Prenatal dexamethasone exposure impairs rat blood-testis barrier function and sperm quality in adult offspring via GR/KDM1B/FSTL3/TGFß signaling.

Both epidemiological and animal studies suggest that adverse environment during pregnancy can change the offspring development programming, but it is difficult to achieve prenatal early warning. In this study we investigated the impact of prenatal dexamethasone exposure (PDE) on sperm quality and function of blood-testis barrier (BTB) in adult offspring and the underlying mechanisms. Pregnant rats were injected with dexamethasone (0.1, 0.2 and 0.4 mg·kg-1·d-1, s.c.) from GD9 to GD20. After weaning (PW4), the pups were fed with lab chow. At PW12 and PW28, the male offspring were euthanized to collect blood and testes samples. We showed that PDE significantly decreased sperm quality (including quantity and motility) in male offspring, which was associated with impaired BTB and decreased CX43/E-cadherin expression in the testis. We demonstrated that PDE induced morphological abnormalities of fetal testicle and Sertoli cell development originated from intrauterine. By tracing to fetal testicular Sertoli cells, we found that PDE dose-dependently increased expression of histone lysine demethylases (KDM1B), decreasing histone 3 lysine 9 dimethylation (H3K9me2) levels of follistatin-like-3 (FSTL3) promoter region and increased FSTL3 expression, and inhibited TGFß signaling and CX43/E-cadherin expression in offspring before and after birth. These results were validated in TM4 Sertoli cells following dexamethasone treatment. Meanwhile, the H3K9me2 levels of FSTL3 promoter in maternal peripheral blood mononuclear cell (PBMC) and placenta were decreased and its expression increased, which was positively correlated with the changes in offspring testis. Based on analysis of human samples, we found that the H3K9me2 levels of FSTL3 promoter in maternal blood PBMC and placenta were positively correlated with fetal blood testosterone levels after prenatal dexamethasone exposure. We conclude that PDE can reduce sperm quality in adult offspring rats, which is related to the damage of testis BTB via epigenetic modification and change of FSTL3 expression in Sertoli cells. The H3K9me2 levels of the FSTL3 promoter and its expression in the maternal blood PBMC can be used as a prenatal warning marker for fetal testicular dysplasia.

Impacts of prenatal environmental exposures on fetal-placental-maternal bile acid homeostasis and long-term health in offspring.

During pregnancy, the maternal body undergoes a series of adaptative physiological changes, leading to a slight increase in serum bile acid (BA) levels. Although the fetal liver can synthesize BAs since the first trimester through the alternative pathway, the BA metabolic system is immature in the fetus. Compared to adults, the fetus has a distinct composition of BA pool and limited expression of BA synthesis enzymes and transporters. Besides, the "enterohepatic circulation" of BAs is absent in fetus. Thus, fetal BAs need to be transported to the mother through the placenta for further metabolism and excretion, and maternal BAs can also be transported to the fetus. That is what we call the "fetal-placental-maternal BA circulation". Various BA transporters and nuclear receptors are essential for maintaining the balance of this BA circulation to ensure normal fetal development. However, prenatal adverse environments can alter fetal BA metabolism, resulting in intrauterine developmental abnormalities and susceptibility to a variety of adult chronic diseases. This review summarizes the current understanding of the fetal-placental-maternal BA circulation and discusses the effects of prenatal adverse environments on this particular BA circulation, aiming to provide a theoretical basis for exploring early prevention and treatment strategies for BA metabolism-associated adverse pregnancy outcomes and long-term impairments.

Valence-Engineered Oxidase-Mimicking Nanozyme with Specificity for Aromatic Amine Oxidation and Identification.

Oxidase-mimicking nanozymes with specificity for catalyzing oxidation of aromatic amines are of great significance for recognition of aromatic amines but rarely reported. Herein, Cu-A nanozyme (synthesized with Cu2+ as a node and adenine as a linker) could specifically catalyze oxidation of o-phenylenediamine (OPD) in Britton-Robinson buffer solution. Such a specific catalytic performance was also corroborated with other aromatic amines, such as p-phenylenediamine (PPD), 1,5-naphthalene diamine (1,5-NDA), 1,8-naphthalene diamine (1,8-NDA), and 2-aminoanthracene (2-AA). Moreover, the presence of salts (1 mM NaNO2, NaHCO3, NH4Cl, KCl, NaCl, NaBr, and NaI) greatly mediated the catalytic activity with the order of NaNO2 < blank ≈ NaHCO3 < NH4Cl ≈ KCl ≈ NaCl < NaBr < NaI, which was due to anions sequentially increasing interfacial Cu+ content via anionic redox reaction, while the effect of cations was negligible. With the increased Cu+ content, Km decreased and Vmax increased, indicating valence-engineered catalytic activity. Based on high specificity and satisfactory activity, a colorimetric sensor array with NaCl, NaBr, and NaI as sensing channels was constructed to identify five representative aromatic amines (OPD, PPD, 1,5-NDA, 1,8-NDA, and 2-AA) as low as 50 µM, quantitatively analyze single aromatic amine (with OPD and PPD as model analysts), and even identify 20 unknown samples with an accuracy of 100%. In addition, the performance was further validated through accurately recognizing various concentration ratios of binary, ternary, quaternary, and quinary mixtures. Finally, the practical applications were demonstrated by successfully discriminating five aromatic amines in tap, river, sewage, and sea water, providing a simple and feasible assay for large-scale scanning aromatic amine levels in environmental water samples.

Disruption of Iron Homeostasis to Induce Ferroptosis with Albumin-Encapsulated Pt(IV) Nanodrug for the Treatment of Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer , accounting for approximately 85% of lung cancers. For more than 40 years, platinum (Pt)-based drugs are still one of the most widely used anticancer drugs even in the era of precision medicine and immunotherapy. However, the clinical limitations of Pt-based drugs, such as serious side effects and drug resistance, have not been well solved. This study constructs a new albumin-encapsulated Pt(IV) nanodrug (HSA@Pt(IV)) based on the Pt(IV) drug and nanodelivery system. The characterization of nanodrug and biological experiments demonstrate its excellent drug delivery and antitumor effects. The multi-omics analysis of the transcriptome and the ionome reveals that nanodrug can activate ferroptosis by affecting intracellular iron homeostasis in NSCLC. This study provides experimental evidence to suggest the potential of HSA@Pt(IV) as a nanodrug with clinical application.

Egr2 contributes to age-dependent vulnerability to sevoflurane-induced cognitive deficits in mice.

Sevoflurane inhalation is prone to initiate cognitive deficits in infants. The early growth response-2 (Egr-2) gene is DNA-binding transcription factor, involving in cognitive function. In this study we explored the molecular mechanisms underlying the vulnerability to cognitive deficits after sevoflurane administration. Six-day-old (young) and 6-week-old (early adult) mice received anesthesia with 3% sevoflurane for 2 h daily for 3 days. We showed that multiple exposures of sevoflurane induced significant learning ability impairment in young but not early adult mice, assessed in Morris water maze test on postnatal days 65. The integrated differential expression analysis revealed distinct transcription responses of Egr family members in the hippocampus of the young and early adult mice after sevoflurane administration. Particularly, Egr2 was significantly upregulated after sevoflurane exposure only in young mice. Microinjection of Egr2 shRNA recombinant adeno-associated virus into the dentate gyrus alleviated sevoflurane-induced cognitive deficits, and abolished sevoflurane-induced dendritic spins loss and BDNF downregulation in young mice. On the contrary, microinjection of the Egr2 overexpression virus in the dentate gyrus aggravated learning ability impairment induced by sevoflurane in young mice but not early adult mice. Furthermore, we revealed that sevoflurane markedly upregulated the nuclear factors of activated T-cells NFATC1 and NFATC2 in young mice, which were involved in Egr2 regulation. In conclusion, Egr2 serves as a critical factor for age-dependent vulnerability to sevoflurane-induced cognitive deficits.

P-gp expression inhibition mediates placental glucocorticoid barrier opening and fetal weight loss.

BACKGROUND: Prenatal adverse environments can cause fetal intrauterine growth retardation (IUGR) and higher susceptibility to multiple diseases after birth, related to multi-organ development programming changes mediated by intrauterine overexposure to maternal glucocorticoids. As a glucocorticoid barrier, P-glycoprotein (P-gp) is highly expressed in placental syncytiotrophoblasts; however, the effect of P-gp on the occurrence of IUGR remains unclear. METHODS: Human placenta and fetal cord blood samples of IUGR fetuses were collected, and the related indexes were detected. Pregnant Wistar rats were administered with 30 mg/kg·d (low dose) and 120 mg/kg·d (high dose) caffeine from gestational day (GD) 9 to 20 to construct the rat IUGR model. Pregnant mice were administered with caffeine (120 mg/kg·d) separately or combined with sodium ferulate (50 mg/kg·d) from gestational day GD 9 to 18 to confirm the intervention target on fetal weight loss caused by prenatal caffeine exposure (PCE). The fetal serum/placental corticosterone level, placental P-gp expression, and related indicator changes were analyzed. In vitro, primary human trophoblasts and BeWo cells were used to confirm the effect of caffeine on P-gp and its mechanism. RESULTS: The placental P-gp expression was significantly reduced, but the umbilical cord blood cortisol level was increased in clinical samples of the IUGR neonates, which were positively and negatively correlated with the neonatal birth weight, respectively. Meanwhile, in the PCE-induced IUGR rat model, the placental P-gp expression of IUGR rats was decreased while the corticosterone levels of the placentas/fetal blood were increased, which were positively and negatively correlated with the decreased placental/fetal weights, respectively. Combined with the PCE-induced IUGR rat model, in vitro caffeine-treated placental trophoblasts, we confirmed that caffeine decreased the histone acetylation and expression of P-gp via RYR/JNK/YB-1/P300 pathway, which inhibited placental and fetal development. We further demonstrated that P-gp inducer sodium ferulate could reverse the inhibitory effect of caffeine on the fetal body/placental weight. Finally, clinical specimens and other animal models of IUGR also confirmed that the JNK/YB-1 pathway is a co-regulatory mechanism of P-gp expression inhibition, among which the expression of YB-1 is the most stable. Therefore, we proposed that YB-1 could be used as the potential early warning target for the opening of the placental glucocorticoid barrier, the occurrence of IUGR, and the susceptibility of a variety of diseases. CONCLUSIONS: This study, for the first time, clarified the critical role and epigenetic regulation mechanism of P-gp in mediating the opening mechanism of the placental glucocorticoid barrier, providing a novel idea for exploring the early warning, prevention, and treatment strategies of IUGR.

Selection of reliable reference genes for analysis of gene expression in the rat placenta.

The selection of suitable reference genes (RGs), especially the identification of the proper combination of RGs is the key to obtain reliable results of gene expression for quantitative real-time polymerase chain reaction (qRT-PCR). To date, there is no relevant study dealing with the stability of RGs in rat placenta. In this study, the geNorm, NormFinder, and BestKeeper software were used to analyze the expression stability of the candidate RGs in placenta under physiological and prenatal caffeine exposure (PCE) conditions. The expression of Tbp, Gapdh and Ywhaz in female and Polr2a, Gapdh and Ywhaz in male placenta were highly stable under physiological conditions, and there was no obvious gender difference. We further found that two RGs were sufficient for reliable normalization in female and male placenta and the combination of Ywhaz and Gapdh was the most suitable compound RGs under physiological conditions. Under PCE conditions, Ywhaz, Gapdh and Polr2a were the most stable genes in both female and male placenta. Among them, Ywhaz and Gapdh were chosen as the best paring. Finally, selected RGs were employed for normalization of the expression of a clear target gene and the results of standardization supported our choice. In conclusion, our study confirmed that Ywhaz/Gapdh combination was the most suitable RGs in rat placenta under physiological and PCE pathological conditions and provided a theoretical and experimental basis for physiological and pathological research of the rat placenta.

lncRNA PAPPA-AS1 Induces the Development of Hypertrophic Scar by Upregulating TLR4 through Interacting with TAF15.

Hypertrophic scar (HTS) is a complicated pathological process induced mainly by burns and wounds, with abnormal proliferation of fibroblasts and the transformation of fibroblasts to myofibroblasts. PAPPA-AS1, a differentially expressed long noncoding RNA (lncRNA) in the HTS tissues, attracted our interests in its potential role and mechanism in the development and process of HTS. In the present study, the regulatory effect of lncRNA PAPPA-AS1 on the Toll-like receptor 4 (TLR4) signal pathway, as well as the molecular mechanism, was investigated. Bioinformatics analysis was utilized to screen the differentially expressed lncRNAs in HTS tissues. PAPPA-AS1 was significantly upregulated in both HTS tissues and hypertrophic scar fibroblast (HTsFb) cells. The expression levels of TLR4, MyD88, TGF-ß1, collagen I, collagen III, and α-SMA were greatly elevated in HTsFb cells. By knocking down PAPPA-AS1, the proliferation of HTsFb cells, TLR4, and TGF-ß1 signal pathway and the expression of fibrosis markers both in HTsFb cells and HTS tissues were suppressed. It was accompanied by the alleviated pathological state in the HTS tissues, which were significantly reversed by cotransfecting with the pcDNA3.1-TLR4 vector. Positive correlation and interaction were observed between PAPPA-AS1 and TAF15 and between TAF15 and the promoter of TLR4, respectively. In conclusion, lncRNA PAPPA-AS1 might induce the development of HTS by upregulating TLR4 through interacting with TAF15.

A Novel Fat Making Strategy With Adipose-Derived Progenitor Cell-Enriched Fat Improves Fat Graft Survival.

BACKGROUND: A low survival rate is one of the main challenges in fat grafting. OBJECTIVES: This study aimed to evaluate whether microfat obtained by a novel strategy promoted the survival and retention of fat grafts. METHODS: A 5-mm-diameter blunt tip cannula with large side holes (~30 mm2/hole) was used to obtain macrofat. A novel strategy based on a newly invented extracorporeal cutting device was then used to cut the macrofat into microfat, which was named adipose-derived progenitor cell enrichment fat (AER fat); Coleman fat was used as the control. Aliquots (0.5 mL) of both types of fat were transplanted into 10 nude mice and analyzed 10 weeks later. Western blotting, flow cytometry, and immunofluorescence were performed to assess the AER fat characteristics and underlying mechanisms. RESULTS: The retention rate of fat grafts in AER fat-treated animals was significantly higher than that in the Coleman group (mean [standard deviation] 54.6% [13%] vs 34.8% [9%]; P < 0.05) after 10 weeks. AER fat contained more dipeptidyl peptidase-4-expressing progenitor cells (3.3 [0.61] × 103 vs 2.0 [0.46] × 103 cells/mL; P < 0.05), adipose-derived plastic-adherent cells (6.0 [1.10] × 104 vs 2.6 [0.17] × 104 cells/mL; P < 0.001), and viable adipocytes than Coleman fat. Moreover, histologic analysis showed that AER fat grafts had better histologic structure and higher capillary density. CONCLUSIONS: AER fat transplantation is a potential strategy to improve the survival and long-term retention of fat grafts. AER fat contained more dipeptidyl peptidase-4-expressing progenitor cells.

Sedation and Analgesia for Liver Cancer Percutaneous Radiofrequency Ablation: Fentanyl and Oxycodone Comparison.

Background: Sedation and analgesia use in percutaneous radiofrequency ablation (RFPA) for liver cancer is a necessary part of the procedure; however, the optimal medicine for sedation and analgesia for PRFA remains controversial. The aim of this study was to compare the perioperative pain management, haemodynamic stability and side effects between oxycodone (OXY) and fentanyl (FEN) use in patients under dexmedetomidine sedation. Methods: Two hundred and five adults with an American Society of Anaesthesiologists physical status score of I to II were included in this study. Patients were assigned to the OXY (n=101) or FEN (n=104) group. Radiofrequency ablation was performed under spontaneous breathing and with painless anaesthesia administered intravenously. The outcomes included fluctuations in mean arterial pressure, heart rate, side effects and the perioperative numerical rating scale (NRS). Results: Radiofrequency ablation was successfully performed in 205 patients. No significant differences were observed in mean blood pressure fluctuations between the two groups despite the longer durations of ablation and total sedation time in the OXY group. The highest NRS score during the surgery and 1 hour and 2 hours after the surgery were significantly lower in the OXY group than in the FEN group. Heart rate fluctuations were significantly lower in the OXY group than in FEN group throughout the surgery. More patients in the FEN group displayed unwanted body movement and respiratory depression. Conclusions: Both oxycodone and fentanyl can be applied for liver cancer percutaneous radiofrequency ablation; however, oxycodone provides a better patient experience, lower postoperative pain, less respiratory depression and stable haemodynamic fluctuations.

Promotion effects of mono-2-ethyhexyl phthalate (MEHP) on migration and invasion of human melanoma cells via activation of TGF-ß signals.

Malignant melanoma is one of the most leading forms of skin cancer associated with a low patient survival rate. There is an urgent need to illustrate risk factors that can trigger the motility of melanoma cancer cells. Our present study revealed that mono-(2-ethylhexyl)phthalate (MEHP) exposure can significantly increase the in vitro migration and invasion of WM983A and A375 cells. Among the tested cytokines, MEHP can increase the expression of transforming growth factor ß (TGF-ß). Inhibition of TGF-ß via its neutralization antibody can attenuate MEHP-induced cell migration and invasion. Further, upregulation of TGF-ß mediated MEHP-induced activation of Smad signals and upregulation of Snail in melanoma cells. Blocking the TGF-ß/Smad signal pathway can attenuate MEHP-induced cell migration. Estrogen receptor α (ERα) was essential for MEHP-induced expression of TGF-ß. In addition, MEHP can increase the expression of ERα in melanoma cells. Collectively, our study found that MEHP can stimulate the progression of melanoma via TGF-ß signals. SIGNIFICANCE: Mono-(2-ethylhexyl)phthalate (MEHP) is the active and most toxic metabolite of di(2-ethylhexyl)phthalate (DEHP). Our present study revealed that MEHP can trigger the in vitro migration and invasion of melanoma cells via upregulation of TGF-ß/Snail signals. It revealed that daily exposure to MEHP might be a risk factor for melanoma patients.

High Platelet Levels Attenuate the Efficacy of Platinum-Based Treatment in Non-Small Cell Lung Cancer.

BACKGROUND/AIMS: The correlation between platelet levels and clinical outcomes has received increasing attention, but it is not yet clear whether and how platelet levels affect the therapeutic response in non-small cell lung cancer (NSCLC). In the current study, we aimed to explore the role of platelet levels in responsive to platinum-based chemotherapy and investigated the underlying mechanism. METHODS: We evaluated the possibility of platelet level as a biomarker for response to platinum-based therapy in NSCLC by retrospective analysis of NSCLC patients. Cell proliferation was evaluated using cell counter and flow cytometry. Cell capillary-like structures of HPMEC were estimated with ECMatrix. The effect of platelets on A549, H1299, and HPMEC apoptosis was measured by flow cytometry. A A549-bearing NOD/ SCID mice model was employed to determine whether platelets could counteract cisplatin-induced apoptosis in vivo. In vivo cell proliferation and apoptosis were evaluated with Ki-67 antibody and TUNEL staining respectively. The angiogenesis of tumor was estimated by CD31 microvessel density. The protein levels of Akt, Bad and Bcl-2 were assessed by western blot. To further examine platelet-driven effects of the chemotherapeutic response, we used platelet depletion and platelet transfusion in A549-bearing NOD/SCID mice. RESULTS: Thrombocytosis at NSCLC diagnosis was associated with lower progression-free survival and median overall survival. Platelet levels before chemotherapy in the no response group were markedly higher than in the responsive group. Platelets rescued the inhibition of cell proliferation and angiogenesis and protected against cell apoptosis induced by cisplatin, platelets rescued cisplatin-induced apoptosis via the Akt/Bad/Bcl-2 signaling pathway under endoplasmic reticulum stress. Platelet transfusion decreased the therapeutic effect of cisplatin, while it was increased by platelet depletion. CONCLUSION: We confirmed an important anti-apoptosis mechanism mediated by platelets and found that platelets could counteract cisplatin-induced apoptosis. Reducing platelet levels or blocking platelet-based cytoprotection may represent new methods for improving the chemotherapeutic effect.

Repurposing lipid-lowering drugs as potential treatment for acne vulgaris: a Mendelian randomization study.

Background: Acne vulgaris, a chronic inflammatory skin condition predominantly seen in teenagers, impacts more than 640 million people worldwide. The potential use of lipid-lowering medications as a treatment for acne vulgaris remains underexplored. This study seeks to investigate the impact of lipid-lowering therapies on the risk of developing acne vulgaris using two-sample Mendelian randomization (MR) analysis. Method: The two-sample MR method was employed for analysis, and information on lipid-lowering drugs was obtained from the DrugBank and ChEMBL databases. The summary data for blood low-density lipoprotein (LDL) and triglycerides were sourced from the Global Lipids Genetics Consortium, while genome-wide association studies (GWAS) summary data for acne vulgaris were obtained from the FinnGen database. Heterogeneity was examined using the Q-test, horizontal pleiotropy was assessed using MR-Presso, and the robustness of analysis results was evaluated using leave-one-out analysis. Results: The MR analysis provided robust evidence for an association between lowering LDL cholesterol through two drug targets and acne vulgaris, with PCSK9 showing an odds ratio (OR) of 1.782 (95%CI: 1.129-2.812, p = 0.013) and LDL receptor (LDLR) with an OR of 1.581 (95%CI: 1.071-2.334, p = 0.021). Similarly, targeting the lowering of triglycerides through lipoprotein lipase (LPL) was significantly associated with an increased risk of acne vulgaris, indicated by an OR of 1.607 (95%CI: 1.124-2.299, p = 0.009). Conclusion: The current MR study presented suggestive evidence of a positive association between drugs targeting three genes (PCSK9, LDLR, and LPL) to lower lipids and a reduced risk of acne vulgaris.

Intravenous Senescent Erythrocyte Vaccination Modulates Adaptive Immunity and Splenic Complement Production.

Targeted delivery of vaccines to the spleen remains a challenge. Inspired by the erythrophagocytotic process in the spleen, we herein report that intravenous administration of senescent erythrocyte-based vaccines profoundly alters their tropism toward splenic antigen-presenting cells (APCs) for imprinting adaptive immune responses. Compared with subcutaneous inoculation, intravenous vaccination significantly upregulated splenic complement expression in vivo and demonstrated synergistic antibody killing in vitro. Consequently, intravenous senescent erythrocyte vaccination produces potent SARS-CoV-2 antibody-neutralizing effects, with potential protective immune responses. Moreover, the proposed senescent erythrocyte can deliver antigens from resected tumors and adjuvants to splenic APCs, thereby inducing a personalized immune reaction against tumor recurrence after surgery. Hence, our findings suggest that senescent erythrocyte-based vaccines can specifically target splenic APCs and evoke adaptive immunity and complement production, broadening the tools for modulating immunity, helping to understand adaptive response mechanisms to senescent erythrocytes better, and developing improved vaccines against cancer and infectious diseases.

Cost-effectiveness analysis of sintilimab plus IBI305 versus sorafenib for unresectable hepatic cell carcinoma in China.

BACKGROUND: Sintilimab combined with IBI305 treatment regimen had potential clinical benefits than sorafenib in the first-line treatment of patients with unresectable hepatic cell carcinoma (HCC). However, whether sintilimab plus IBI305 has economic benefits in China remains unclear. METHODS: From the perspective of Chinese payers, we used the Markov model to simulate patients with HCC receiving treatment with sintilimab plus IBI305 and sorafenib. The transition probability between health states was estimated using the parametric survival model, and the cumulative medical costs and utility of the two treatment methods were estimated. Considering the incremental cost-effectiveness ratios (ICERs) as the evaluation index, sensitivity analyses were performed to explore the impact of uncertainty on the results. RESULTS: Compared to sorafenib, sintilimab plus IBI305 generated an additional $17552.17 and 0.33 quality-adjusted life years, resulting in an ICER of $52817.89. The analysis outcomes were most sensitive to the total cost of sintilimab plus IBI305. With a willingness-to-pay threshold of $38,334, sintilimab plus IBI305 showed a 1.28% probability of being cost-effective. The total cost of sintilimab plus IBI305 should be reduced by at least 31.9% to be accepted by Chinese payers. CONCLUSIONS: Regardless of whether the price of sintilimab plus IBI305 and sorafenib is covered by Medicare, sintilimab plus IBI305 is unlikely to be cost-effective for first-line treatment of patients with unresectable HCC.

Nanoparticle-Mediated CD47-SIRPα Blockade and Calreticulin Exposure for Improved Cancer Chemo-Immunotherapy.

Enabling macrophages to phagocytose tumor cells holds great potential for cancer therapy but suffers from tremendous challenges because the tumor cells upregulate antiphagocytosis molecules (such as CD47) on their surface. The blockade of CD47 alone is insufficient to stimulate tumor cell phagocytosis in solid tumors due to the lack of "eat me" signals. Herein, a degradable mesoporous silica nanoparticle (MSN) is reported to simultaneously deliver anti-CD47 antibodies (aCD47) and doxorubicin (DOX) for cancer chemo-immunotherapy. The codelivery nanocarrier aCD47-DMSN was constructed by accommodating DOX within the mesoporous cavity, while adsorbing aCD47 on the surface of MSN. aCD47 blocks the CD47-SIRPα axis to disable the "don't eat me" signal, while DOX induces immunogenic tumor cell death (ICD) for calreticulin exposure as an "eat me" signal. This design facilitated the phagocytosis of tumor cells by macrophages, which enhanced antigen cross-presentation and elicited efficient T cell-mediated immune response. In 4T1 and B16F10 murine tumor models, aCD47-DMSN generated a strong antitumor effect after intravenous injection by increasing tumor-infiltration of CD8+ T cells. Taken together, this study offers a nanoplatform to modulate the phagocytosis of macrophages for efficacious cancer chemo-immunotherapy.

Tetrathiomolybdate as an old drug in a new use: As a chemotherapeutic sensitizer for non-small cell lung cancer.

BACKGROUND: Cisplatin-based chemotherapy is the standard treatment for non-small cell lung cancer (NSCLC). However, cisplatin resistance is a major obstacle to successful therapeutic efficacy. Novel therapeutic strategies are urgently needed to reverse chemotherapy resistance and improve prognosis. In the present study, we aimed to investigate whether copper chelator Tetrathiomolybdate (TM) can enhance the anticancer effect of cisplatin, and elucidate the underlying mechanisms. METHODS: Cell viability, wounding healing, and colony formation assays were performed on H1299 and A549 cells. The combination indices (CI) were determined by the Chou-Talalay method. Flow cytometry was used to detect cell apoptosis and ROS generation. GSH levels were measured in a microplate reader. RNA-seq and bioinformatics analyses were used to analyze the differentially expressed genes (DEGs) and enriched biology processes. The concentrations of Pt and Cu were determined by ICP-MS. Animal xenograft tumor model was established to evaluate the synergistic anticancer effect of TM and cisplatin. RESULTS: Combination treatment with TM and cisplatin decreased cell viability and migration of H1299 and A549 cells compared with cisplatin alone. Mechanistically, combination treatment could significantly increase ROS and reduce GSH content, leading to a notable increase in DNA-bound Pt and cell apoptosis. Moreover, in animal xenograft tumor model, TM enhanced cisplatin-elicited antitumor effect, but did not increase cisplatin-induced side effects. CONCLUSION: Our study suggests that TM may be a promising chemotherapeutic sensitizer for non-small cell lung cancer.

Research on Rheology and Formability of SiO2 Ceramic Slurry Based on Additive Manufacturing Technology via a Light Curing Method.

SiO2 ceramic parts with complex structures were formed by additive manufacturing technology via a light curing method combined with a heat treatment process. To reveal the influence mechanism of rheology and formability of SiO2 ceramic slurry, the microstructure, morphology, and properties of light-cured SiO2 ceramic samples were characterized by a viscosity test, thermogravimetric analysis (TG-DTG), X-ray diffraction (XRD), a scanning electron microscope (SEM), and a series of tests for physical properties (bending strength, mass burning rate, and densification). The results indicate that the main effect of the dispersant-type factor was more significant than the pH value. When the dispersant was ammonium polyacrylate (PMAA-NH4) with a content of 1.0 wt % and the pH value of the slurry system was 9, the viscosity of SiO2 ceramic slurry could be controlled to the lowest. It was also found that the sintering temperature in the experiment had no effect on the crystalline phase of SiO2 ceramics. When the sintering temperature was 1250 °C and the solid content was 65 vol %, the micromorphology of the samples was uniform. Under this condition, the bending strength of the sample reached 14.9 MPa and the densification was 76.43%.