osteogenesis and oxidative stress in the AGE environment, and further explored the CpG island methylation of specific genes potentially mediated by POSTN. The optimal concentration of AGEs was screened using CCK8. AGEs were found to contribute to oxidative stress. Conversely, reactive oxygen species production and malondialdehyde and superoxide activity indicated that the AGE + POSTN group decreased oxidative injury. According to an alkaline phosphatase assay, Alizarin Red S staining, and the expression of key genes and proteins involved in osteogenesis, POSTN mitigated the inhibitory effects of AGE on cell proliferation and osteogenic differentiation potential during osteogenic differentiation. In contrast, the growth and osteogenesis of human periodontal stem cells were notably suppressed by POSTN knockdown. Bisulfite sequencing PCR was used to evaluate the DNA methylation status. Moreover, AGE elevated the expression of DNA methyltransferas 1 (DNMT1) and inhibited the activation of CALAL promoter methylation, which was rescued by the addition of POSTN and 5-Azacytidine (5-AZA). In conclusion, POSTN attenuated the AGE-induced inhibition of osteogenesis in periodontal ligament stem cells by reducing AGE receptor levels and DNA methylation of the calcitonin-related polypeptide α (CALCA) promoter. Thus, POSTN is a promising candidate for dental bone regeneration, representing a novel therapeutic agent for diabetic patients. The mechanism underlying these processes may provide new insights into novel therapeutic targets for improving abnormal bone metabolism in patients with diabetes.

rs9390123 and rs9399451 influence the DNA repair capacity of lung cancer by regulating PEX3 and PHACTR2­AS1 expression instead of PHACTR2.

Lung cancer is a common cancer type, and has the highest mortality rate in the world. A genome­wide association study suggests that the genetic marker rs9390123 is significantly associated with DNA repair capacity (DRC) in lung cancer. Analysis of the data derived from the 1000 Genomes Project indicated that there is another single nucleotide polymorphism (SNP), rs9399451, in strong linkage disequilibrium with rs9390123 in Caucasian individuals, thus suggesting that this SNP could be associated with DRC. However, the causal SNP and mechanism of DRC remain unclear. In the present study, dual luciferase assay results indicated that both SNPs are functional in lung cells. Through chromosome conformation capture, an enhancer containing the two functional SNPs was observed to bind the promoter of peroxisomal biogenesis factor 3 and phosphatase and actin regulator 2 antisense RNA 1 (PHACTR2­AS1). Knockdown of PHACTR2­AS1 could significantly influence lung cell proliferation, colony formation, migration and wound healing, which verified that PHACTR2­AS1 is a novel oncogene for lung cancer. Through chromatin immunoprecipitation, the transcription factor POU class 2 homeobox 1 (POU2F1) was identified to bind to the surrounding segments of these two SNPs, and their interaction was investigated. The present study identified the mechanism via which rs9390123 and rs9399451 could influence DRC.