Hemostatic and Ultrasound-Controlled Bactericidal Silk Fibroin Hydrogel via Integrating a Perfluorocarbon Nanoemulsion.

Excessive blood loss and infections are the prominent risks accounting for mortality and disability associated with acute wounds. Consequently, wound dressings should encompass adequate adhesive, hemostatic, and bactericidal attributes, yet their development remains challenging. This investigation presented the benefits of incorporating a perfluorocarbon nanoemulsion (PPP NE) into a silk-fibroin (SF)-based hydrogel. By stimulating the ß-sheet conformation of the SF chains, PPP NEs drastically shortened the gelation time while augmenting the elasticity, mechanical stability, and viscosity of the hydrogel. Furthermore, the integration of PPP NEs improved hemostatic competence by boosting the affinity between cells and biomacromolecules. It also endowed the hydrogel with ultrasound-controlled bactericidal ability through the inducement of inner cavitation by perfluorocarbon and reactive oxygen species (ROS) generated by the sonosensitizer protoporphyrin. Ultimately, we employed a laparotomy bleeding model and a Staphylococcus aureus-infected trauma wound to demonstrate the first-aid efficacy. Thus, our research suggested an emulsion-incorporating strategy for managing emergency wounds.

ALYREF-JunD-SLC7A5 axis promotes pancreatic ductal adenocarcinoma progression through epitranscriptome-metabolism reprogramming and immune evasion.

Pancreatic ductal adenocarcinoma (PDAC) is a kind of tumor lacking nutrients due to its poor vascularity and desmoplasia. Recent studies have shown that cancer cells might achieve growth advantage through epitranscriptome reprogramming. However, the role of m5C in PDAC was not fully understood. We found that Aly/REF export factor (ALYREF), a reader of m5C modification, was overexpressed in PDAC, and associated with bad prognosis. In addition, the ALYREF expression was negatively related to CD8+ T cells infiltration in clinical samples. ALYREF knockdown decreased tumor growth in vivo partly dependent of immunity. ALYREF silencing decreased SLC7A5 expression and subsequently inactivated mTORC1 pathway, resulting in decreased tumor proliferation. Mechanically, ALYREF specifically recognized m5C sites in JunD mRNA, maintained the stabilization of JunD mRNA and subsequently upregulated transcription of SLC7A5. Since SLC7A5 was a key transporter of large neutral amino acids (LNAAs), overexpression of SLC7A5 on tumor cells depleted amino acid in microenvironment and restricted CD8+ T cells function. Moreover, ALYREF-JunD-SLC7A5 axis was overexpressed and negatively related with survival through TMA assays. In conclusion, this research revealed the relationship between m5C modification, amino acid transportation and immune microenvironment. ALYREF might be a novel target for PDAC metabolic vulnerability and immune surveillance.

Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance.

Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance and cancer immunotherapy is unclear. The present study revealed that the inhibition of CAF autophagy suppresses in vivo tumor development in immune-deficient xenografts. This deletion compromises anti-tumor immunity and anti-tumor efficacy both in vitro and in vivo by upregulating CD274/PDL1 levels in an immune-competent mouse model. A block in CAF autophagy reduced the production of IL6 (interleukin 6), disrupting high desmoplastic TME and decreasing USP14 expression at the transcription level in pancreatic cancer cells. We further identify USP14 as the post-translational factor responsible for downregulating CD274 expression by removing K63 linked-ubiquitination at the K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, by accurately targeting CAFs, inhibited CAF autophagy, improving the efficacy of immunochemotherapy to combat pancreatic cancer.Abbreviation: AIR: adaptive immune resistance; ATRA: all-trans-retinoicacid; CAF: cancer-associated fibroblast; CD274/PDL1: CD274 molecule; CM: conditioned medium; CQ: chloroquine diphosphate; CyTOF: Mass cytometry; FGF2/bFGF: fibroblast growth factor 2; ICB: immune checkpoint blockade; IF: immunofluorescence; IHC: immunohistochemistry; IP: immunoprecipitation; MS: mass spectrometer; MSC: mesenchymal stem cell; PDAC: pancreatic ductal adenocarcinoma; TEM: transmission electron microscopy; TILs: tumor infiltrating lymphocytes; TME: tumor microenvironment; USP14: ubiquitin specific peptidase 14.

Effect of surfactants on the interfacial viscoelasticity and stability of silk fibroin at different oil-water interfaces.

BACKGROUND: The biocompatible amphiphilic silk fibroin, extracted from domesticated silkworms, can adsorb at the oil-water interface and form elastic interfacial layers. In this study, three surfactants (cationic cetyltrimethylammonium bromide, the nonionic polyoxyethylene sorbitan monolaurate, and the anionic sodium dodecyl sulfate) were selected to investigate, through interfacial shear rheology, the influences of surfactants on the interfacial viscoelasticity and stability of silk fibroin at the interfaces between water and two different oils. RESULTS: The presence of surfactant prolongs the equilibration time and enhances the interfacial elastic modulus and toughness of the interfacial silk fibroin layers, especially at the nonpolar dodecane-water interface. However, when the surfactant exceeds a critical concentration, the shear modulus and stability of interfacial silk fibroin layers begin to decrease due to the competitive adsorption of surfactant molecules and the weakening of the protein network. Owing to electrostatic interactions, the ionic surfactants cetyltrimethylammonium bromide and sodium dodecyl sulfate can form more hydrophobic complexes with silk fibroin, which results in higher shear moduli than for silk fibroin and silk fibroin-polyoxyethylene sorbitan monolaurate mixture. CONCLUSION: Both the surfactant type and oil polarity play important roles in the adsorption, shear viscoelasticity, and stability of silk fibroin at the oil-water interface. Enhanced interactions between a silk fibroin-surfactant mixture and the oil phase delay the equilibration of the adsorption layers but strengthen the stability of interfacial layers. © 2023 Society of Chemical Industry.

The Role of DNMT1 and C/EBPα in the Regulation of CYP11A1 Expression During Syncytialization of Human Placental Trophoblasts.

Progesterone synthesized in the placenta is essential for pregnancy maintenance. CYP11A1 is a key enzyme in progesterone synthesis, and its expression increases greatly during trophoblast syncytialization. However, the underlying mechanism remains elusive. Here, we demonstrated that passive demethylation of CYP11A1 promoter accounted for the upregulation of CYP11A1 expression during syncytialization with the participation of the transcription factor C/EBPα. We found that the methylation rate of a CpG locus in the CYP11A1 promoter was significantly reduced along with decreased DNA methyltransferase 1 (DNMT1) expression and its enrichment at the CYP11A1 promoter during syncytialization. DNMT1 overexpression not only increased the methylation of this CpG locus in the CYP11A1 promoter, but also decreased CYP11A1 expression and progesterone production. In silico analysis disclosed multiple C/EBPα binding sites in both CYP11A1 and DNMT1 promoters. C/EBPα expression and its enrichments at both the DNMT1 and CYP11A1 promoters were significantly increased during syncytialization. Knocking-down C/EBPα expression increased DNMT1 while it decreased CYP11A1 expression during syncytialization. Conclusively, C/EBPα plays a dual role in the regulation of CYP11A1 during syncytialization. C/EBPα not only drives CYP11A1 expression directly, but also indirectly through downregulation of DNMT1, which leads to decreased methylation in the CpG locus of the CYP11A1 promoter, resulting in increased progesterone production during syncytialization.

Doctors' recommendations and healthy lifestyle behaviors among individuals with hypertension in Brazil.

Little is known about whether doctors' recommendations encourage healthy behaviors among individuals with hypertension in Brazil. This study examined the biological, social, and health factors related to doctor's recommendations and the associations between doctor's recommendations and healthy behaviors. The sample consisted of individuals with hypertension (N = 18,260) from Brazil's 2019 National Health Survey. The outcomes examined included smoking, drinking, diet, salt intake, physical activity, and doctor visits. Study findings indicated that more than 80% of people with hypertension in Brazil received doctors' recommendations to adhere to medical care and engage in healthy behaviors. Those who received recommendations were more likely to practice healthy eating and exercise regularly but also to be obese/overweight, smoke, and drink excessively. Nonetheless, the findings concerning diet and exercise suggest the value of doctors' recommendations for individuals with hypertension in Brazil.

Preparation of Microporous Molding Activated Carbon Derived from Bamboo Pyrolysis Gasification Byproducts for Toluene Gas Adsorption.

The effective utilization of charcoal and tar byproducts is a challenge for pyrolysis gasification of bamboo. Herein, the bamboo tar was modified via polymerization and acted as a new adhesive for the preparation of excellent bamboo-charcoal-derived molding activated carbon (MBAC). As compared with pristine tar and other adhesives, the aromatization of tar with phenol increased its molecular weight, oxygenic functional groups, and thermal stability, leading to the decreased blocking impact of charcoal pore and improved bonding and pyrolytic crosslinking effect between charcoal particles. These further contribute to the high mechanical strength, specific surface area, pore volume, and amount of oxygenic functional groups for fabricated MBAC. Owing to the high microporous volume of MBAC, it exhibited 385 mg·g-1 toluene and 75.2% tetrachloride gas adsorption performances. Moreover, the pseudo-first-order, pseudo-second-order, and Bangham models were used to evaluate the kinetic data. The toluene adsorption process conforms to the Bangham kinetic model, suggesting that the diffusion mechanism of toluene adsorption mainly followed intraparticle diffusion.

IL-33/ST2 axis of human amnion fibroblasts participates in inflammatory reactions at parturition.

BACKGROUND: Inflammation of the fetal membranes is an indispensable event of labor onset at both term and preterm birth. Interleukin-33 (IL-33) is known to participate in inflammation via ST2 (suppression of tumorigenicity 2) receptor as an inflammatory cytokine. However, it remains unknown whether IL-33/ST2 axis exists in human fetal membranes to promote inflammatory reactions in parturition. METHODS: The presence of IL-33 and ST2 and their changes at parturition were examined with transcriptomic sequencing, quantitative real-time polymerase chain reaction, Western blotting or immunohistochemistry in human amnion obtained from term and preterm birth with or without labor. Cultured primary human amnion fibroblasts were utilized to investigate the regulation and the role of IL-33/ST2 axis in the inflammation reactions. A mouse model was used to further study the role of IL-33 in parturition. RESULTS: Although IL-33 and ST2 expression were detected in both epithelial and fibroblast cells of human amnion, they are more abundant in amnion fibroblasts. Their abundance increased significantly in the amnion at both term and preterm birth with labor. Lipopolysaccharide, serum amyloid A1 and IL-1ß, the inflammatory mediators pertinent to labor onset, could all induce IL-33 expression through NF-κB activation in human amnion fibroblasts. In turn, via ST2 receptor, IL-33 induced the production of IL-1ß, IL-6 and PGE2 in human amnion fibroblasts via the MAPKs-NF-κB pathway. Moreover, IL-33 administration induced preterm birth in mice. CONCLUSION: IL-33/ST2 axis is present in human amnion fibroblasts, which is activated in both term and preterm labor. Activation of this axis leads to increased production of inflammatory factors pertinent to parturition, and results in preterm birth. Targeting the IL-33/ST2 axis may have potential value in the treatment of preterm birth.

Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor immune evasion might be partly responsible. We isolated CD8+ T cells and cultured them in vitro. Proteomics analysis was performed to compare changes in Panc02 cell lines cultured with conditioned medium, and leucine-rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cell spatial distribution in PDAC clinical samples and upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro. Knockdown or pharmacological inhibition of LRRK2 activated an anti-pancreatic cancer immune response in mice, which meant that LRRK2 acted as an immunosuppressive gene. Mechanistically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced upregulation of LRRK2/PD-L1, thus sensitizing the mice to anti-PD-L1 therapy. In addition, adenosylcobalamin, the activated form of vitamin B12, which was found to be a broad-spectrum inhibitor of LRRK2, could inhibit LRRK2 in vivo and sensitize PDAC to immunotherapy as well, which potentially endows LRRK2 inhibition with clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC.

Alleviation of Limosilactobacillus reuteri in polycystic ovary syndrome protects against circadian dysrhythmia-induced dyslipidemia via capric acid and GALR1 signaling.

Knowledge gaps that limit the development of therapies for polycystic ovary syndrome (PCOS) concern various environmental factors that impact clinical characteristics. Circadian dysrhythmia contributes to glycometabolic and reproductive hallmarks of PCOS. Here, we illustrated the amelioration of Limosilactobacillus reuteri (L. reuteri) on biorhythm disorder-ignited dyslipidemia of PCOS via a microbiota-metabolite-liver axis. A rat model of long-term (8 weeks) darkness treatment was used to mimic circadian dysrhythmia-induced PCOS. Hepatic transcriptomics certified by in vitro experiments demonstrated that increased hepatic galanin receptor 1 (GALR1) due to darkness exposure functioned as a critical upstream factor in the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway to suppress nuclear receptors subfamily 1, group D, member 1 (NR1D1) and promoted sterol regulatory element binding protein 1 (SREBP1), inducing lipid accumulation in the liver. Further investigations figured out a restructured microbiome-metabolome network following L. reuteri administration to protect darkness rats against dyslipidemia. Notably, L. reuteri intervention resulted in the decrease of Clostridium sensu stricto 1 and Ruminococcaceae UCG-010 as well as gut microbiota-derived metabolite capric acid, which could further inhibit GALR1-NR1D1-SREBP1 pathway in the liver. In addition, GALR antagonist M40 reproduced similar ameliorative effects as L. reuteri to protect against dyslipidemia. While exogenous treatment of capric acid restrained the protective effects of L. reuteri in circadian disruption-induced PCOS through inhibiting GALR1-dependent hepatic lipid metabolism. These findings purport that L. reuteri could serve for circadian disruption-associated dyslipidemia. Manipulation of L. reuteri-capric acid-GALR1 axis paves way for clinical therapeutic strategies to prevent biorhythm disorder-ignited dyslipidemia in PCOS women.

Targeting MFAP5 in cancer-associated fibroblasts sensitizes pancreatic cancer to PD-L1-based immunochemotherapy via remodeling the matrix.

Highly desmoplastic and immunosuppressive tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) contributes to tumor progression and resistance to current therapies. Clues targeting the notorious stromal environment have offered hope for improving therapeutic response whereas the underlying mechanism remains unclear. Here, we find that prognostic microfibril associated protein 5 (MFAP5) is involved in activation of cancer-associated fibroblasts (CAFs). Inhibition of MFAP5highCAFs shows synergistic effect with gemcitabine-based chemotherapy and PD-L1-based immunotherapy. Mechanistically, MFAP5 deficiency in CAFs downregulates HAS2 and CXCL10 via MFAP5/RCN2/ERK/STAT1 axis, leading to angiogenesis, hyaluronic acid (HA) and collagens deposition reduction, cytotoxic T cells infiltration, and tumor cells apoptosis. Additionally, in vivo blockade of CXCL10 with AMG487 could partially reverse the pro-tumor effect from MFAP5 overexpression in CAFs and synergize with anti-PD-L1 antibody to enhance the immunotherapeutic effect. Therefore, targeting MFAP5highCAFs might be a potential adjuvant therapy to enhance the immunochemotherapy effect in PDAC via remodeling the desmoplastic and immunosuppressive microenvironment.

Regulation of early diagnosis and prognostic markers of lung adenocarcinoma in immunity and hypoxia.

Lung adenocarcinoma is still cancer with the highest mortality. Hypoxia and immunity play an essential role in the occurrence and development of tumors. Therefore, this study is mainly to find new early diagnosis and prognosis markers and explore the relationship among the markers and immunity and hypoxia, to improve the prognosis of patients. Firstly, based on the clinical database in TCGA, we determined the most critical clinicopathological parameters affecting the prognosis of patients through a variety of analysis methods. According to pathological parameters, logistic most minor absolute contraction selection operator (lasso), univariate and multivariate regression analysis, the risk genes related to early prognosis were screened, and the risk model was established. Then, in different risk groups, GSEA and CIBERSORT algorithms were used to analyze the distribution and enrichment of the immune cells and hypoxia, to study the effects of early prognostic indicators on hypoxia and immunity. At the same time, we analyzed the different levels of risk genes in normal cells (BSEA-2B) and tumor cells (H1299, A549, PC9, and H1975). Finally, A549 and PC9 cells were induced by CoCl2 to establish a hypoxic environment, and the correlation between risk genes and HIF1A was analyzed. The risk model based on risk genes (CYP4B1, KRT6A, and FAM83A) was accurate and stable for the prognosis of patients. It is closely related to immunity and hypoxia. In BSEA-2B cells, the mRNA and protein expression of CYP4B1 was higher, while the expression of KRT6A and FAM83A was lower. Finally, we found that FAM83A and HIF1A showed a significant positive correlation when A549 and PC9 cells were exposed to hypoxia. The discovery of early diagnostic markers related to immunity, hypoxia, and prognosis, provides a new idea for early screening and prognostic treatment of lung adenocarcinoma.

Amnion-derived serum amyloid A1 participates in sterile inflammation of fetal membranes at parturition.

OBJECTIVES: Sterile inflammation of fetal membranes is an indispensable event of normal parturition. However, triggers of sterile inflammation are not fully resolved. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver. Fetal membranes can also synthesize SAA1 but its functions are not well defined. Given the role of SAA1 in the acute phase response to inflammation, we postulated that SAA1 synthesized in the fetal membranes may be a trigger of local inflammation at parturition. METHODS: The changes of SAA1 abundance in parturition were studied in the amnion of human fetal membranes. The role of SAA1 in chemokine expression and leukocyte chemotaxis was examined in cultured human amnion tissue explants as well as primary human amnion fibroblasts. The effects of SAA1 on monocytes, macrophages and dendritic cells were investigated in cells derived from a human leukemia monocytic cell line (THP-1). RESULTS: SAA1 synthesis increased significantly in human amnion at parturition. SAA1 evoked multiple chemotaxis pathways in human amnion fibroblasts along with upregulation of a series of chemokines via both toll-like receptor 4 (TLR4) and formyl peptide receptor 2 (FPR2). Moreover, SAA1-conditioned medium of cultured amnion fibroblasts was capable of chemoattracting virtually all types of mononuclear leukocytes, particularly monocytes and dendritic cells, which reconciled with the chemotactic activity of conditioned medium of cultured amnion tissue explants collected from spontaneous labor. Furthermore, SAA1 could induce the expression of genes associated with inflammation and extracellular matrix remodeling in monocytes, macrophages and dendritic cells derived from THP-1. CONCLUSIONS: SAA1 is a trigger of sterile inflammation of the fetal membranes at parturition.

Editorial: Focus issue on biomaterials approaches to the repair and regeneration of cartilage tissue.

Traditional joint replacement surgery faces the risk of enormous trauma and secondary revision while using medication to relieve symptoms can cause bone thinning, weight gain and interference with the patient's pain signalling. Medical research has therefore focused on minimally invasive solutions for implanting tissue-engineered scaffolds to induce cartilage regeneration and repair. In cartilage tissue engineering, there are still technical barriers to seed cells, scaffold construction techniques, mechanical properties, and the regulation of the internal environment on the transplanted material. This issue focuses on the development of cartilage repair, cutting-edge discoveries, manufacturing technologies, and the current technological queries still faced in cartilage regenerative medicine research. The articles in this collection cover the coordination of physical and biochemical signals, genes, and regulations by the extracellular environment.

Nanoparticles that Transcytosed through Cancer Cells Can Elicit Immune Response.

Transcytosis is a crucial process that nanomedicines can experience in various delivery stages. However, little was known about whether it endows biofunctions to the nanomedicines. Here, we reported that transporting photodynamic nanoparticles across cancer cells via the endoplasmic reticulum (ER)-Golgi pathway formulated them with abundant neoantigens and damage-associated molecular patterns. The resultant nanoparticles (Tran-NPs) were potent in dendritic cell maturation and T cell activation. Meanwhile, the photodynamic Tran-NPs maintained their primary function of repolarizing immunosuppressive cells. The immune responses were observed in melanoma B16F10 tumor models. Our work suggested that the transcytosis process reprogrammed the nanoparticles with immunological properties, which might shed light on the design of nanomedicines.

Interlayer Structure and Chemistry Engineering of MXene-Based Anode for Effective Capture of Chloride Anions in Asymmetric Capacitive Deionization.

Negatively charged surfaces and readily oxidizabile characteristics fundamentally restrict the use of MXene building blocks as anodes for anion intercalation. Herein, by embedding bacterial cellulose nanofibers with conformal polypyrrole coating (BC@PPy) and populating them between MXene (Ti3C2Tx) interlayers, we enable the fabricated MXene/BC@PPy (MBP) composite films to be highly efficient anodes for Cl--capturing in asymmetric capacitive deionization (CDI) systems. Performance gains are realized due to the surface electronegativity of MXene nanosheets becoming compensated by positively charged BC@PPy nanofibers, alleviating electrostatic repulsion, thus realizing reversible Cl- intercalation. More crucially, the anodization voltage of MBP is effectively enhanced as a result of the increase of the Ti valence state in MXene nanosheets with the addition of the BC@PPy spacer. Furthermore, BC@PPy nanopillars effectively enlarge the interlayer space for facile Cl- de-/intercalation, improve the vertical electron transfer between loosely deposited MXene nanosheets, and perform as additional active materials for Cl--capturing. Consequently, the MBP anode exhibits a promising desalination capacity of up to 17.56 mg g-1 at 1.2 V with a high capacity retention of 94.6% after 30 cycles in an asymmetric CDI system. This work offers a simple and effective strategy to unlock the application potential of MXene building blocks as anodes for Cl--capturing in electrochemical desalination.

B cell-related tertiary lymphoid structure may exert inhibitory effects on lung adenocarcinoma and SARS-COV-2.

Background: The prognosis of lung adenocarcinoma (LUAD) is poor. Infection with coronavirus disease 2019 (COVID-19) may further worsen the outcome of LUAD. This study utilized the immune model and the COVID-19 receptor signal to identify the potential immune structure affecting the prognosis of COVID-19 and LUAD. Methods: A prognostic model was established and verified. The correlation between immune cells and risk score was examined through a variety of immune calculation methods. Gene set variation analysis (GSVA) was used to explore the correlation between the immune signaling pathway, risk model, COVID-19 binding receptor (CO19ORS) signal, and different clinicopathological factors. Results: The analysis showed that the prognosis of patients was better in the low-risk group versus the high-risk group. The tertiary lymphoid structure dominated by T and B cells (TLS1) can improve the prognosis of patients in the low-risk group. Interestingly, the CO19ORS was enriched only in females and aged >65 years. The age group >65 years is closely related to the tertiary lymphatic structure of the newborn (TLS2), while the female sex is closely related to the TLS2 and TLS1 signature. The two groups exhibited a high level of inflammation-related signal distribution. In the near future, I will collect LUAD and COVID-19 related organizations to verify the changes of 8 risk protein. Conclusion: TLS1 structure may improve the prognosis of patients with LUAD and SARS-COV-2 (Severe acute respiratory syndrome coronavirus 2). This unexpected discovery provides new insight into the comprehensive treatment of patients with LUAD and SARS-COV-2.

Long-term Pu-erh tea consumption improves blue light-induced depression-like behaviors.

Blue light emitted by smartphones and tablets at night increases the risk of depression. Pu-erh tea has been reported to reduce the risk of depression by regulating tryptophan metabolism, but its underlying protective mechanism on depression induced by blue light at night (BLAN) remains unclear. In this work, two groups of C57BL6/J mice were given water or 0.25% (w/v) Pu-erh tea for 120 days, followed by a 45-day BLAN treatment (400 lux blue light between 21:00 and 23:00) to simulate blue light emitted from electronic equipment. Our results indicated that BLAN induced depression-like behaviors and gut microbiota disorders in healthy mice. Pu-erh tea intake significantly reshaped the gut microbiome (especially Bifidobacterium) and regulated the metabolism of short-chain fatty acids (SCFAs) which protected the integrity of the intestinal barrier. This improvement further reduced blood-brain barrier (BBB) damage and alleviated neuroinflammation by inhibiting MyD88/NF-κB pathways which finally regulated neurotransmitters such as brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT). Collectively, 0.25% (w/v) Pu-erh tea has the potential to prevent BLAN-induced depression-like behaviors by reshaping the gut microbiota and increasing the generation of SCFAs via the gut-brain axis.

Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer.

Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) help tumor cells evade immune surveillance, and are regarded as important targets of anti-tumor immunotherapy. Post-translational modification of PD-L1 has potential value in immunosuppression. Here, we identified that ubiquitin-specific protease 8 (USP8) deubiquitinates PD-L1. Pancreatic cancer tissues exhibited significantly increased USP8 levels compared with those in normal tissues. Clinically, the expression of USP8 showed a significant association with the tumor-node-metastasis stage in multiple patient-derived cohorts of pancreatic cancer. Meanwhile, USP8 deficiency could reduce tumor invasion and migration and tumor size in an immunity-dependent manner, and improve anti-tumor immunogenicity. USP8 inhibitor pretreatment led to reduced tumorigenesis and immunocompetent mice with Usp8 knockdown tumors exhibited extended survival. Moreover, USP8 interacted positively with PD-L1 and upregulated its expression by inhibiting the ubiquitination-regulated proteasome degradation pathway in pancreatic cancer. Combination therapy with a USP8 inhibitor and anti-PD-L1 effectively suppressed pancreatic tumor growth by activation of cytotoxic T-cells and the anti-tumor immunity was mainly dependent on the PD-L1 pathway and CD8 + T cells. Our findings highlight the importance of targeting USP8, which can sensitize PD-L1-targeted pancreatic cancer to immunotherapy and might represent a novel therapeutic strategy to treat patients with pancreatic tumors in the future.