Sex-Specific Appetite Regulation of Lipocalin-2 in High-Fat-Diet-Induced Obese Mice.

INTRODUCTION: Lipocalin 2 (Lcn2) is a key factor in appetite suppression. However, the effect of Lcn2 on appetite in terms of sex differences has not been thoroughly studied. METHODS: Young (3-month-old) whole-body Lcn2 knockout (Lcn2-/-) mice were fed a normal diet (ND) or high-fat diet (HFD) for 8 weeks to investigate obesity, food intake, serum metabolism, hepatic lipid metabolism, and regulation of gastrointestinal hormones. RESULTS: Lcn2 deficiency significantly increased the body weight and food intake of male mice when fed ND instead of HFD and females when fed HFD but not ND. Compared to wild-type (WT) male mice, the adiponectin level and phosphorylated form of adenosine 5'-monophosphate-activated protein kinase (AMPK) in the hypothalamus were both increased in ND-fed Lcn2-/- male mice but decreased in HFD-fed Lcn2-/- male mice. However, in female mice, adiponectin and its energy metabolism pathway were not altered. Instead, estradiol was found to be substantially higher in ND-fed Lcn2-/- female mice and substantially lower in HFD-fed Lcn2-/- female mice compared with WT female mice. Estradiol alteration also caused similar changes in ERα in the hypothalamus, leading to changes in the PI3K/AKT energy metabolism pathway. It suggested that the increased appetite caused by Lcn2 deficiency in male mice may be due to increased adiponectin expression and promotion of AMPK phosphorylation, while in female mice it may be related to the decrease of circulating estradiol and the inhibition of the hypothalamic ERα/PI3K/AKT energy metabolism pathway. CONCLUSION: Lcn2 plays in a highly sex-specific manner in the regulation of appetite in young mice.

Lcn2 deficiency accelerates the infection of Escherichia coli O157:H7 by disrupting the intestinal barrier function.

Bacterial infections result in intestinal inflammation and injury, which affects gut health and nutrient absorption. Lipocalin 2 (Lcn2) is a protein that reacts to microbial invasion, inflammatory responses, and tissue damage. However, it remains unclear whether Lcn2 has a protective effect against bacterial induced intestinal inflammation. Therefore, this study endeavors to investigate the involvement of Lcn2 in the intestinal inflammation of mice infected with Enterohemorrhagic Escherichia coli O157:H7 (E. coli O157:H7). Lcn2 knockout (Lcn2-/-) mice were used to evaluate the changes of inflammatory responses. Lcn2 deficiency significantly exacerbated clinical symptoms of E. coli O157:H7 infection by reducing body weight and encouraging bacterial colonization of. Compared to infected wild type mice, infected Lcn2-/- mice had significantly elevated levels of pro-inflammatory cytokines in serum and ileum, including interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α), as well as severe villi destruction in the jejunum. Furthermore, Lcn2 deficiency aggravated intestinal barrier degradation by significantly reducing the expression of tight junction proteins occludin and claudin 1, the content of myeloperoxidase (MPO) in the ileum, and the number of goblet cells in the colon. Our findings indicated that Lcn2 could alleviate inflammatory damage caused by E. coli O157:H7 infection in mice by enhancing intestinal barrier function.

Causal relationship between blood metabolites and risk of five infections: a Mendelian randomization study.

OBJECTIVE: Infectious diseases continue to pose a significant threat in the field of global public health, and our understanding of their metabolic pathogenesis remains limited. However, the advent of genome-wide association studies (GWAS) offers an unprecedented opportunity to unravel the relationship between metabolites and infections. METHODS: Univariable and multivariable Mendelian randomization (MR) was commandeered to elucidate the causal relationship between blood metabolism and five high-frequency infection phenotypes: sepsis, pneumonia, upper respiratory tract infections (URTI), urinary tract infections (UTI), and skin and subcutaneous tissue infection (SSTI). GWAS data for infections were derived from UK Biobank and the FinnGen consortium. The primary analysis was conducted using the inverse variance weighted method on the UK Biobank data, along with a series of sensitivity analyses. Subsequently, replication and meta-analysis were performed on the FinnGen consortium data. RESULTS: After primary analysis and a series of sensitivity analyses, 17 metabolites were identified from UK Biobank that have a causal relationship with five infections. Upon joint analysis with the FinGen cohort, 7 of these metabolites demonstrated consistent associations. Subsequently, we conducted a multivariable Mendelian randomization analysis to confirm the independent effects of these metabolites. Among known metabolites, genetically predicted 1-stearoylglycerol (1-SG) (odds ratio [OR] = 0.561, 95% confidence interval [CI]: 0.403-0.780, P < 0.001) and 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) (OR = 0.780, 95%CI: 0.689-0.883, P < 0.001) was causatively associated with a lower risk of sepsis, and genetically predicted phenylacetate (PA) (OR = 1.426, 95%CI: 1.152-1.765, P = 0.001) and cysteine (OR = 1.522, 95%CI: 1.170-1.980, P = 0.002) were associated with an increased risk of UTI. Ursodeoxycholate (UDCA) (OR = 0.906, 95%CI: 0.829-0.990, P = 0.029) is a protective factor against pneumonia. Two unknown metabolites, X-12407 (OR = 1.294, 95%CI: 1.131-1.481, P < 0.001), and X-12847 (OR = 1.344, 95%CI: 1.152-1.568, P < 0.001), were also identified as independent risk factors for sepsis. CONCLUSIONS: In this MR study, we demonstrated a causal relationship between blood metabolites and the risk of developing sepsis, pneumonia, and UTI. However, there was no evidence of a causal connection between blood metabolites and the risk of URTI or SSTI, indicating a need for larger-scale studies to further investigate susceptibility to certain infection phenotypes.

WAVE-based intensified perfusion cell culture for fast process development.

OBJECTIVE: This study was to evaluate the feasibility of using a rocking type bioreactor system, specifically the WAVE 25, in an intensified perfusion culture (IPC) mode for monoclonal antibody (mAb) production in Chinese hamster ovary (CHO) cell line. METHODS: A disposable perfusion bag with floating membrane was used in the IPC process. An automated filter switching system was employed to continuously clarify the harvested post-membrane culture fluid. The overall cell culture performance, product titer, and quality were compared to those of a typical IPC conducted in a bench-top glass bioreactor. RESULTS: The results showed that the overall trends of cell culture performance, product titer (accumulated harvest volumetric titer) were similar to those of the typical IPC conducted in the glass bioreactor, while the purity related quality were slightly better than the typical run. Furthermore, with the automated filter switching system, the harvested post-membrane culture fluid could be continuously clarified, making it suitable for downstream continuous chromatography. CONCLUSION: The study demonstrated the feasibility of using the WAVE-based rocking type bioreactor in the N stage IPC process, which increases the flexibility in adopting IPC process. The results suggest that the rocking type bioreactor system could be a viable alternative to traditional stirred tank bioreactors for perfusion culture in the biopharmaceutical industry.

Nano-Bio Interactions in Cancer: From Therapeutics Delivery to Early Detection.

Understanding the interactions between nanomaterials and biological systems plays a pivotal role in enhancing the efficacy of nanomedicine and advancing the disease diagnosis. The nanoparticle-protein corona, an active biomolecular layer, is formed around nanoparticles (NPs) upon mixing with biological fluid. The surface layer which consists of rapidly exchanged biomolecules is called the "soft" corona. The inner layer which is more stable and tightly packed is called the "hard" corona. It has been suggested that the NP-protein corona has a decisive effect on the in vivo fate of nanomedicine upon intravenously administration into the mouse. Furthermore, the features of the NP-protein corona make it a powerful platform to enrich low-abundance proteins from serum/plasma for downstream mass-spectrometry (MS)-based proteomics for biomarker discovery and disease diagnosis.Herein, we summarize our recent work on the development of nanomedicine and disease detection from the level of nano-bio interactions between nanoparticles and biological systems. Nanomedicine has made substantial progress over the past two decades. However, the significant enhancement of overall patient survival by nanomedicine remains a challenge due to the lack of a deep understanding of nano-bio interactions in the clinical setting. The pharmacokinetic effect of the protein corona on PEGylated NPs during blood circulation indicated that the adsorbed apolipoproteins could prolong the circulation time of NPs. This mechanistic understanding of the protein corona (active biomolecule) formed around polymeric NPs offered insights into enhancing the efficacy of nanomedicine from the biological interactions point of view. Moreover, we discuss the basic rationale for developing bioresponsive cancer nanomedicine by exploiting the pathophysiological environment around the tumor, typically the pH, reactive oxygen species (ROS), and redox-responsive supramolecular motifs based on synthetic amphiphilic polymers. The protein corona in vivo determines the biological fate of NPs, whereas it opens a new avenue to enrich low abundant proteins in a biospecimen ex vivo to render them "visible" for downstream analytical workflows, such as MS-based proteomics. Blood serum/plasma, due to easy accessibility and great potential to uncover and monitor physiological and pathological changes in health and disease, has remained a major source of detecting protein biomarker candidates. Inspired by the features of the NP-protein corona, a Proteograph platform, which integrates multi-NP-protein coronas with MS for large-scale efficient and deep proteome profiling has been developed. Finally, we conclude this Account with a better understanding of nano-bio interactions to accelerate the nanomedicine translation and how MS-based proteomics can boost our understanding of the corona composition and facilitate the identification of disease biomarkers.

GNAQ Negatively Regulates Antiviral Innate Immune Responses in a Calcineurin-Dependent Manner.

Although guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) constitute the largest cell surface membrane receptor family and transduce thousands of extracellular signals into the cytoplasm, only four kinds of G protein α subunits (Gαs, Gαi/o, Gαq/11, and Gα12/13) are coupled to regulate cAMP or phosphatidylinositol signals. Growing evidence suggests that viruses tend to hijack GPCRs and harness their activated intracellular signaling pathways. Thus, understanding the roles of G protein signaling will further uncover the GPCR signaling pathways that are exploited by viruses. In this study, we demonstrate that the expression of GNAQ (Gq α subunit) was downregulated during viral infection and that small interfering RNA-mediated GNAQ knockdown protected host cells from both vesicular stomatitis virus (VSV) and HSV type 1 infection. Meanwhile, VSV and HSV type 1 replication was reduced significantly in Gnaq-deficient macrophages. Accordingly, the VSV distribution in the liver, spleen, and lung was reduced in Gnaq-deficient mice during VSV infection, and Gnaq-deficient mice were much more resistant to VSV infection than wild-type mice. Mechanistically, GNAQ limits type I IFN production through the canonical PLC-ß/Ca2+/CALNA signaling pathway, which has been demonstrated to dephosphorylate virus-activated TANK-binding kinase 1 (TBK1). Thus, our data demonstrate that GNAQ negatively regulates the antiviral innate immune responses in a calcineurin-dependent manner. These findings also provide insights into the function and cross-talk of the classic GPCR signaling pathway with antiviral innate immune responses and suggest a potential therapeutic role for GNAQ in controlling viral diseases.

Virus-Triggered ATP Release Limits Viral Replication through Facilitating IFN-ß Production in a P2X7-Dependent Manner.

Accumulating evidence shows that innate immune responses are associated with extracellular nucleotides, particularly ATP. In this article, we demonstrate extensive protection of ATP/P2X7 signaling in a host against viral infection. Interestingly, we observed a significant increase in ATP as a danger signal in vesicular stomatitis virus (VSV)-infected cell supernatant and VSV-infected mice in an exocytosis- and pannexin channel-dependent manner. Furthermore, extracellular ATP reduces the replication of VSV, Newcastle disease virus, murine leukemia virus, and HSV in vivo and in vitro through the P2X7 receptor. Meanwhile, ATP significantly increases IFN-ß expression in a concentration- and time-dependent manner. Mechanistically, ATP facilitates IFN-ß secretion through P38/JNK/ATF-2 signaling pathways, which are crucial in promoting antiviral immunity. Taken together, these results demonstrate the protective role of extracellular ATP and P2X7 in viral infection and suggest a potential therapeutic role for ATP/P2X7 in viral diseases.

Leucine-rich repeat-containing G protein-coupled receptor 4 facilitates vesicular stomatitis virus infection by binding vesicular stomatitis virus glycoprotein.

Vesicular stomatitis virus (VSV) and rabies and Chandipura viruses belong to the Rhabdovirus family. VSV is a common laboratory virus to study viral evolution and host immune responses to viral infection, and recombinant VSV-based vectors have been widely used for viral oncolysis, vaccination, and gene therapy. Although the tropism of VSV is broad, and its envelope glycoprotein G is often used for pseudotyping other viruses, the host cellular components involved in VSV infection remain unclear. Here, we demonstrate that the host protein leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4) is essential for VSV and VSV-G pseudotyped lentivirus (VSVG-LV) to infect susceptible cells. Accordingly, Lgr4-deficient mice had dramatically decreased VSV levels in the olfactory bulb. Furthermore, Lgr4 knockdown in RAW 264.7 cells also significantly suppressed VSV infection, and Lgr4 overexpression in RAW 264.7 cells enhanced VSV infection. Interestingly, only VSV infection relied on Lgr4, whereas infections with Newcastle disease virus, influenza A virus (A/WSN/33), and herpes simplex virus were unaffected by Lgr4 status. Of note, assays of virus entry, cell ELISA, immunoprecipitation, and surface plasmon resonance indicated that VSV bound susceptible cells via the Lgr4 extracellular domain. Pretreating cells with an Lgr4 antibody, soluble LGR4 extracellular domain, or R-spondin 1 blocked VSV infection by competitively inhibiting VSV binding to Lgr4. Taken together, the identification of Lgr4 as a VSV-specific host factor provides important insights into understanding VSV entry and its pathogenesis and lays the foundation for VSV-based gene therapy and viral oncolytic therapeutics.

pH- and redox-responsive nanoparticles composed of charge-reversible pullulan-based shells and disulfide-containing poly(ß-amino ester) cores for co-delivery of a gene and chemotherapeutic agent.

A novel pH- and redox-responsive nanoparticle system was designed based on a charge-reversible pullulan derivative (CAPL) and disulfide-containing poly(ß-amino ester) (ssPBAE) for the co-delivery of a gene and chemotherapeutic agent targeting hepatoma. The end-alkene groups of ssPBAE were reacted with diethylenetriamine to form amino-modified ssPBAE (NH-ssPBAE). Methotrexate (MTX), a chemotherapy agent, was then conjugated to NH-ssPBAE via an amide bond to obtain the polymeric prodrug ssPBAE-MTX. ssPBAE-MTX exhibited a good capability for condensing genes, including plasmid DNA (pDNA) and tetramethyl rhodamine-labeled DNA (TAMRA-DNA), and almost completely condensed pDNA at the weight ratio of 5/1 to form spherical nanocomplexes with a uniform size. In a D,L-dithiothreitol solution, the ssPBAE-MTX/pDNA nanocomplexes showed rapid release of pDNA and MTX, indicating their redox-responsive capability. CAPL, a pullulan derivative containing ß-carboxylic amide bond, was efficiently coated on the surfaces of ssPBAE-MTX/pDNA nanocomplexes to form polysaccharide shells, thus realizing co-loading of the gene and chemotherapeutic agent. CAPL/ssPBAE-MTX/pDNA nanoparticles displayed an obvious pH-responsive charge reversal ability due to the rupture of the ß-carboxylic amide bond under the weakly acidic condition. In human hepatoma HepG2 cells, CAPL/ssPBAE-MTX/TAMRA-DNA nanoparticles were efficiently internalized via endocytosis and successfully escaped from the endo/lysosomes into the cytoplasm, and CAPL/ssPBAE-MTX/pDNA nanoparticles remarkably inhibited the cell growth. In summary, this nanoparticle system based on CAPL and ssPBAE showed great potential for combined gene/chemotherapy on hepatomas.

[Recent progress in nanomedicine for hepatocellular carcinoma therapy].

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with insidious onset, insensitive to chemotherapy and poor prognosis, which make its clinical treatment face an enormous challenge. In recent years, with the rapid development of nanotechnology, increasing kinds of nanomedicine come to the forefront in biomedical fields. Through rational design, nanomedicine can be prepared in suitable size and modified with specific liver targeting ligands. Moreover, various therapeutic agents of different mechanisms can be co-loaded into the same nanosystem, thus achieving the synergistic therapeutic effects towards HCC. Nanomedicine is able to enhance drug bioavailability and liver-targeting effect as well as reduce the side effects to normal tissues, which provide a great potential in HCC therapy. This review summarizes the recent progress in the application of nanomedicine for HCC therapy from two aspects: their liver-targeting design strategies and the recent progress in combination therapy of HCC.

Elimination of GPR146-mediated antiviral function through IRF3/HES1-signalling pathway.

As the most important host defence against viral infection, interferon (IFN) stimulates hundreds of antiviral genes (ISGs) that together establish an 'antiviral state'. However, the antiviral function of most ISGs in viral infection still need further exploration. Here, we demonstrated that the expression of G-protein-coupled receptor 146 (GPR146) is highly increased by both IFN-ß and IFN-γ in a signal transducer and activator of transcription 1-dependent signalling pathway. Most importantly, overexpression of GPR146 protects the host cells from vesicular stomatitis virus and Newcastle disease virus infection but not from infection by herpes simplex virus. In contrast, the virus-induced IFN-ß production changed little in Gpr146-knockout cells. Furthermore, the Gpr146-deficient mice showed similar susceptibility to wild-type mice with vesicular stomatitis virus infection. Interestingly, the expression of GPR146 in virus-infected cells was strikingly reduced and can partially explain why the viral infection was little influenced in Gpr146-knockout mice. Surprisingly, virus-activated IFN regulatory factor 3 (IRF3) signalling not only induces the expression of IFN but also represses GPR146 expression through HES1 (hairy and enhancer of split-1)-mediated transcriptional activity to establish a dynamic equilibrium between pro-viral and antiviral stages in host cells. Taken together, these data reveal the antiviral role of GPR146 in fighting viral infection although the GPR146-mediated protection is eliminated by IRF3/HES1-signalling, which suggests a potential therapeutic significance of both GPR146 and HES1 signalling in viral infection.

[Study of collagen mimetic peptide's triple-helix structure and its thermostability by circular dichroism].

In the present study, the authors explore the triple-helix conformation and thermal stability of collagen mimetic peptides (CMPs) as a function of peptide sequence and/or chain length by circular dichroism(CD). Five CMPs were designed and synthetized varying the number of POG triplets or incorporating an integrin alpha2beta1 binding motif Gly-Phe-Hyp-Gly-Glu-Arg (GFOGER). CD spectroscopy from 260 to 190 nm was recorded to confirm the existence of triple-helix conformation at room temperature, while thermal melting and thermal annealing of triple-helix (thermal unfolding and refolding of triple-helix, respectively) was characterized by monitoring ellipticity at 225 nm as a function of temperature. The results demonstrated that all the CMPs adopted triple-helix conformation, and the thermal stability of the CMPs was enhanced with increasing the number of POG triplets. In contrast to natural collagen, the thermal denaturation processes of CMPs were reversible, i. e. the triple-helix unfolded upon heating while refolded upon cooling. Meanwhile, the phenomenon of "hysteresis" was observed by comparing melting and thermal curves. These findings add new insights to the mechanisms of collagen and CMPs assembly, as well as provide an alternative approach to the fabrication of artificial collagen-likes biomaterials.

Differentiation of intestinal stem cells toward goblet cells under systemic iron overload stress are associated with inhibition of Notch signaling pathway and ferroptosis.

Iron overload can lead to oxidative stress and intestinal damage and happens frequently during blood transfusions and iron supplementation. However, how iron overload influences intestinal mucosa remains unknown. Here, the aim of current study was to investigate the effects of iron overload on the proliferation and differentiation of intestinal stem cells (ISCs). An iron overload mouse model was established by intraperitoneal injection of 120 mg/kg body weight iron dextran once a fortnight for a duration of 12 weeks, and an iron overload enteroid model was produced by treatment with 3 mM or 10 mM of ferric ammonium citrate for 24 h. We found that iron overload caused damage to intestinal morphology with a 64 % reduction in villus height/crypt depth ratio, and microvilli injury in the duodenum. Iron overload mediated epithelial function by inhibiting the expression of nutrient transporters and enhancing the expression of secretory factors in the duodenum. Meanwhile, iron overload inhibited the proliferation of ISCs and regulated their differentiation into secretory mature cells, such as goblet cells, through inhibiting Notch signaling pathway both in mice and enteroid. Furthermore, iron overload caused oxidative stress and ferroptosis in intestinal epithelial cells. In addition, ferroptosis could also inhibit Notch signaling pathway, and affected the proliferation and differentiation of ISCs. These findings reveal the regulatory role of iron overload on the proliferation and differentiation of ISCs, providing a new insight into the internal mechanism of iron overload affecting intestinal health, and offering important theoretical basis for the scientific application of iron nutrition regulation.

Hypoxia-Responsive Hydrogen-Bonded Organic Framework-Mediated Protein Delivery for Cancer Therapy.

The efficient delivery of therapeutic proteins to tumor sites is a promising cancer treatment modality. Hydrogen-bonded organic frameworks (HOFs) are successfully used for the protective encapsulation of proteins; however, easy precipitation and lack of controlled release of existing HOFs limit their further application for protein delivery in vivo. Here, a hypoxia-responsive HOF, self-assembled from azobenzenedicarboxylate/polyethylene glycol-conjugated azobenzenedicarboxylate and tetrakis(4-amidiniumphenyl)methane through charge-assisted hydrogen-bonding, is developed for systemic protein delivery to tumor cells. The newly generated HOF platform efficiently encapsulates representative cytochrome C, demonstrating good dispersibility under physiological conditions. Moreover, it can respond to overexpressed reductases in the cytoplasm under hypoxic conditions, inducing fast intracellular protein release to exert therapeutic effects. The strategy presented herein can be applied to other therapeutic proteins and can be expanded to encompass more intrinsic tumor microenvironment stimuli. This offers a novel avenue for utilizing HOFs in protein-based cancer therapy.

Targeting TUBB3 Suppresses Anoikis Resistance and Bone Metastasis in Prostate Cancer.

Bone metastases occur in more than 70% of advanced prostate cancer (PCa) patients, leading to a poor prognosis. Resistance to detachment-induced apoptosis, also known as anoikis, plays a crucial role in the onset of tumor metastasis. Targeting anoikis resistance is of immense therapeutic significance in repression of metastatic spread. In this study, based on an anoikis-related prognostic risk model of PCa, this study identifies TUBB3 as a key anoikis-related prognostic gene that is highly expressed in bone metastatic PCa. TUBB3 expression is increased in anoikis-resistant PCa cells, and TUBB3 depletion significantly reverses anoikis resistance during extracellular matrix (ECM) detachment and inhibits anoikis-resistance-induced PCa cell invasion and migration as well as epithelial-mesenchymal transition (EMT) process. TUBB3 knockdown significantly reduces αvß3/FAK/Src axis activation, blocking its downstream oncogenic signaling. In addition, this work develops bone-targeting lipid nanoparticles (BT-LNP) based on bisphosphonate-modified ionizable lipid for systemic delivery of siRNA targeting TUBB3 (siTUBB3). BT-LNP-delivered siTUBB3 therapy with localization in the bone microenvironment significantly attenuate PCa bone metastasis progression in vivo upon intravenous administration. These findings pinpoint that TUBB3, as a key regulator of anoikis resistance, is an effective therapeutic target in bone metastatic PCa and that BT-LNP-mediated systemic delivery of siTUBB3 can be developed as a novel therapeutic strategy for this disease.

Secondary iron overload induces chronic pancreatitis and ferroptosis of acinar cells in mice.

Disruption of iron homeostasis is associated with multiple diseases. It has been found that patients with genetic iron overload develop massive iron deposition in the pancreas. However, few studies have focused on the effect of secondary iron overload on the pancreas. The objective of the present study was to investigate the pathogenic consequences of secondary iron overload in mice. An iron overload mouse model was constructed by intraperitoneal injection of 120 mg/kg body weight of iron dextran every other week for 12 weeks. Iron deposition, immunocyte infiltration, fibrosis, oxidative stress and ferroptosis were assessed using Prussian blue staining, immunohistochemical analysis, Masson staining, Sirius red staining, RT­qPCR analysis and western blot analysis. It was found that iron­overloaded mice showed pancreatic iron overload, together with elevated gene expression of the iron storage factor ferritin H, and decreased expression of the iron transportation mediator divalent metal transporter 1, ferroportin 1 and transferrin receptor. Iron­overloaded mice developed mild pancreatitis with increased serum amylase and lipase activities, as well as elevated gene expression levels of pro­inflammatory cytokines, including interleukin (IL)­1ß, IL­6 and inducible nitric oxide synthase. Acinar atrophy, massive immunocyte infiltration and pancreatic fibrosis were noted in the iron­overloaded mice. As an underlying mechanism, iron­overloaded mice showed increased pancreatic oxidative stress, with an elevated malondialdehyde level, and decreased SOD and glutathione peroxidase activity. Furthermore, iron overload led to ferroptosis with promoted expression of cytochrome c oxidase subunit II, and decreased transcripts of glutathione peroxidase 4 and solute carrier family 7 member 11. These results provided evidence that multiple intraperitoneal injections of iron dextran in mice lead to iron overload­induced chronic pancreatitis, which suggested that secondary iron overload is a risk factor for pancreatitis and highlights the importance of iron in maintaining the normal functions of the pancreas.

Self-strengthen luminescent hydrogel.

For typical synthetic materials, continue mechanical loading usually cause damage and even failure, because they are closed systems, without substance exchange with surroundings and structural reconstruction after damage. Double-network (DN) hydrogels have recently been demonstrated to generate radicals under mechanical loading. In this work, DN hydrogel provided with sustained monomer and lanthanide complex supply undergo self-growth, and thus simultaneous self-strengthen in both mechanical performance and luminescence intensity are realized through bond rupture-initiated mechanoradical polymerization. This strategy proves the feasibility of imparting desired functions to the DN hydrogel by mechanical stamping, and provides a new strategy for the design of luminescent soft materials with high fatigue resistance.

Interface-directed self-assembly of gold nanoparticles and fabrication of hybrid hollow capsules by interfacial cross-linking polymerization.

Amphiphilic gold nanoparticles (AuNPs) were produced at liquid-liquid interface via ligand exchange between hydrophilic AuNPs and disulfide-containing polymer chains. By using oil droplets as templates, hybrid hollow capsules with AuNPs on the surfaces were obtained after interfacial cross-linking polymerization. The volume ratio of toluene to water exerts an important effect on the size of capsules. The average size of the capsules increases with the volume ratio. Transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM) were used to characterize the hollow structures. In this research, not only one-component but also multicomponent hollow capsules were prepared by copolymerization of acrylamide and hybrid AuNPs at liquid-liquid interface. Because of the improvement in hydrophilicity of the hollow capsules, the average size of multicomponent capsules is bigger than one-component ones in aqueous solution.

Placental cell translocation of folate-conjugated pullulan acetate non-spherical nanoparticles.

Due to the adverse effects of free drugs on the fetus, placental-mediated pregnancy complications still lack effective pharmacotherapy. This study aims to construct a non-spherical drug delivery system based on folate-conjugated pullulan acetate (FPA) for placental targeting and translocation. By adjusting the initial solvent system, FPA nanoparticles with different morphologies were prepared using dialysis method without a surfactant. Cytotoxicity and lactate dehydrogenase release assays indicated the good biocompatibility of FPA nanoparticles in BeWo b30 cells. Cellular uptake and in vitro placental barrier transportation studies showed that FPA nanoparticles entered the cells and transported across the cell monolayer, benefiting from the active target effect mediated by the folate receptor. Moreover, non-spherical FPA nanoparticles showed nuclear translocation due to their shape effect. These findings provide a novel aspect in placental-mediated pregnancy treatment and applications in the obstetrics field of drug use during pregnancy.

LRP1B mutation associates with increased tumor mutation burden and inferior prognosis in liver hepatocellular carcinoma.

BACKGROUND: Liver hepatocellular carcinoma (LIHC) is the most common primary liver cancer and the main cause of death in patients with cirrhosis. LRP1B is found to involve in a variety of cancers, but the association of LRP1B mutation with tumor mutation burden (TMB) and prognosis of LIHC is rarely studied. METHODS AND RESULTS: Herein, we analyzed the somatic mutation data of 364 LIHC patients from The Cancer Genome Atlas (TCGA) and found that LRP1B showed elevated mutation rate. Calculation of the TMB in LRP1B mutant and LRP1B wild-type groups showed that LRP1B mutant group had higher TMB compared with that in LRP1B wild-type group. Then survival analysis was performed and the survival curve showed that LRP1B mutation was associated with poor survival outcome, and this association remained to be significant after adjusting for multiple confounding factors including age, gender, tumor stage, mutations of BRCA1, BRCA2, and POLE. CONCLUSION: Collectively, our results revealed that LRP1B mutation was related to high TMB value and poor prognosis in LIHC, indicating that LRP1B mutation is probably helpful for the selection of immunotherapy and prognosis prediction in LIHC.