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Multidrug-resistant (MDR) bacterial infections have gained increasing attention due to the high incidence rates and high mortality, especially for the carbapenem-resistant Klebsiella pneumoniae (CRKP) infection that can cause severe complications (e.g., pneumonia and sepsis) in multiple organs. Therefore, the development of new antibacterial agents against CRKP is imperative. Inspired by natural plant antibacterial agents with broad-spectrum antibacterial properties, the antibacterial/biofilm activity of eugenol (EG) on CRKP and their underlying mechanisms are investigated in our work. It is found that EG exhibits remarkable inhibitory effects on planktonic CRKP in a dose-dependent fashion. Meanwhile, the destruction of membrane integrity induced by the formation of reactive oxygen species (ROS) and glutathione reduction results in the leakage of bacterial cytoplasmic components, including DNA, β-galactosidase, and protein. Moreover, when EG contacts with bacterial biofilm, the whole thickness of the dense biofilm matrix decreases, and the integrity is destroyed. Overall, this work verified that EG could eliminate CRKP via ROS-induced membrane rupture, which offers vital evidence to explain the antibacterial ability of EG against CRKP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Chen, Dou, Yi, Wang, Zhou and Sun.)

Retinal neovascularization (RNV) is a typical feature of ischemic retinal diseases that can lead to traction retinal detachment and even blindness in patients, in which the vascular endothelial cell growth factor (VEGF) plays a pivotal role. However, most anti-VEGF drugs currently used for treating RNV, such as ranibizumab, need frequent and repeated intravitreal injections due to their short intravitreal half-life, which increases the incidence of complications. Herein, a hydrogel intravitreal drug delivery system (DDS) is prepared by a dynamic Schiff base reaction between aminated hyaluronic acid and aldehyde-functionalized Pluronic 127 for sustained release of ranibizumab. The prepared hydrogel system named HP@Ran exhibits excellent injectability, self-healing ability, structural stability, cytocompatibility, and blood compatibility. According to an in vitro drug release study, the hydrogel system continuously releases the model drug bovine serum albumin for more than 56 days. Importantly, in an in vivo rabbit persistent RNV model, the HP@Ran hydrogel system continuously releases pharmacologically active ranibizumab for more than 7 weeks and also exhibits superior anti-angiogenic efficacy over ranibizumab treatment by decreasing vascular leakage and neovascularization at 12 weeks. Thus, the developed HP@Ran hydrogel system possesses great potential for intravitreal DDS for the treatment of RNV.

Tooth extraction commonly leads to postoperative wound bleeding, bacterial infection, and even the occurrence of dry socket. Therefore, developing a biomedical material with favorable antibacterial and excellent hemostatic properties to prevent the post-extraction dry socket is necessary. Herein, quaternary ammonium chitosan/ carboxymethyl starch/alginate (ACQ) sponges are developed via Ca 2+ cross-linking, electrostatic interaction, and lyophilization methods. The results show that the bio-multifunctional sponges exhibit interconnected porous structures with significant fluid absorption rates and suitable water vapor transmission rates. In vitro cellular and hemolysis experiments indicate that the developed sponges have acceptable biocompatibility. Notably, the constructed sponges effectively inhibit the growth of E. coli , S. aureus, and C. albicans , as well as achieve rapid hemostasis in the mouse liver injury and mini-pig tooth extraction models by absorbing blood and promoting red blood cell adhesion. Thus, the created bio-multifunctional sponges show tremendous promise as a hemostatic material for wound management after tooth extraction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Deng, Wang, Zhang, Sun, Zhou, Wang, Kong, Yuan and Zhou.)

White blood cells (WBCs) play essential roles against inflammatory disorders, bacterial infections, and cancers. Inspired by nature, WBC membrane-camouflaged nanocarriers (WBC-NCs) have been developed to mimic the "dynamic" functions of WBCs, such as transendothelial migration, adhesion to injured blood vessels, etc , which make them promising for diverse medical applications. WBC-NCs inherit the cell membrane antigens of WBCs, while still exhibiting the robust inflammation-related therapeutic potential of synthetic nanocarriers with excellent (bio)physicochemical performance. This review summarizes the proposed concept of cell membrane engineering, which utilizes physical engineering, chemical modification, and biological functionalization technologies to endow the natural cell membrane with abundant functionalities. In addition, it highlights the recent progress and applications of WBC-NCs for inflammation targeting, biological neutralization, and immune modulation. Finally, the challenges and opportunities in realizing the full potential of WBC-NCs for the manipulation of inflammation-related therapeutics are discussed., Competing Interests: All authors have given approval to the final version of the manuscript. The authors declare no competing financial interest., (© 2022 The Authors.)

Objectives: We aimed to explore whether Lactobacillus reuteri could have a positive role in reducing inflammation and bacterial translocation in rats with acute liver failure., Methods: Lactobacillus reuteri were gavaged to Sprague-Dawley (SD) rats at a dose of 1 × 10 9 CFU/mL once a day for 14 d. D-galactosamine was injected intraperitoneally to induce acute liver failure for 24 h on the 15th day. Liver function, liver and ileum histology, intestinal cytokines, intestinal tight junction proteins, lipopolysaccharide binding protein, apoptosis molecules, and nuclear factor erythroid-derived 2 (Nrf-2) / heme oxygenase (HO-1) molecules were assessed., Results: The results showed that L. reuteri alleviated liver injury and intestinal inflammation induced by D-galactosamine. L. reuteri also improved the expression of intestinal tight junction proteins and maintained the integrity of the intestinal barrier by inhibiting apoptosis of intestinal epithelial cells. L reuteri induced an increase in Nrf-2 nuclear translocation and elevated induction of HO-1. L. reuteri treatment significantly enhanced the expression of phosphoinositide 3-kinase/protein kinase B (PI3 K/Akt), protein kinase C (PKC), and their phosphorylated forms but not mitogen-activated protein kinase. The nuclear factor kappa B (NF-κB) pathway was inhibited after L. reuteri treatment. Interleukin (IL)-17A produced by Th17 cells and γδT17 cells may not contribute to an improved function of the intestinal barrier in L. reuteri-treated SD rats., Conclusions: Overall, our study indicated that L. reuteri-induced expression of intestinal tight junction proteins is mediated by the PI3 K/Akt-Nrf-2/HO-1-NF-κB and PKC-Nrf-2/HO-1-NF-κB pathways, which leads to inhibition of the apoptosis of intestinal epithelial cells, thus maintaining the integrity of the damaged intestinal barrier., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Fucoidan has sparked considerable interest in biomedical applications because of its inherent (bio)physicochemical characteristics, particularly immunomodulatory effects on macrophages, neutrophils, and natural killer cells. However, the effect of fucoidan on T cells and the following regulatory interaction on cellular function has not been reported. In this work, the effect of sterile fucoidan on the T-cell response and the subsequent modulation of osteogenesis is investigated. The physicochemical features of fucoidan treated by high-temperature autoclave sterilization are characterized by UV-visible spectroscopy, X-ray diffraction, Fourier transform infrared and nuclear magnetic resonance analysis. It is demonstrated that high-temperature autoclave treatment resulted in fucoidan depolymerization, with no change in its key bioactive groups. Further, sterile fucoidan promotes T cells proliferation and the proportion of differentiated T cells decreases with increasing concentration of fucoidan. In addition, the supernatant of T cells co-cultured with fucoidan greatly suppresses the osteogenic differentiation of MC3T3-E1 by downregulating the formation of alkaline phosphatase and calcium nodule compared with fucoidan. Therefore, our work offers new insight into the fucoidan-mediated T cell and osteoblast interplay., Competing Interests: Author ZS is employed by Qingdao Bright Moon Seaweed Group Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Guo, Deng, Yan, Wang, Sun, Yuan and Zhou.)

An intronic (G 4 C 2 ) n expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia primarily through gain-of-function mechanisms: the accumulation of sense and antisense repeat RNA foci and dipeptide repeat (DPR) proteins (poly-GA/GP/GR/PA/PR) translated from repeat RNA. To therapeutically block this pathway, we screen a library of 1,430 approved drugs and known bioactive compounds in patient-derived induced pluripotent stem cell-derived neurons (iPSC-Neurons) for inhibitors of DPR expression. The clinically used guanosine/cytidine analogs decitabine, entecavir, and nelarabine reduce poly-GA/GP expression, with decitabine being the most potent. Hit compounds nearly abolish sense and antisense RNA foci and reduce expression of the repeat-containing nascent C9orf72 RNA transcript and its mature mRNA with minimal effects on global gene expression, suggesting that they specifically act on repeat transcription. Importantly, decitabine treatment reduces (G 4 C 2 ) n foci and DPRs in C9orf72 BAC transgenic mice. Our findings suggest that nucleoside analogs are a promising compound class for therapeutic development in C9orf72 repeat-expansion-associated disorders., Competing Interests: Declaration of interests T.K. and J.M. are employees of Orion Pharma. The other authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Due to the persistent presence of Enterococcus faecalis biofilms in apical root canals, persistent endodontic infections (PEIs) have always been an intractable disease to solve. The conventional root canal disinfectants (e.g., calcium hydroxide, chlorhexidine) are arduous to scavenge the stubborn infection. With the progress of nanomedicine in the biomedical field, antimicrobial photodynamic therapy (aPDT) is emerging as a prospective anti-infective therapy for PEIs. Herein, quaternized chitosan (QCh) modified upconversion nanoparticles (UCNP)@SiO 2 /methylene blue (MB) are developed with enhanced antibacterial/biofilm performance for aPDT in PEIs. QCh is coated on the UCNP@SiO 2 /MB by testing the changes in diameter, chemical functional group, and charge. Interestingly, QCh also increases the conversion efficiency of UCNP to generate more reactive oxygen species (ROS). Furthermore, the prepared UCNP@SiO 2 /MB@QCh exhibits highly effective antibacterial activity against free E. faecalis and related biofilm in vitro and extracted teeth. Importantly, the additional QCh with positive charges enhance UCNP@SiO 2 /MB@QCh contact with E. faecalis (negative charges) through electrostatic interaction. Then, UCNP@SiO 2 /MB@QCh could stick close to the E. faecalis and generate ROS under the irradiation by a 980 nm laser. The in vitro cellular test shows that UCNP@SiO 2 /MB@QCh has acceptable cytocompatibility. Thus, UCNP@SiO 2 /MB@QCh could offer a novel strategy for the potential aPDT clinical applications in the treatment of PEIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zong, Li, Xu, Wang, Gao and Zhou.)

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families., (© 2021. The Author(s).)

Sepsis, the syndrome of infection complicated by acute organ dysfunction, is a serious and growing global problem, which not only leads to enormous economic losses but also becomes one of the leading causes of mortality in the intensive care unit. The detection of sepsis-related pathogens and biomarkers in the early stage plays a critical role in selecting appropriate antibiotics or other drugs, thereby preventing the emergence of dangerous phases and saving human lives. There are numerous demerits in conventional detection strategies, such as high cost, low efficiency, as well as lacking of sensitivity and selectivity. Recently, the aptamer-based biosensor is an emerging strategy for reasonable sepsis diagnosis because of its accessibility, rapidity, and stability. In this review, we first introduce the screening of suitable aptamer. Further, recent advances of aptamer-based biosensors in the detection of bacteria and biomarkers for the diagnosis of sepsis are summarized. Finally, the review proposes a brief forecast of challenges and future directions with highly promising aptamer-based biosensors., (© 2021. The Author(s).)

Circular RNAs (circRNAs) are single-strand covalently closed circular noncoding RNAs that are endogenous transcripts generated from linear precursor mRNA through a backsplicing mechanism. With the development of high-throughput sequencing technology, a number of circRNAs have been identified and proved to play key roles in various pathophysiological processes, such as metabolic diseases, cancers, and cardiovascular diseases. An increasing number of studies have shown that circRNAs are widely expressed in cardiac tissues and play important roles in the development of multiple cardiovascular diseases. Here, we review the current understanding of circRNA biogenesis and functions and the roles of circRNAs in cardiovascular diseases. We also highlight the molecular mechanisms underlying the role of circRNAs in the pathogenesis of cardiovascular diseases. A better understanding of the biological function of circRNAs in cardiovascular diseases will be helpful for the development of effective biomarkers for the diagnosis and treatment of these diseases.

Expansion of a (G 4 C 2 ) n repeat in C9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the link of the five repeat-encoded dipeptide repeat (DPR) proteins to neuroinflammation, TDP-43 pathology, and neurodegeneration is unclear. Poly-PR is most toxic in vitro, but poly-GA is far more abundant in patients. To directly compare these in vivo, we created congenic poly-GA and poly-PR mice. 40% of poly-PR mice were affected with ataxia and seizures, requiring euthanasia by 6 weeks of age. The remaining poly-PR mice were asymptomatic at 14 months of age, likely due to an 80% reduction of the transgene mRNA in this subgroup. In contrast, all poly-GA mice showed selective neuron loss, inflammation, as well as muscle denervation and wasting requiring euthanasia before 7 weeks of age. In-depth analysis of peripheral organs and blood samples suggests that peripheral organ failure does not drive these phenotypes. Although transgene mRNA levels were similar between poly-GA and affected poly-PR mice, poly-GA aggregated far more abundantly than poly-PR in the CNS and was also found in skeletal muscle. In addition, TDP-43 and other disease-linked RNA-binding proteins co-aggregated in rare nuclear inclusions in the hippocampus and frontal cortex only in poly-GA mice. Transcriptome analysis revealed activation of an interferon-responsive pro-inflammatory microglial signature in end-stage poly-GA but not poly-PR mice. This signature was also found in all ALS patients and enriched in C9orf72 cases. In summary, our rigorous comparison of poly-GA and poly-PR toxicity in vivo indicates that poly-GA, but not poly-PR at the same mRNA expression level, promotes interferon responses in C9orf72 disease and contributes to TDP-43 abnormalities and neuron loss selectively in disease-relevant regions.

The unique physicochemical characteristics of nanoparticles have recently gained increasing attention in a diverse set of applications, particularly in the biomedical field. However, concerns about the potential toxicological effects of nanoparticles remain, as they have a higher tendency to generate excessive amounts of reactive oxygen species (ROS). Due to the strong oxidation potential, the excess ROS induced by nanoparticles can result in the damage of biomolecules and organelle structures and lead to protein oxidative carbonylation, lipid peroxidation, DNA/RNA breakage, and membrane structure destruction, which further cause necrosis, apoptosis, or even mutagenesis. This review aims to give a summary of the mechanisms and responsible for ROS generation by nanoparticles at the cellular level and provide insights into the mechanics of ROS-mediated biotoxicity. We summarize the literature on nanoparticle toxicity and suggest strategies to optimize nanoparticles for biomedical applications.

Introduction: Epstein-Barr virus (EBV) associated smooth muscle tumors (SMTs) usually present under the condition of immunosuppression, including congenital immunodeficiency syndrome-SMT, post-transplantation-SMT and HIV-SMT. HIV-SMTs are most likely to invade the central nervous system, followed by the liver, lungs, and other locations. Many laboratory techniques, including serological techniques, polymerase chain reaction and immunohistochemistry (IHC), are employed to determine the aetiologies of these tumours. With respect to therapy, surgical resection is the main treatment. In patients with immunodeficiency, improving immune status is significant for defending against other viruses. We describe a case of the primary focus of SMT in the liver of HIV-positive patient without any metastasis., Patient Concerns: A young male HIV-positive patient complained of fever and abdominal pain for 2 months., Diagnosis: IHC of liver tissue confirmed the finding: EBV-related smooth muscle tumor., Interventions: Given the patient's general condition, he was not a suitable candidate for surgical resection. He was given antibiotics, antifungal agents and EBV-directed agents to control infection as well as highly active antiretroviral therapy to enhance the immunity., Outcomes: The patient's symptoms improved. He was discharged., Conclusions: In conclusion, EBV-related HIV-SMTs is a rare neoplasm found in the liver among immunodeficient patients. This case highlights that a variety of examinations such as IHC for smooth muscle markers (smooth muscle actin and desmin) and EBER, as well as polymerase chain reaction for EBV DNA should be done when diagnoses are ambiguous.

New high-throughput technologies for cell-material interaction studies provide researchers with powerful tools to speed up research in the field of biomaterial-cell interactions. However, sharing technologies is often difficult due to the necessity of specific knowledge and experiences. Engineered surfaces can elucidate effects of surface topography on cell behavior, which is of critical value for gaining control over cellular processes. Here, the translation of a gradient-based high-throughput cell screening approach for aligned nano/micro topographies interacting with cells is presented. An aligned topography 96-well plate is created by upscaling of highly specific gradient technology. The resulting cell culture dishes are compatible with general laboratory and imaging equipment, and the platform allows for studying cell behavior with regard to adhesion and alignment. The challenge lies in increasing the dimensions of the previous 1 × 1 cm gradient topography substrate, to be able to cover the span of a 96-well plate and translate it into a standardized cell-screening tool. Adhesion experiments of human bone marrow derived mesenchymal stem cells confirm the standardization, compatibility, and usability of the technology. In the process of using multi-system imaging and analysis, it becomes apparent that future challenges need to include universally applied data analysis approaches., (© 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To examine the relationship between Pneumocystis jirovecii DNA (PJ-DNA) levels in blood from AIDS-associated Pneumocystis pneumonia (AIDS-PCP) and mortality, and to correlate mitochondrial large subunit rRNA (mtLSUrRNA) gene polymorphism with mortality, we performed a retrospective study including AIDS-PCP patients between 2014 and 2016 from one hospital in China. PJ-DNA in plasma was measured by nested polymerase chain reaction (PCR) of the mtLSUrRNA gene and in positive specimens we further detected the level of PJ-DNA using qPCR. Polymorphisms were observed at two positions (85 and 248) of the mtLSUrRNA gene by sequencing. The PJ-DNA positivity rate for survivors and nonsurvivors was 13.64% (9/66) and 78.57% (11/14) (P ≤ .001), respectively. Using multivariate analysis, we found that lactate dehydrogenase, PaO2, albumin and PJ-positive in blood were independent predictors of death (P = .011; P = .042; P = .01; P ≤ .001, respectively). The PJ-DNA level in the nonsurvivor group (n = 11) was higher than that of the survivor group (n = 9) (54610.3copies/ ml vs. 934.5 copies/ml, P = .006). Nine had genotype 1, and 88.89% (8/9) patients died. Of nine with genotype 3, 11.11% (1/9) died (P = .003). In conclusion, high PJ-DNA level detected by analyzing plasma and mtLSUrRNA genotype 1 are strongly associated with death in AIDS-PCP patients., (© The Author(s) 2018. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins (DPR). Repeat-dependent toxicity may affect nuclear import. hnRNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA We now report that a reduction of nuclear hnRNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hnRNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hnRNPA3. Reduced nuclear hnRNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci., (© 2016 The Authors.)