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Abd Wahid Rizaldi Akili,1 Nisrina Azizah Thurfah,1 Ari Hardianto,1 Jalifah Latip,2 Tati Herlina1 1Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia; 2Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi, Selangor, 46300, MalaysiaCorrespondence: Tati Herlina, Email tati.herlina@unpad.ac.idPurpose: This study aimed to evaluate the potency of 471 flavonoids from the genus Erythrina as potential acetylcholinesterase (AChE) inhibitors and free radical scavengers through computational studies to develop Alzheimer’s disease (AD) therapies from natural products.Methods: A total of 471 flavonoids from the genus Erythrina were subjected to molecular docking against AChE, followed by toxicity screening. The potential AChE inhibitors with the least toxic profile were subjected to further investigation through molecular dynamics (MD) simulations, density functional theory (DFT) study, and in silico pharmacokinetic predictions.Results: A combination of molecular docking and in silico toxicity screening led to the identification of 2(S)‒5,7‒dihydroxy‒5′‒methoxy‒[2′′,2′′‒(3′′‒hydroxy)‒dimethylpyrano]‒(5′′,6′′:3′,4′) flavanone (89) and Abyssinoflavanone IV (83) as potential AChE inhibitors. These compounds had stable binding to AchE and exhibited lower Root Mean Square Deviation (RMSD) values compared to the apo state of AChE. In addition, Molecular Mechanics Generalized Born Surface Area (MMGBSA) analysis revealed that the binding energies of 89 and 83 were significantly lower compared to acetylcholine, the natural substrate of AChE. Based on DFT study, these compounds exhibited a higher energy in the highest occupied molecular orbital (EHOMO) and lower electron affinity (EA) than Quercetin. This indicated that 89 and 83 could be potential radical scavengers through their electron-donating activity.Conclusion: Although this study primarily relied on computational methods, the results showed the dual functionality of compounds 89 and 83 as both potential AChE inhibitors and free radical scavengers. Further investigation in wet laboratory experiments is required to validate their therapeutic potential for AD.Keywords: flavonoids, erythrina, acetylcholinesterase, free radical scavenger, in silico

The genus Hydrurus contains a solitary species, Hydrurus foetidus. Its thalli exhibit a remarkable structure, consisting of a firm central axis surrounded by peripheral branches, all enveloped within a viscous, gelatinous coating. Molecular data pertaining to the genus Hydrurus are scarce, necessitating further investigation into its phylogenetic relationships.A new site with benthic freshwater alga Hydrurus foetidus (Villars) Trevisan has been discovered in the Fenhe River in Shanxi Province, China. The physical and chemical parameters of water were meticulously measured and documented. Detailed morphological observations were conducted on the specimen, measuring different cell categories. The SSU, LSU, ITS and rbcL DNA sequence data of H. foetidus collected from Shanxi were determined. An extensive three-gene phylogenetic tree was constructed, revealing a strong relationship between the specimen in this study and H. foetidus specimen from Norway. Time-calibrated molecular phylogenetic analysis further indicated that the genus Hydrurus diverged approximately 125 million years ago (Early Cretaceous), while the two H. foetidus strains from Shanxi, China and Norway diverged approximately 6 million years ago (Neogene). The results of this study supplement new molecular evidence for H. foetidus and contribute significantly to our understanding of the geographical distribution and evolutionary history of the genus Hydrurus.

Aziza cave, which is also known as kef Aziza or Tazouguert cave, represents an important and large karstic system that consists of more than 3.5 km of surveyed galleries, standing as the fifth most extensive cave system in Morocco and one of the ten largest in North Africa. This study unveils Aziza cave as an important spot of subterranean diversity in Africa. Here, we provide the first checklist of subterranean fauna in this cave, with 26 taxa, comprising 22 troglobiotic and 4 stygobiotic species. Of this total, eight species still require further confirmation of their status. The richest taxa include Coleoptera (5 species), Araneae (4 species), Entomobryomorpha (3 species), and Isopoda (2 species). However, it is noteworthy that only around 34.6% of the cave-restricted species found in the cave have been formally described to date. Additionally, the biodiversity of large system areas remains to be discovered as these areas need to be further explored. Furthermore, this paper highlights the broader conservation challenges faced by subterranean habitats in Morocco, particularly considering human-induced impacts on these remarkable ecosystems. We aim to draw attention to the crucial ecological role of subterranean environments and their extraordinary biological diversity. By doing so, we aim to inspire increased research and conservation initiatives, not just in this area but across Africa.

Abstract Preeclampsia (PE) is a common pregnancy disorder characterized by hypertension and proteinuria. Trophoblast behavior severely affect PE progression. Transcription factor Forkhead box protein P2 (FOXP2) was involved in cell migration and invasion, but its role in PE progression remains unknown. Laminin subunit alpha 4 (LAMA4) was predicted as a downstream gene of FOXP2 and related to PE. Thus, we supposed that FOXP2 might regulate PE by regulating LAMA4. We found the decreased FOXP2 expression in patients with PE compared with healthy pregnant women. The rat model of PE was induced by L-NAME oral gavage. FOXP2 overexpression lowered systolic and diastolic blood pressure and restored pathological changes of rats with PE. Trophoblasts under the hypoxia/reoxygenation (H/R) treatment were used to mimic PE in vitro. The results revealed that FOXP2 overexpression inhibited apoptosis but promoted migration, invasion, and angiogenesis of H/R-treated trophoblasts. Dual luciferase and chromatin immunoprecipitation-polymerase chain reaction assays confirmed that FOXP2 transcriptionally upregulated the LAMA4 expression in trophoblasts. LAMA4 knockdown reversed the migration and invasion-promoting role of FOXP2 overexpression in trophoblasts with H/R treatment. Collectively, our findings suggest that the FOXP2/LAMA4 axis regulates PE by suppressing trophoblast apoptosis and promoting its migration, invasion, and angiogenesis.

Abstract Drosophila nephrocytes are specialised cells that share critical functional, morphological, and molecular features with mammalian podocytes. Accordingly, nephrocytes represent a preferred invertebrate model for human glomerular disease. Here, we established a method for cell-specific isolation of the two types of Drosophila nephrocytes, garland and pericardial cells, from animals of different developmental stages and ages. Mass spectrometry-based proteomics and RNA-Seq-based transcriptomics were applied to characterise the proteome and transcriptome of the respective cells in an integrated and complementary manner. We observed characteristic changes in the proteome and transcriptome due to cellular ageing. Furthermore, functional enrichment analyses suggested that larval and adult nephrocytes, as well as garland and pericardial nephrocytes, fulfil distinct physiological functions. In addition, the pericardial nephrocytes were characterised by transcriptomic and proteomic profiles suggesting an atypical energy metabolism with very low oxidative phosphorylation rates. Moreover, the nephrocytes displayed typical signatures of extensive immune signalling and showed an active antimicrobial response to an infection. Factor-specific comparisons identified novel candidate proteins either expressed and secreted by the nephrocytes or sequestered by them. The data generated in this study represent a valuable basis for a more specific application of the Drosophila model in analysing renal cell function in health and disease.

Abstract The widespread bacterial genus Sulfurimonas is metabolically versatile and occupies a key ecological niche in different habitats, but its interaction with bacteriophages remains unexplored. Here we systematically investigated the genetic diversity, taxonomy and interaction patterns of Sulfurimonas-associated phages based on sequenced microbial genomes and metagenomes. High-confidence phage contigs related to Sulfurimonas were retrieved from various ecosystems, clustered into 61 viral operational taxonomic units across three viral realms, including Duplodnaviria, Monodnaviria and Varidnaviria. Head-tail phages of Caudoviricetes were assigned to 19 genus-level viral clusters, the majority of which were distantly related to known viruses. Notably, diverse double jelly-roll viruses and inoviruses were also linked to Sulfurimonas, representing two commonly overlooked phage groups. Historical and current phage infections were revealed, implying viral impact on the evolution of host adaptive immunity. Additionally, phages carrying auxiliary metabolic genes might benefit hosts by compensating or augmenting sulfur metabolism. This study highlights the diversity and novelty of Sulfurimonas-associated phages with divergent tailless lineages, providing basis for further investigation of phage-host interactions within this genus.

Abstract In wildlife populations, parasites often go unnoticed, as infected animals appear asymptomatic. However, these infections can subtly alter behaviour. Field evidence of how these subclinical infections induce changes in movement behaviour is scarce in free-ranging animals, yet it may be crucial for zoonotic disease surveillance. We used an ultra-high-resolution tracking system (ATLAS) to monitor the movements of 60 free-ranging swallows every 8 seconds across four breeding seasons, resulting in over 1 million localizations. About 40% of these swallows were naturally infected with haemosporidian parasites. Here, we show that infected individuals had reduced foraging ranges, foraged in lower quality habitats, and faced a lowered survival probability, with an average reduction of 7.4%, albeit with some variation between species and years. This study highlights the impact of subclinical infections on movement behaviour and survival, emphasizing the importance of considering infection status in movement ecology. Our findings provide insights into individual variations in behaviour and previously unobservable local parasite transmission dynamics.

Abstract Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1) is a human deafness gene, responsible for autosomal recessive deafness-124 (DFNB124). Sensory hair cells of the cochlea are essential for hearing, relying on the mechanosensitive stereocilia bundle at their apical pole for their function. PKHD1L1 is a stereocilia protein required for the formation of the developmentally transient stereocilia surface coat. In this study, we carry out an in depth characterization of PKHD1L1 expression in mice during development and adulthood, analyze hair-cell bundle morphology and hearing function in aging PKHD1L1-deficient mouse lines, and assess their susceptibility to noise damage. Our findings reveal that PKHD1L1-deficient mice display no disruption to bundle cohesion or tectorial membrane attachment-crown formation during development. However, starting from 6 weeks of age, PKHD1L1-deficient mice display missing stereocilia and disruptions to bundle coherence. Both conditional and constitutive PKHD1L1 knockout mice develop high-frequency hearing loss progressing to lower frequencies with age. Furthermore, PKHD1L1-deficient mice are susceptible to permanent hearing loss following moderate acoustic overexposure, which induces only temporary hearing threshold shifts in wild-type mice. These results suggest a role for PKHD1L1 in establishing robust sensory hair bundles during development, necessary for maintaining bundle cohesion and function in response to acoustic trauma and aging.

Abstract Forkhead box O4 (FOXO4), a human transcription factor, recognizes target DNA through its forkhead domain (FHD) while maintaining comparable binding affinity to non-target DNA. The conserved region 3 (CR3), a transactivation domain, modulates DNA binding kinetics to FHD and contributes to target DNA selection, but the underlying mechanism of this selection remains elusive. Using paramagnetic relaxation enhancement analysis, we observed a minor state of CR3 close to FHD in the presence of non-target DNA, a state absent when FHD interacts with target DNA. This minor state suggests that CR3 effectively masks the non-target DNA-binding interface on FHD. The interaction weakens significantly under high salt concentration, implying that CR3 or high salt concentrations can modulate electrostatic interactions with non-target DNA. Our 15N relaxation measurements revealed FHD’s flexibility with non-target DNA and increased rigidity with target DNA binding. Our findings offer insights into the role of FOXO4 as a transcription initiator.

Abstract Victims of explosive events frequently suffer from blast lung injuries. Immune system has been implicated in the pathogenesis of this disease. However, systemic immune responses underlying the progression and recovery of injury repair remain poorly understood. Here, we depict the systemic landscape of immune dysregulation during blast lung injury and uncover immune recovery patterns. Single-cell analyses reveal dramatic changes in neutrophils, macrophages, monocytes, dendritic cells, and eosinophils after a gas explosion, along with early involvement of CD4 T, CD8 T, and Th17 cells. We demonstrate that myeloid cells primarily exert functions during the acute phase, while the spleen serves as an alternative source of granulocytes. Granulopoiesis is initiated in the bone marrow at a later stage during blast lung injury recovery, rather than at the acute stage. These findings contribute to a better understanding of the pathogenesis and provide valuable insights for potential immune interventions in blast lung injury.

Abstract Drug-induced liver injury (DILI) refers to drug-mediated damage to the structure and function of the liver, ranging from mild elevation of liver enzymes to severe hepatic insufficiency, and in some cases, progressing to liver failure. The mechanisms and clinical symptoms of DILI are diverse due to the varying combination of drugs, making clinical treatment and prevention complex. DILI has significant public health implications and is the primary reason for post-marketing drug withdrawals. The search for reliable preclinical models and validated biomarkers to predict and investigate DILI can contribute to a more comprehensive understanding of adverse effects and drug safety. In this review, we examine the progress of research on DILI, enumerate in vitro models with potential benefits, and highlight cellular molecular perturbations that may serve as biomarkers. Additionally, we discuss omics approaches frequently used to gather comprehensive datasets on molecular events in response to drug exposure. Finally, three commonly used gene modulation techniques are described, highlighting their application in identifying causal relationships in DILI. Altogether, this review provides a thorough overview of ongoing work and approaches in the field of DILI.

Abstract Ribosomal proteins (RPs) are essential components of ribosomes, playing a role not only in ribosome biosynthesis, but also in various extra-ribosomal functions, some of which are implicated in the development of different types of tumors. As universally acknowledged, hepatocellular carcinoma (HCC) has been garnering global attention due to its complex pathogenesis and challenging treatments. In this review, we analyze the biological characteristics of RPs and emphasize their essential roles in HCC. In addition to regulating related signaling pathways such as the p53 pathway, RPs also act in proliferation and metastasis by influencing cell cycle, apoptosis, angiogenesis, and epithelial-to-mesenchymal transition in HCC. RPs are expected to unfold new possibilities for precise diagnosis and individualized treatment of HCC.

Abstract Background The maximal sensitivity for local pairwise alignment makes the Smith-Waterman algorithm a popular choice for protein sequence database search. However, its quadratic time complexity makes it compute-intensive. Unfortunately, current state-of-the-art software tools are not able to leverage the massively parallel processing capabilities of modern GPUs with close-to-peak performance. This motivates the need for more efficient implementations. Results CUDASW++4.0 is a fast software tool for scanning protein sequence databases with the Smith-Waterman algorithm on CUDA-enabled GPUs. Our approach achieves high efficiency for dynamic programming-based alignment computation by minimizing memory accesses and instructions. We provide both efficient matrix tiling, and sequence database partitioning schemes, and exploit next generation floating point arithmetic and novel DPX instructions. This leads to close-to-peak performance on modern GPU generations (Ampere, Ada, Hopper) with throughput rates of up to 1.94 TCUPS, 5.01 TCUPS, 5.71 TCUPS on an A100, L40S, and H100, respectively. Evaluation on the Swiss-Prot, UniRef50, and TrEMBL databases shows that CUDASW++4.0 gains over an order-of-magnitude performance improvements over previous GPU-based approaches (CUDASW++3.0, ADEPT, SW#DB). In addition, our algorithm demonstrates significant speedups over top-performing CPU-based tools (BLASTP, SWIPE, SWIMM2.0), can exploit multi-GPU nodes with linear scaling, and features an impressive energy efficiency of up to 15.7 GCUPS/Watt. Conclusion CUDASW++4.0 changes the standing of GPUs in protein sequence database search with Smith-Waterman alignment by providing close-to-peak performance on modern GPUs. It is freely available at https://github.com/asbschmidt/CUDASW4 .

Abstract Background The study focuses on enhancing the effectiveness of precision agriculture through the application of deep learning technologies. Precision agriculture, which aims to optimize farming practices by monitoring and adjusting various factors influencing crop growth, can greatly benefit from artificial intelligence (AI) methods like deep learning. The Agro Deep Learning Framework (ADLF) was developed to tackle critical issues in crop cultivation by processing vast datasets. These datasets include variables such as soil moisture, temperature, and humidity, all of which are essential to understanding and predicting crop behavior. By leveraging deep learning models, the framework seeks to improve decision-making processes, detect potential crop problems early, and boost agricultural productivity. Results The study found that the Agro Deep Learning Framework (ADLF) achieved an accuracy of 85.41%, precision of 84.87%, recall of 84.24%, and an F1-Score of 88.91%, indicating strong predictive capabilities for improving crop management. The false negative rate was 91.17% and the false positive rate was 89.82%, highlighting the framework's ability to correctly detect issues while minimizing errors. These results suggest that ADLF can significantly enhance decision-making in precision agriculture, leading to improved crop yield and reduced agricultural losses. Conclusions The ADLF can significantly improve precision agriculture by leveraging deep learning to process complex datasets and provide valuable insights into crop management. The framework allows farmers to detect issues early, optimize resource use, and improve yields. The study demonstrates that AI-driven agriculture has the potential to revolutionize farming, making it more efficient and sustainable. Future research could focus on further refining the model and exploring its applicability across different types of crops and farming environments.

Integrating the 21st-century skills into Indonesia’s education system is crucial for equipping students to face future challenges. This study investigates the knowledge of pre-service biology teachers in Indonesia regarding the 21st -century skills and their understanding of instructional models that support skill development. Conducted from March to September 2024, the research employed a cross-sectional survey design with a total sampling technique, involving 78 students from a Biology Education program at a public Islamic university in North Sumatra, all of whom had completed a course on biology learning strategies. Data were gathered using questionnaires and analyzed quantitatively to determine key trends. The findings indicate that although most students recognize the significance of the 21st-century skills in biology education, their understanding is limited. Only a small number could identify all essential skills, with creative thinking being the most recognized. Students were well-acquainted with project-based learning as a model for developing these skills but had limited knowledge of the structure and application of other instructional models, such as discovery and inquiry learning. These findings emphasize the need for curriculum improvement to deepen students’ comprehension of various instructional models and the integration of diverse information sources, enabling more effective integration of the 21st -century skills into biology education.

Background: Alzheimer’s disease is a neurodegenerative disease that has no cure. The drugs used to treat Alzheimer’s disease are based on the inhibition of the enzyme acetylcholinesterase (AChE). In this sense, marine fungal metabolites represent an alternative source for the discovery of drugs based on AChE inhibition (IAChE). The present research carried out a bioprospecting study of marine fungi with acetylcholinesterase inhibition potential. Results: A total of 17 marine fungi were isolated from three stony corals from the Veracruz Reef System. The fungal genera identified were Geotrichum, Curvularia, Penicillium, Aspergillus, and Daldinia. The IAChE was evaluated from the broth and biomass extracts of each fungal strain. As a result, Daldinia eschscholtzii was one of the three fungi with the greatest IAChE effect (32.7%). Subsequently, a bio-directed chromatographic purification of the methanolic extract of the biomass of D. eschscholtzii was carried out. The FRL8.1 fraction was the most active with an IAChE of 41.0%, a value close to Galantamine positive control (44.0%). Furthermore, compound analysis was carried out by GC-MS. Finally, it was determined that the metabolites responsible for the inhibitory effect are probably 4,7-dihydroxycoumarin and 5-nitro-2-naphthalenamine, which was demonstrated by their interactions with the AChE enzyme receptor through molecular docking studies. Conclusions: Coral-associated marine fungi produce secondary metabolites that inhibit acetylcholinesterase. This is the first report of D. eschscholtzii isolated from the stony coral Siderastrea siderea. Finally, we consider that more studies are needed to demonstrate the IAChE potential of marine fungi associated with corals or other marine organisms.How to cite: Olivo-Flores KG, Couttolenc A, Suárez-Medellín J, et al. Acetylcholinesterase inhibition exerted by the extract of Daldinia eschscholtzii, a marine fungus associated with the coral Siderastrea siderea: GC–MS analysis and molecular docking of identified compounds. Electron J Biotechnol 2024;72. https://doi.org/10.1016/j.ejbt.2024.08.001.

Dysregulated inflammation after trauma or infection could result in the further disease and delayed tissue reconstruction. The conventional anti-inflammatory drug treatment suffers to the poor bioavailability and side effects. Herein, we developed an amphiphilic multifunctional poly (citrate-polyglycol-curcumin) (PCGC) nano oligomer with the robust anti-inflammatory activity for treating acute lung injury (ALI) and Methicillin-resistant staphylococcus aureus (MRSA) infected wound. PCGC demonstrated the sustained curcumin release, inherent photoluminescence, good cellular compatibility, hemocompatibility, robust antioxidant activity and enhanced cellular uptake. PCGC could efficiently scavenge nitrogen-based free radicals, oxygen-based free radicals, and intracellular oxygen species, enhance the endothelial cell migration and reduce the expression of pro-inflammatory factors through the NF-κB signal pathway. Combined the anti-inflammation and antioxidant properties, PCGC can shortened the inflammatory process. In animal model of ALI, PCGC was able to reduce the pulmonary edema, bronchial cell infiltration, and lung inflammation, while exhibiting rapid metabolic behavior in vivo. The MRSA-infection wound model showed that PCGC significantly reduced the expression of pro-inflammatory factors, promoted the angiogenesis and accelerated the wound healing. The transcriptome sequencing and molecular mechanism studies further demonstrated that PCGC could inhibit multiple inflammatory related pathways including TNFAIP3, IL-15RA, NF-κB. This work demonstrates that PCGC is efficient in resolving inflammation and promotes the prospect of application in inflammatory diseases as the drug-loaded therapeutic system.

Current gold standard for the replacement of small-diameter blood vessel (ID

Infected wounds pose a significant clinical challenge due to bacterial resistance, recurrent infections, and impaired healing. Reactive oxygen species (ROS)-based strategies have shown promise in eradicating bacterial infections. However, the excess ROS in the infection site after treatments may cause irreversible damage to healthy tissues. To address this issue, we developed bovine serum albumin-iridium oxide nanoclusters (BSA-IrOx NCs) which enable photo-regulated ROS generation and scavenging using near infrared (NIR) laser. Upon NIR laser irradiation, BSA-IrOx NCs exhibit enhanced photodynamic therapy, destroying biofilms and killing bacteria. When the NIR laser is off, the nanoclusters' antioxidant enzyme-like activities prevent inflammation and repair damaged tissue through ROS clearance. Transcriptomic and metabolomic analyses revealed that BSA-IrOx NCs inhibit bacterial nitric oxide synthase, blocking bacterial growth and biofilm formation. Furthermore, the nanoclusters repair impaired skin by strengthening cell junctions and reducing mitochondrial damage in a fibroblast model. In vivo studies using rat infected wound models confirmed the efficacy of BSA-IrOx NCs. This study presents a promising strategy for treating biofilm-induced infected wounds by regulating the ROS microenvironment, addressing the challenges associated with current ROS-based antibacterial approaches.

Hemostatic materials are essential for managing acute bleeding in medical settings. Chitosan (CS) shows promise in hemostasis but its underlying mechanism remains incompletely understood. We unexpectedly discovered that certain protonated-chitosan (PCS) rapidly assembled plasma proteins to form protein membrane (PM) upon contact with platelet-poor plasma (PPP). We hypothesized that the novel observation was intricately related to the procoagulant effect of chitosan. Herein, the study aimed to elucidate the conditions necessary and mechanism for PM formation, identify the proteins within the PM and PCS's procoagulant action at the molecule levels. We confirmed that the amount of –NH3+ groups (>4.9 mmol/g) on PCS molecules played a crucial role in promoting coagulation. The –NH3+ group interacted with blood's multiple active components to exert hemostatic effects: assembling plasma proteins including coagulation factors such as FII, FV, FX, activating blood cells and promoting the secretion of coagulation-related substances (FV, ADP, etc) by platelets. Notably, the hemostatic mechanism can be extended to protonated-chitosan derivatives like quaternized, alkylated, and catechol-chitosan. In the blood clotting index (BCI) experiment, compared to other groups, PCS95 achieved the lowest BCI value (∼6 %) within 30 s. Protonated-chitosan exhibited excellent biocompatibility and antibacterial properties, with PCS95 demonstrating inhibition effectiveness of over 95 % against Escherichia coli (E.coil) and Staphylococcus aureus (S. aureus). Moreover, PCS performed enhanced hemostatic effectiveness over chitosan-based commercially agents (Celox™ and ChitoGauze®XR) in diverse bleeding models. In particular, PCS95 reduced bleeding time by 70 % in rabbit models of coagulopathy. Overall, this study investigated the coagulation mechanism of materials at the molecular level, paving the way for innovative approaches in designing new hemostatic materials.

Non-small cell lung cancer (NSCLC) is a major disease with high incidence, low survival rate and prone to develop drug resistance to chemotherapy. The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex, and studies have shown that the abnormal activation of STAT3 (Signal Transducer and Activator of Transcription 3) plays an important role in it. In this study, the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target. By modifying hydrophilic and hydrophobic blocks onto chitosan, a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine (VES-CTS-mPEG-His) micelles were synthesized. The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly, and load the recombinant pGPU6/GFP/Neo STAT3-shRNA (pDNA) through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA. The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN (Phosphatase and Tensin Homolog), down-regulate the expression of CD31, and induce apoptosis of tumor cells. The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein, further enhancing the efficacy of chemotherapy. Through this study, precision personalized treatment of NSCLC could be effectively achieved, reversing its resistance to chemotherapy drugs, and providing new strategies for the treatment of drug-resistant NSCLC.

Magnesium alloys, noted for their substantial mechanical strength and exceptional biocompatibility, are increasingly being considered for use in biodegradable implants. However, their rapid degradation and significant hydrogen release have limited their applications in orthopaedics. In this study, a novel Mg-RE-Sr alloy was created by friction stir processing to modify its microstructure and enhance its degradation performance. Through microstructural characterization, the friction stir processing effectively refined the grains, accelerated the re-dissolution of precipitates, and ensured a uniform distribution of these phases. The processed alloy demonstrated improved comprehensive properties, with an in vitro corrosion rate of approximately 0.4 mm/y and increases in ultimate tensile strength and elongation by 37 % and 166 %, respectively. Notably, in vivo experiments involving a rat subcutaneous implantation model revealed a slower degradation rate of 0.09 mm/y and a uniform degradation process, basically achieving the requirements for ideal performance in orthopaedic applications. The superior degradation characteristics were attributed to the synergistic effect of attenuated galvanic corrosion and the formation of a dense Y(OH)3/Y2O3 film induced by an exceptional microstructure with a highly solid-soluted matrix and uniformly refined precipitates. Meanwhile, the alloys exhibited excellent biocompatibility and did not cause undesirable inflammation or produce toxic degradation products. These improvements in biocompatibility and degradation characteristics indicate great promise for the use of this friction stir processed alloy in osteosynthesis systems in the clinical setting.

Prolonged extra-oral period in dental avulsion is often associated with loss of viability of Periodontal fibroblasts (PDLF) and increased risk of ankylosis. Root surface treatment with bioactive agents to reduce the risk of ankylosis can be a potential strategy. The objective of the study was to investigate the impact of an engineered chitosan nanoparticles (CSNP), photosensitizer Rose Bengal (RB) functionalized CSNP (CSRB) and sustained dexamethasone (CSDEX) releasing CSNP for application in management of delayed replantation of avulsed teeth. The 3D PDLF-macrophage (Mϕ) collagen model was developed and exposed to LPS, MCSF, RANKL with and without CSDEX/CSNP. Immunofluorescence and cytokine analysis was done at 2 and 7 days to assess cellular interactions. Maxillary right incisors in male Wistar rats were extracted, exposed to extraoral dry or LPS for 1 h and treated with or without CSDEX/CSRB for 1 min before replantation. Rats were euthanized after 21 days for micro-CT, TRAP, and immunofluorescence analysis. CSDEX/CSNP treatment in 3D model significantly reduced CD80, NFATc1, STAT6 and increased CD206 and periostin expression (p

In the field of cancer therapy, inhibiting autophagy has emerged as a promising strategy. However, pharmacological disruption of autophagy can lead to the upregulation of programmed death-ligand 1 (PD-L1), enabling tumor immune evasion. To address this issue, we developed innovative ROS-responsive cationic poly(ethylene imine) (PEI) nanogels using selenol chemistry-mediated multicomponent reaction (MCR) technology. This procedure involved simple mixing of low-molecular-weight PEI (LMW PEI), γ-selenobutylacetone (γ-SBL), and poly(ethylene glycol) methacrylate (PEGMA). Through high-throughput screening, we constructed a library of AxSeyOz nanogels and identified the optimized A1.8Se3O0.5/siPD-L1 nanogels, which exhibited a size of approximately 200 nm, excellent colloidal stability, and the most effective PD-L1 silencing efficacy. These nanogels demonstrated enhanced uptake by tumor cells, excellent oxidative degradation ability, and inhibited autophagy by alkalinizing lysosomes. The A1.8Se3O0.5/siPD-L1 nanogels significantly downregulated PD-L1 expression and increased the expression of major histocompatibility complex class I (MHC-I), resulting in robust proliferation of specific CD8+ T cells and a decrease in MC38 tumor growth. As a result, the A1.8Se3O0.5/siPD-L1 nanogels inhibited tumor growth through self-inhibition of autophagy, upregulation of MHC-I, and downregulation of PD-L1. Designed with dynamic diselenide bonds, the A1.8Se3O0.5/siPD-L1 nanogels showed synergistic antitumor efficacy through self-inhibition of autophagy and prevention of immune escape.

Decellularized extracellular matrices (dECM) have strong regenerative potential as tissue engineering scaffolds; however, current clinical options for dECM scaffolds are limited to freeze-drying its native form into sheets. Electrospinning is a versatile scaffold fabrication technique that allows control of macro- and microarchitecture. It remains challenging to electrospin dECM, which has led researchers to either blend it with synthetic materials or use enzymatic digestion to fully solubilize the dECM. Both strategies reduce the innate bioactivity of dECM and limit its regenerative potential. Herein, we developed a new suspension electrospinning method to fabricate a pure dECM fibrous mesh that retains its innate bioactivity. Systematic investigation of suspension parameters was used to identify critical rheological properties required to instill “spinnability,” including homogenization, concentration, and particle size. Homogenization enhanced particle interaction to impart the requisite elastic behavior to withstand electrostatic drawing without breaking. A direct correlation between concentration and viscosity was observed that altered fiber morphology; whereas, particle size had minimal impact on suspension properties and fiber morphology. The versatility of this new method was demonstrated by electrospinning dECM with three common decellularization techniques (Abraham, Badylak, Luo) and tissue sources (intestinal submucosa, heart, skin). Bioactivity retention after electrospinning was confirmed using cell proliferation, angiogenesis, and macrophage polarization assays. Collectively, these findings provide a framework for researchers to electrospin dECM for diverse tissue engineering applications.

The specific induction of hepatic differentiation presents a significant challenge in developing alternative liver cell sources and viable strategies for clinical therapy of acute liver failure (ALF). The past decade has witnessed the blossom of microRNAs in regenerative medicine. Herein, microRNA 122-functionalized tetrahedral framework nucleic acid (FNA-miR-122) has emerged as an unprecedented and potential platform for directing the hepatic differentiation of adipose-derived mesenchymal stem cells (ADMSCs), which offers a straightforward and cost-effective method for generating functional hepatocyte-like cells (FNA-miR-122-iHep). Additionally, we have successfully established a liver organoid synthesis strategy by optimizing the co-culture of FNA-miR-122-iHep with endothelial cells (HUVECs), resulting in functional Hep:HUE-liver spheroids. Transcriptome analysis not only uncovered the potential molecular mechanisms through which miR-122 influences hepatic differentiation in ADMSCs, but also clarified that Hep:HUE-liver spheroids could further facilitate hepatocyte maturation and improved tissue-specific functions, which may provide new hints to be used to develop a hepatic organoid platform. Notably, compared to transplanted ADMSCs and Hep-liver spheroid, respectively, both FNA-miR-122-iHep-based single cell therapy and Hep:HUE-liver spheroid-based therapy showed high efficacy in treating ALF in vivo. Collectively, this research establishes a robust system using microRNA to induce ADMSCs into functional hepatocyte-like cells and to generate hepatic organoids in vitro, promising a highly efficient therapeutic approach for ALF.

Developing an oral in situ-forming hydrogel that targets the inflamed intestine to suppress bleeding ulcers and alleviate intestinal inflammation is crucial for effectively treating ulcerative colitis (UC). Here, inspired by sandcastle worm adhesives, we proposed a water-immiscible coacervate (EMNs-gel) with a programmed coacervate-to-hydrogel transition at inflammatory sites composed of dopa-rich silk fibroin matrix containing embedded inflammation-responsive core-shell nanoparticles. Driven by intestinal peristalsis, the EMNs-gel can be actuated forward and immediately transform into a hydrogel once contacting with the inflamed intestine to yield strong tissue adhesion, resulting from matrix metalloproteinases (MMPs)-triggered release of Fe3+ from embedded nanoparticles and rearrangement of polymer network of EMNs-gel on inflamed intestine surfaces. Extensive in vitro experiments and in vivo UC models confirmed the preferential hydrogelation behavior of EMNs-gel to inflamed intestine surfaces, achieving highly effective hemostasis, and displaying an extended residence time (> 48 h). This innovative EMNs-gel provides a non-invasive solution that accurately suppresses severe bleeding and improves intestinal homeostasis in UC, showcasing great potential for clinical applications.

Background: Probiotics, like Lactobacillus plantarum, show promise in managing obesity, but delivery challenges hinder their effectiveness. This study explores the effects of NCAP microcapsules with L. plantarum on weight, lipids, liver function, and insulin in rats over eight weeks, enhancing the bacteria’s survivability through microencapsulation. Results: NCAP microcapsules (10–15 μm, >79% survival) effectively protected L. plantarum. In rats, a high-fat diet with NCAP microcapsules (HFDC) significantly reduced body weight (176 g vs 179 g, p

Viral vectors are among the main approaches currently used in studies for executing gene delivery to target cells. During the past decades of active studies in gene therapy, including viruses, adenoviruses (Ads), lentiviruses (LVs), and adeno-associated viruses (AAVs), have received the most attention among the biological approaches where potentially successful outcomes are recorded for numerous genetic conditions. The success of delivery methods, however, remains unsatisfactory. Using some additives that can improve transgene expression, transfection efficiency, viral particle production, and transduction efficiency is considered as a solution to overcoming the limitations of gene delivery approaches. These additives include caffeine, histone deacetylase (HDAC) inhibitors like sodium butyrate and valproic acid, and polycationic agents like polybrene and protamine sulfate. In this review article, we present an overview of viral vector-mediated retinal gene therapies and the application of some enhancers used to improve the outcomes of gene delivery. Three routes of administrating viral vectors into ocular compartments are employed for the delivery of target genes into impacted cells, and some additives have shown enhanced efficiency of gene delivery in retinal cells. The current study places a special focus on the viral vectors and enhancers used for gene therapies of inherited retinal diseases.How to cite: Najafi S, Rahimpour A, Ahmadieh H, et al. The significance of chemical transfection/transduction enhancers in promoting the viral vectors-assisted gene delivery approaches: A focus on potentials for inherited retinal diseases. Electron J Biotechnol 2024;72. https://doi.org/10.1016/j.ejbt.2024.07.005.

Wholly defined ex vivo expansion conditions for biliary tree stem cell (BTSC) organoids were established, consisting of a defined proliferative medium (DPM) used in combination with soft hyaluronan hydrogels. The DPM consisted of commercially available Kubota's Medium (KM), to which a set of small molecules, particular paracrine signals, and heparan sulfate (HS) were added. The small molecules used were DNA methyltransferase inhibitor (RG108), TGF- β Type I receptor inhibitor (A83-01), adenylate cyclase activator (Forskolin), and L-type Ca2+ channel agonist (Bay K8644). A key paracrine signal proved to be R-spondin 1 (RSPO1), a secreted protein that activates Wnts. Soluble hyaluronans, 0.05 % sodium hyaluronate, were used with DPM to expand monolayer cultures. Expansion of organoids was achieved by using DPM in combination with embedding organoids in Matrigel that was replaced with a defined thiol-hyaluronan triggered with PEGDA to form a hydrogel with a rheology [G*] of less than 100 Pa. The combination is called the BTSC-Expansion-Glycogel-System (BEX-gel system) for expanding BTSCs as a monolayer or as organoids. The BTSC organoids were expanded more than 3000-fold ex vivo in the BEX-gel system within 70 days while maintaining phenotypic traits indicative of stem/progenitors. Stem-cell-patch grafting of expanded BTSC organoids was performed on the livers of Fah-/- mice with tyrosinemia and resulted in the rescue of the mice and restoration of their normal liver functions. The BEX-gel system for BTSC organoid expansion provides a strategy to generate sufficient numbers of organoids for the therapeutic treatments of liver diseases.

Background: Endophytic fungi produce biologically robust metabolites suitable for diverse applications, which support the increasing exploration of these fungi. The study aimed to investigate the in vitro antimicrobial properties of the metabolites of endophytic fungus Aspergillus terreus which isolated from the leaves of Psidium guajava plants while the acute oral toxicity was assessed in vivo. Results: A. terreus (OR125572) was successfully isolated for the first time from P. guajava. The ethyl acetate extract of A. terreus exhibited antibactericidal effects against Enterobacter aerogenes with a minimum inhibitory concentration of 18.75 mg/ml in contrast to 75.00 ± 0.0, 37.50, and 37.50 mg/ml, respectively against Staphylococcus aureus, Escherichia coli, and Bacillus sphaericus were 75.00 ± 0.0, 37.50, and 37.50 mg/ml, respectively. Analysis of the crude extract obtained from A. terreus by GC-MS revealed a total of 32 distinct compounds. The major components included 1,2-benzenedicarboxylic acid, di-iso-octyl ester; hexyl oxecan-2-one and phenol. The acute oral toxicity study found no symptoms of toxicity and no mortality until the 14th d, suggesting that the LD50 value of A. terreus extract might exceed 1 ml/kg. The group receiving 0.5 ml/kg of A. terreus extract experienced a 42.9% increase in body weight, while administration of varying dosages resulted in a significant reduction in MCV levels. There was also a significant increase in the proportion of monocytes across all treated groups. Conclusions: The study demonstrated the potential of A. terreus as a source of antimicrobial and other bioactive compounds, with relatively low acute toxicity.How to cite: Shehabeldine AM, Abdelaziz AM, Abdel-Maksoud MA, et al. Antimicrobial characteristics of endophytic Aspergillus terreus and acute oral toxicity analysis. Electron J Biotechnol 2024;72. https://doi.org/10.1016/j.ejbt.2024.07.003.

Magnesium (Mg) – based alloys are becoming attractive materials for medical applications as temporary bone implants for support of fracture healing, e.g. as a suture anchor. Due to their mechanical properties and biocompatibility, they may replace titanium or stainless-steel implants, commonly used in orthopedic field. Nevertheless, patient safety has to be assured by finding a long-term balance between metal degradation, osseointegration, bone ultrastructure adaptation and element distribution in organs. In order to determine the implant behavior and its influence on bone and tissues, we investigated two Mg alloys with gadolinium contents of 5 and 10 wt percent in comparison to permanent materials titanium and polyether ether ketone. The implants were present in rat tibia for 10, 20 and 32 weeks before sacrifice of the animal. Synchrotron radiation-based micro computed tomography enables the distinction of features like residual metal, degradation layer and bone structure. Additionally, X-ray diffraction and X-ray fluorescence yield information on parameters describing the bone ultrastructure and elemental composition at the bone-to-implant interface. Finally, with element specific mass spectrometry, the elements and their accumulation in the main organs and tissues are traced. The results show that Mg-xGd implants degrade in vivo under the formation of a stable degradation layer with bone remodeling similar to that of Ti after 10 weeks. No accumulation of Mg and Gd was observed in selected organs, except for the interfacial bone after 8 months of healing. Thus, we confirm that Mg-5Gd and Mg-10Gd are suitable material choices for bone implants.

Orthopedic and dental implantations under bacterial infection microenvironment face significant challenges in achieving high-quality bone-implant integration. Designing implant coatings that incorporate both immune defense and anti-inflammation is difficult in conventional single-functional coatings. We introduce a multifunctional nanointerface using a zinc finger-inspired peptide-metal-phenolic nanocoating, designed to enhance implant osseointegration under such conditions. Abaloparatide (ABL), a second-generation anabolic drug for treating osteoporosis, can be integrated into the design of a zinc-phenolic network constructed on the implant surface (ABL@ZnTA). Importantly, the phenolic-coordinated Zn2+ ions in ABL@ZnTA can act as zinc finger motif to co-stabilize the configuration of ABL through multiple molecular interactions, enabling high bioactivity, high loading capacity (1.36 times), and long-term release (>7 days) of ABL. Our results showed that ABL@ZnTA can modulate macrophage polarization from the pro-inflammatory M1 towards the anti-inflammatory M2 phenotype, promoting immune osteogenesis with increased OCN, ALP, and SOD 1 expression. Furthermore, the ABL@ZnTA significantly reduces inflammatory fibrous tissue encapsulation and enhances the long-term stability of the implants, indicated by enhanced binding strength (6 times) and functional connectivity (1.5−3 times) in the rat bone defect model infected by S. aureus. Overall, our research offers a nano-enabled synergistic strategy that balances infection defense and osteogenesis promotion in orthopedic and dental implantations.

Peripheral nervous system (PNS) injuries often lead to significant sensory and motor impairments. Traditional artificial nerve conduits, lacking anisotropic structures, have been associated with prolonged repair time and failures in nerve regeneration. This study aimed to address these challenges by developing a novel approach for rapid repair of peripheral nerve injuries (PNI). A 3D oriented fibers scaffold featuring distinct radial (RFs) and longitudinal (LFs) fibers orientations was engineered using coaxial electrospinning and gas directional foaming techniques. This scaffold was then integrated with a shape memory conduit to form a directional multi-channel nerve conduit with micro/nanostructures. The results revealed that the grooved surface of the fibers significantly improved cellular directional guidance, effectively facilitating the migration of SCs from the periphery towards the center and from the base to the apex of the scaffold. In a rat model with a 10 mm nerve defect, the ND-PLATMC/LF ND-PCL scaffold significantly enhanced nerve regeneration and motor function recovery within 4 weeks. These results suggest the potential of this innovative scaffold for efficient repair of the nerve injuries.

Photoimmunotherapy (PIT) combines the specificity of antibodies with the cytotoxicity of light activatable photosensitizers (PS) and is a promising new cancer therapy. We designed and synthesized, in a highly convergent manner, the silicon phthalocyanine dye WB692-CB2, which is novel for being the first light-activatable PS that can be directly conjugated via a maleimide linker to cysteines. In the present study we conjugated WB692-CB2 to a humanized antibody with engineered cysteines in the heavy chains that specifically targets the prostate-specific membrane antigen (PSMA). The resulting antibody dye conjugate revealed high affinity and specificity towards PSMA-expressing prostate cancer cells and induced cell death after irradiation with red light. Treated cells exhibited morphological characteristics associated with pyroptosis. Mechanistic studies revealed the generation of reactive oxygen species, triggering a cascade of intracellular events involving lipid peroxidation, caspase-1 activation, gasdermin D cleavage and membrane rupture followed by release of pro-inflammatory cellular contents. In first in vivo experiments, PIT with our antibody dye conjugate led to a significant reduction of tumor growth and enhanced overall survival in mice bearing subcutaneous prostate tumor xenografts. Our study highlights the future potential of the new phthalocyanine dye WB692-CB2 as PS for the fluorescence-based detection and PIT of cancer, including local prostate tumor lesions, and systemic activation of anti-tumor immune responses by the induction of pyroptosis.

Chronic bladder dysfunction due to bladder disease or trauma is detrimental to affected patients as it can lead to increased risk of upper urinary tract dysfunction. Current treatment options include surgical interventions that enlarge the bladder with autologous bowel tissue to alleviate pressure on the upper urinary tract. This highly invasive procedure, termed bladder augmentation enterocystoplasty (BAE), significantly increases the risk of patient morbidity and mortality due to the incompatibility between bowel and bladder tissue. Therefore, patients would significantly benefit from an alternative treatment strategy that can regenerate healthy tissue and restore overall bladder function. Previous research has demonstrated the potential of citrate-based scaffolds co-seeded with bone marrow-derived stem/progenitor cells as an alternative graft for bladder augmentation. Recognizing that contact guidance can potentially influence tissue regeneration, we hypothesized that microtopographically patterned scaffolds would modulate cell responses and improve overall quality of the regenerated bladder tissue. We fabricated microgrooved (MG) scaffolds using the citrate-based biomaterial poly (1,8-octamethylene-citrate-co-octanol) (POCO) and co-seeded them with human bone marrow-derived mesenchymal stromal cells (MSCs) and CD34+ hematopoietic stem/progenitor cells (HSPCs). MG POCO scaffolds supported MSC and HSPC attachment, and MSC alignment within the microgrooves. All scaffolds were characterized and assessed for bladder tissue regeneration in an established nude rat bladder augmentation model. In all cases, normal physiological function was maintained post-augmentation, even without the presence of stem/progenitor cells. Urodynamic testing at 4-weeks post-augmentation for all experimental groups demonstrated that bladder capacity increased and bladder compliance was normal. Histological evaluation of the regenerated tissue revealed that cell-seeded scaffolds restored normal bladder smooth muscle content and resulted in increased revascularization and peripheral nerve regeneration. The presence of microgrooves on the cell-seeded scaffolds increased microvasculature formation by 20 % and urothelial layer thickness by 25 % in the regenerating tissue. Thus, this work demonstrates that microtopography engineering can influence bladder tissue regeneration to improve overall anatomical structure and re-establish bladder physiology.

Recent cumulative findings signify the adaptive immunity of materials as a key agenda in tissue healing that can improve regenerative events and outcomes. Modulating immune responses, mainly the recruitment and functions of T and B cells and their further interplay with innate immune cells (e.g., dendritic cells, macrophages) can be orchestrated by materials. For instance, decellularized matrices have been shown to promote muscle healing by inducing T helper 2 (Th2) cell immunity, while synthetic biopolymers exhibit differential effects on B cell responses and fibrosis compared decellularized matrices. We discuss the recent findings on how implantable materials instruct the adaptive immune events and the subsequent tissue healing process. In particular, we dissect the materials’ physicochemical properties (shape, size, topology, degradation, rigidity, and matrix dynamic mechanics) to demonstrate the relations of these parameters with the adaptive immune responses in vitro and the underlying biological mechanisms. Furthermore, we present evidence of recent in vivo phenomena, including tissue healing, cancer progression, and fibrosis, wherein biomaterials potentially shape adaptive immune cell functions and in vivo outcomes. Our discussion will help understand the materials-regulated immunology events more deeply, and offer the design rationale of materials with tunable matrix properties for accelerated tissue repair and regeneration.

The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delays stent reendothelialization, increasing the risk of stent thrombosis (ST) and sudden cardiac death. Here we present a new strategy for promoting stent reendothelialization and preventing ST by exploring the application of precise molecular targets with EC specificity. Proteomics was used to investigate the molecular mechanism of EC injury caused by rapamycin. Endothelial protein C receptor (EPCR) was screened out as a crucial EC-specific effector. Limus and paclitaxel repressed the EPCR expression, while overexpression of EPCR protected EC from coating (eluting) drug-induced injury. Furthermore, the ligand activated protein C (APC), polypeptide TR47, and compound parmodulin 2, which activated the target EPCR, promoted EC functions and inhibited platelet or neutrophil adhesion, and enhanced rapamycin stent reendothelialization in the simulated stent environment and in vitro. In vivo, the APC/rapamycin-coating promoted reendothelialization rapidly and prevented ST more effectively than rapamycin-coating alone, in both traditional metal stents and biodegradable stents. Additionally, overexpression or activation of the target EPCR did not affect the cellular behavior of SMC or the inhibitory effect of rapamycin on SMC. In conclusion, EPCR is a promising therapeutical agonistic target for pro-reendothelialization and anti-thrombosis of eluting stent. Activation of EPCR protects against coating drugs-induced EC injury, inflammatory cell, or platelet adhesion onto the stent. The novel application formula for APC/rapamycin-combined eluting promotes stent reendothelialization and prevents ST.

Chronic bioenergetic imbalances and inflammation caused by hyperglycemia are obstacles that delay diabetic wound healing. However, it is difficult to directly deliver energy and metabolites to regulate intracellular energy metabolism using biomaterials. Herein, we propose a light-driven bioenergetic and oxygen-releasing hydrogel (PTKM@HG) that integrates the thylakoid membrane-encapsulated polyphenol nanoparticles (PTKM NPs) to regulate the energy metabolism and inflammatory response in diabetic wounds. Upon red light irradiation, the PTKM NPs exhibited oxygen generation and H2O2 deletion capacity through a photosynthetic effect to restore hypoxia-induced mitochondrial dysfunction. Meanwhile, the PTKM NPs could produce exogenous ATP and NADPH to enhance mitochondrial function and facilitate cellular anabolism by regulating the leucine-activated mTOR signaling pathway. Furthermore, the PTKM NPs inherited antioxidative and anti-inflammatory ability from polyphenol. Finally, the red light irradiated PTKM@HG hydrogel augmented the survival and migration of cells keratinocytes, and then accelerated angiogenesis and re-epithelialization of diabetic wounds. In short, this study provides possibilities for effectively treating diseases by delivering key metabolites and energy based on such a light-driven bioenergetic hydrogel.

Aerogel scaffolds are nanostructured materials with beneficial properties for tissue engineering applications. The tracing of the state of the aerogels after their implantation is challenging due to their variable biodegradation rate and the lack of suitable strategies capable of in vivo monitoring the scaffolds. Upconversion nanoparticles (UCNPs) have emerged as advanced tools for in vitro bioimaging because of their fluorescence properties. In this work, highly fluorescent UCNPs were loaded into aerogels to obtain theranostic implants for tissue engineering and bioimaging applications. 3D-printed alginate-hydroxyapatite aerogels labeled with UCNPs were manufactured by 3D-printing and supercritical CO2 drying to generate personalize-to-patient aerogels. The physicochemical performance of the resulting structures was evaluated by printing fidelity measurements, nitrogen adsorption-desorption analysis, and different microscopies (confocal, transmission and scanning electron microscopies). Stability of the aerogels in terms of physicochemical properties was also tested after 3 years of storage. Biocompatibility was evaluated in vitro by different cell and hemocompatibility assays, in ovo and in vivo by safety and bioimaging studies using different murine models. Cytokines profile, tissue index and histological evaluations of the main organs unveiled an in vivo downregulation of the inflammation after implantation of the scaffolds. UCNPs-decorated aerogels were first-time manufactured and long-term traceable by fluorescence-based bioimaging until 3 weeks post-implantation, thereby endorsing their suitability as tissue engineering and theranostic nanodevices (i.e. bifunctional implants).

Osteoporotic bone defects pose a significant challenge for bone regeneration as they exhibit impaired healing capacity and delayed healing period. To address this issue, this study introduces a hydrogel that creates a rejuvenating microenvironment, thereby facilitating efficient bone repair during the initial two weeks following bone defect surgery. The hydrogel, named GelHFS, was created through host-guest polymerization of gelatin and acrylated β-cyclodextrin. Incorporation of the human fetal mesenchymal stem cell secretome (HFS) formed GelHFS hydrogel aimed at mimicking a rejuvenated stem cell niche. Our results demonstrated that GelHFS hydrogel promotes cell stellate spreading and osteogenic differentiation via integrin β1-induced focal adhesion pathway. Implantation of GelHFS hydrogel in an osteoporotic bone defect rat model recruited endogenous integrin β1-expressing cells and enhanced new bone formation and bone strength. Our findings reveal that GelHFS hydrogel provides a rejuvenating niche for endogenous MSCs and enhances bone regeneration in osteoporotic bone defect. These findings highlight the potential of GelHFS hydrogel as an effective therapeutic strategy for addressing challenging bone healing such as osteoporotic bone regeneration.

Utilizing transplanted human umbilical cord mesenchymal stem cells (HUMSCs) for cartilage defects yielded advanced tissue regeneration, but the underlying mechanism remain elucidated. Early after HUMSCs delivery to the defects, we observed substantial apoptosis. The released apoptotic vesicles (apoVs) of HUMSCs promoted cartilage regeneration by alleviating the chondro-immune microenvironment. ApoVs triggered M2 polarization in macrophages while simultaneously facilitating the chondrogenic differentiation of endogenous MSCs. Mechanistically, in macrophages, miR-100-5p delivered by apoVs activated the MAPK/ERK signaling pathway to promote M2 polarization. In MSCs, let-7i-5p delivered by apoVs promoted chondrogenic differentiation by targeting the eEF2K/p38 MAPK axis. Consequently, a cell-free cartilage regeneration strategy using apoVs combined with a decellularized cartilage extracellular matrix (DCM) scaffold effectively promoted the regeneration of osteochondral defects. Overall, new mechanisms of cartilage regeneration by transplanted MSCs were unconcealed in this study. Moreover, we provided a novel experimental basis for cell-free tissue engineering-based cartilage regeneration utilizing apoVs.

Approaches to regenerating bone often rely on integrating biomaterials and biological signals in the form of cells or cytokines. However, from a translational point of view, these approaches are challenging due to the sourcing and quality of the biologic, unpredictable immune responses, complex regulatory paths, and high costs. We describe a simple manufacturing process and a material-centric 3D-printed composite scaffold system (CSS) that offers distinct advantages for clinical translation. The CSS comprises a 3D-printed porous polydiolcitrate-hydroxyapatite composite elastomer infused with a polydiolcitrate-graphene oxide hydrogel composite. Using a micro-continuous liquid interface production 3D printer, we fabricate a precise porous ceramic scaffold with 60 wt% hydroxyapatite resembling natural bone. The resulting scaffold integrates with a thermoresponsive hydrogel composite in situ to fit the defect, which is expected to enhance surface contact with surrounding tissue and facilitate biointegration. The antioxidative properties of citrate polymers prevent long-term inflammatory responses. The CSS stimulates osteogenesis in vitro and in vivo. Within 4 weeks in a calvarial critical-sized bone defect model, the CSS accelerated ECM deposition (8-fold) and mineralized osteoid (69-fold) compared to the untreated. Through spatial transcriptomics, we demonstrated the comprehensive biological processes of CSS for prompt osseointegration. Our material-centric approach delivers impressive osteogenic properties and streamlined manufacturing advantages, potentially expediting clinical application for bone reconstruction surgeries.

Camptothecin (CPT) exhibits potent antitumor activity; however, its clinical application is limited by significant gastrointestinal adverse effects (GAEs). Although the severity of GAEs associated with CPT derivatives has decreased, the incidence rate of these adverse effects has remained high. CPT multifunctional nanoparticles (PCRHNs) have the potential to increase the efficacy of CPT while reducing side effects in major target organs; however, the impact of PCRHNs on the GAEs from CPT remains uncertain. Here, we investigated the therapeutic effects of PCRHNs and different doses of CPT and examined their impacts on the intestinal barrier and the intestinal microbiota. We found that the therapeutic efficacy of PCRHNs + Laser treatment was superior to that of high-dose CPT, and PCRHNs + Laser treatment also provided greater benefits by helping maintain intestinal barrier integrity, intestinal microbiota diversity, and intestinal microbiota abundance. In summary, compared to high-dose CPT treatment, PCRHNs + Laser treatment can effectively balance therapeutic effects and GAEs. A high dose of CPT promotes the enrichment of the pathogenic bacteria Escherichia-Shigella, which may be attributed to diarrhea caused by CPT, thus leading to a reduction in microbial burden; additionally, Escherichia-Shigella rapidly grows and occupies niches previously occupied by other bacteria that are lost due to diarrhea. PCRHNs + Laser treatment increased the abundance of Lactobacillus (probiotics), possibly due to the photothermal effect of the PCRHNs. This effect increased catalase activity, thus facilitating the conversion of hydrogen peroxide into oxygen within tumors and increasing oxygen levels in the body, which is conducive to the growth of facultative anaerobic bacteria.

Zinc (Zn)-based biodegradable metals (BMs) fabricated through conventional manufacturing methods exhibit adequate mechanical strength, moderate degradation behavior, acceptable biocompatibility, and bioactive functions. Consequently, they are recognized as a new generation of bioactive metals and show promise in several applications. However, conventional manufacturing processes face formidable limitations for the fabrication of customized implants, such as porous scaffolds for tissue engineering, which are future direction towards precise medicine. As a metal additive manufacturing technology, laser powder bed fusion (L-PBF) has the advantages of design freedom and formation precision by using fine powder particles to reliably fabricate metallic implants with customized structures according to patient-specific needs. The combination of Zn-based BMs and L-PBF has become a prominent research focus in the fields of biomaterials as well as biofabrication. Substantial progresses have been made in this interdisciplinary field recently. This work reviewed the current research status of Zn-based BMs manufactured by L-PBF, covering critical issues including powder particles, structure design, processing optimization, chemical compositions, surface modification, microstructure, mechanical properties, degradation behaviors, biocompatibility, and bioactive functions, and meanwhile clarified the influence mechanism of powder particle composition, structure design, and surface modification on the biodegradable performance of L-PBF Zn-based BM implants. Eventually, it was closed with the future perspectives of L-PBF of Zn-based BMs, putting forward based on state-of-the-art development and practical clinical needs.

Postmenopausal osteoporosis (PMOP) is a prevalent condition among elderly women. After menopause, women exhibit decreased iron excretion, which is prone to osteoporosis. To design a specific titanium implant for PMOP, we first analyze miRNAs and DNA characteristics of postmenopausal patients with and without osteoporosis. The results indicate that iron overload disrupts iron homeostasis in the pathogenesis of PMOP. Further experiments confirm that iron overload can cause lipid peroxidation and ferroptosis of MSCs, thus breaking bone homeostasis. Based on the findings above, we have designed a novel Ti implant coated with nanospheres of caffeic acid (CA) and deferoxamine (DFO). CA can bind on the Ti surface through the two adjacent phenolic hydroxyls and polymerize into polycaffeic acid (PCA) dimer, as well as the PCA nanospheres with the repetitive 1,4-benzodioxan units. DFO was grafted with PCA through borate ester bonds. The experimental results showed that modified Ti can inhibit the ferroptosis of MSCs in the pathological environment of PMOP and promote osseointegration in two main ways. Firstly, DFO was released under high oxidative stress, chelating with excess iron and decreasing the labile iron pool in MSCs. Meanwhile, CA and DFO activated the KEAP1/NRF2/HMOX1 pathway in MSCs and reduced the level of intracellular lipid peroxidation. So, the ferroptosis of MSCs is inhibited by promoting the SLC7A11/GSH/GPX4 pathway. Furthermore, the remained CA coating on the Ti surface could reduce the extracellular oxidative stress and glutathione level. This study offers a novel inspiration for the specific design of Ti implants in the treatment of PMOP.

Improving the comprehensive performance of low alloyed Mg is a significant challenge for biomedical applications. This paper developed a high-performance Mg–Zn alloy with uniform ultrafine grains and nano-precipitates through a straightforward, high-temperature reciprocating equal channel angle extrusion (ECAP) process and researched the microstructure, mechanical property, degradation behaviour, and biocompatibility of the developed alloy. Results showed that the lean Mg–2Zn alloy successfully refined grain to about 1 μm and produced plenty of nano-particles with uniform distribution, providing high comprehensive mechanical properties (YS: 235 MPa, UTS: 267 MPa, EL: 15.6 %). Additionally, Zn-riched nano-particles in the matrix could decrease the Zn aggregation at the corrosion layer-matrix interface and form a dense oxide film, achieving a low degradation rate (0.13 mm/year in vivo). Finally, this work realizes the low alloy content, low cost, and good properties of one biodegradable Mg alloy, which will benefit the promotion of future clinical applications.

Oxidative stress and aging lead to progressive senescence of nucleus pulposus (NP) cells, resulting in intervertebral disc (IVD) degeneration (IVDD). In some cases, degenerative IVD can further cause low back pain (LBP). Several studies have confirmed that delaying and rejuvenating the senescence of NP cells can attenuate IVDD. However, the relatively closed tissue structure of IVDs presents challenges for the local application of anti-senescence drugs. Here, we prepared an anti-senescence hydrogel by conjugating phenylboronic acid-modified gelatin methacryloyl (GP) with quercetin to alleviate IVDD by removing senescent NP cells. The hydrogel exhibited injectability, biodegradability, prominent biocompatibility and responsive release of quercetin under pathological conditions. In vitro experiments demonstrated that the hydrogel could reduce the expression of senescence markers and restore the metabolic balance in senescent NP cells. In vivo studies validated that a single injection of the hydrogel in situ could maintain IVD tissue structure and alleviate sensitivity to noxious mechanical force in the rat models, indicating a potential therapeutic approach for ameliorating IVDD and LBP. This approach helps prevent potential systemic toxicity associated with systemic administration and reduces the morbidity resulting from repeated injections of free drugs into the IVD, providing a new strategy for IVDD treatment.

Due to the limited self-repair ability of the annulus fibrosus (AF), current tissue engineering strategies tend to use structurally biomimetic scaffolds for AF defect repair. However, the poor integration between implanted scaffolds and tissue severely affects their therapeutic effects. To solve this issue, we prepared a multifunctional scaffold containing loaded lysyl oxidase (LOX) plasmid DNA exosomes and manganese dioxide nanoparticles (MnO2 NPs). LOX facilitates extracellular matrix (ECM) cross-linking, while MnO2 NPs inhibit excessive reactive oxygen species (ROS)-induced ECM degradation at the injury site, enhancing the crosslinking effect of LOX. Our results revealed that this multifunctional scaffold significantly facilitated the integration between the scaffold and AF tissue. Cells were able to migrate into the scaffold, indicating that the scaffold was not encapsulated as a foreign body by fibrous tissue. The functional scaffold was closely integrated with the tissue, effectively enhancing the mechanical properties, and preventing vascular invasion, which emphasized the importance of scaffold-tissue integration in AF repair.

Periodontitis is an inflammatory disease caused by bacterial biofilms, which leads to the destruction of periodontal tissue. Current treatments, such as mechanical cleaning and antibiotics, struggle to effectively address the persistent biofilms, inflammation, and tissue damage. A new approach involves developing a Janus nanomotor (J-CeM@Au) by coating cerium dioxide-doped mesoporous silica (CeM) with gold nanoparticles (AuNPs). This nanomotor exhibits thermophoretic motion when exposed to near-infrared (NIR) laser light due to the temperature gradient produced by the photothermal effects of asymmetrically distributed AuNPs. The NIR laser provides the energy for propulsion and activates the nanomotor's antibacterial properties, allowing it to penetrate biofilms and kill bacteria. Additionally, the nanomotor's ability to scavenge reactive oxygen species (ROS) can modulate the immune response and create a regenerative environment, promoting the healing of periodontal tissue. Overall, this multifunctional nanomotor offers a promising new approach for treating periodontitis by simultaneously addressing biofilm management and immune modulation with autonomous movement.