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Yue Zhu,1,* Rongjia Zhu,2,* Kun Liu,3,* Xin Li,1 Dezhong Chen,4 Dunyao Bai,5 Jieli Luo,5 Yixun Liu,6 Yan Zhang,7 Li Li,8 Junfang Hu,9 Dayong Xu,10 Yan Liu,10 Robert Chunhua Zhao2,11 1Stem Cell Lab, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, People’s Republic of China; 3Otorhinolaryngology, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 5Molecular Laboratory, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 6Gonadal Biology Research Group, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China; 7National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China; 8The Ministry of Science and Education, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 9Department of Pharmacy, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 10Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of China; 11School of Life Sciences, Shanghai University, Shanghai 200444, People’s Republic of China*These authors contributed equally to this workCorrespondence: Robert Chunhua ZhaoInstitute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, People’s Republic of ChinaEmail zhaochunhua@vip.163.comYan LiuStem Cell Lab, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430081, People’s Republic of ChinaEmail liuyan@wust.edu.cnBackground: COVID-19 (coronavirus disease 2019) has become a global public health emergency since patients were first detected in Wuhan, China, in December 2019. Currently, there are no satisfying antiviral medications and vaccines available.Case Presentation: We reported the treatment process and clinical outcome of a 48-year-old man critically ill COVID-19 patient who received transfusion of allogenic human umbilical cord mesenchymal stem cells (UC-MSCs).Conclusions: We proposed that UC-MSC transfusion might be a new option for critically ill COVID-19. Although only one case we were shown, more similar clinical cases are inquired for further evidence providing the potential effectiveness of UC-MSC treatment.Keywords: COVID-19, UC-MSCs, critically ill, cell transplantation, case report

Li Wan,1,* Xinglei Yao,1–3,* Francesco Faiola,3 Bojun Liu,4 Tianyuan Zhang,2 Yasuhiko Tabata,5 Hiroyuki Mizuguchi,6 Shinsaku Nakagawa,7 Jian-Qing Gao,2 Robert Chunhua Zhao1 1Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing, 2Institute of Pharmaceutics, Zhejiang University, Hangzhou, 3State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 4YouAn Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 6Department of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 7Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan *These authors contributed equally to this work Abstract: Mesenchymal stem cells (MSCs) are adult stem cells with multilineage potential, which makes them attractive tools for regenerative medicine applications. Efficient gene transfer into MSCs is essential not only for basic research in developmental biology but also for therapeutic applications involving gene-modification in regenerative medicine. Adenovirus vectors (Advs) can efficiently and transiently introduce an exogenous gene into many cell types via their primary receptors, the coxsackievirus and adenovirus receptors, but not into MSCs, which are deficient in coxsackievirus and adenovirus receptors expression. To overcome this problem, we developed an Adv coated with a spermine-pullulan (SP) cationic polymer and investigated its physicochemical properties and internalization mechanisms. We demonstrated that the SP coating could enhance adenoviral transduction of MSCs without detectable cytotoxicity or effects on differentiation. Our results argue in favor of the potentiality of the SP-coated Adv as a prototype vector for efficient and safe transduction of MSCs. Keywords: mesenchymal stem cells, adenovirus vectors, spermine-pullulan, polymer, gene transduction

Bacterial infections in wounds and bacteremia present significant global health challenges, driving the urgent need for innovative alternatives to traditional antibiotics. Here, the development of PEI-EDTA-2Na carbon quantum dots (PECDs) synthesized via a hydrothermal method is reported. Synthesis conditions affect PECDs' antibacterial efficacy; those at 180 °C have optimal -NH 2 functionalization for better adhesion and activity. PECDs are pH - responsive, eradicating bacteria in weakly acidic conditions by disrupting DNA and proteins. Following the resolution of infection, PECDs adapt to neutral and alkaline environments, where they scavenge reactive oxygen species (ROS), reduce inflammation, promote macrophage polarization, and accelerate wound healing. Furthermore, PECDs significantly improve survival in bacteremia models. Their intrinsic fluorescence enables real-time pH monitoring of wounds, offering a non-invasive diagnostic tool. Genomic and transcriptomic analyses reveal that PECDs disrupt bacterial metabolism and resistance pathways, while simultaneously supporting antibacterial and anti-inflammatory responses during tissue repair. This dual functionality-combining therapeutic efficacy in wound healing with antimicrobial and anti-inflammatory properties in bacteremia-positions PECDs as a versatile platform for smart wound management and an emerging candidate for advanced biomedical applications., (© 2025 Wiley‐VCH GmbH.)

Osteoarthritis (OA) is a prevalent degenerative joint disease that significantly impacts the quality of life in the elderly. Traditional Chinese medicine, particularly Medicinal Cyathula Root and its active component Cyaonoside A (CyA), has been utilized to treat OA by promoting chondrocyte proliferation, inhibiting inflammatory factors, and maintaining joint homeostasis. Concurrently, mesenchymal stem cells (MSC) derived from placental umbilical cord, bone marrow, and adipose tissue have gained attention for their potential in OA treatment due to their chondrogenic differentiation capabilities. This study explored the therapeutic synergy of CyA and MSC for enhanced cartilage regeneration. Optimal chondrogenic differentiation was achieved by treating MSC with 0.5 mg/mL CyA for 3 days, significantly increasing the expression of key cartilage-specific genes ACAN, COL2A, and SOX9. Comparative gene expression and pathway analyses revealed that CyA-induced MSC (C-MSC) modulate critical signaling pathways, including TGF-β, PI3K-Akt, and Wnt, demonstrating their potential in cartilage repair. Furthermore, C-MSC-derived exosomes exhibited superior anti-inflammatory and anti-apoptotic effects compared to MSC-derived exosomes in IL-1β-treated human chondrocytes, enhancing chondrogenic gene expression and reducing cartilage degradation. To enable targeted delivery, a novel injectable hydrogel system (HAMA@C-MSC) was developed using methylacrylated hyaluronic acid (HAMA). This hydrogel facilitated uniform cell distribution, maintained structural integrity, and demonstrated excellent biocompatibility and biosafety, with no cytotoxic or hemolytic effects. In vivo studies using a rat destabilization of the medial meniscus OA model confirmed that HAMA@C-MSC significantly improved cartilage structure, enhanced chondrocyte regeneration, and restored collagen integrity, outperforming other treatment groups as validated through imaging, histology, and molecular analyses. These findings highlight HAMA@C-MSC as a promising therapeutic strategy for OA, leveraging the synergistic effects of C-MSC and advanced hydrogel technology to achieve enhanced cartilage regeneration and joint protection.

The integration of hydrogen-bonded organic frameworks (HOFs) with flexible electronic technologies offers a promising strategy for monitoring detailed health information, owing to their inherent porosity, excellent biocompatibility, and tunable catalytic capabilities. However, their application in wearable and real-time health monitoring remains largely unexplored, primarily due to the mechanical mismatch between the traditionally fragile HOFs particles and the softness of human skin. Herein, this study demonstrates an epidermal biosensor that maintains reliable sensing capability even under extreme deformation and complex environmental conditions by integrating HOFs films with wavy bioelectrodes. This wearable biosensor demonstrates ultrasensitive detection capabilities, with a limit of detection of 49.64 nM, and accurately measures nutritional content in sweat while conforming to curved skin surfaces. The sensor's performance is comparable to those obtained using high-performance liquid chromatography (HPLC). More strikingly, scratched HOFs films can be regenerated through a simple solvent rinsing process, enabling their reuse in the fabrication of new biosensors and offering a significant advantage over conventional sensing materials. This work has the potential to inspire the development of more flexible electronic devices, leveraging the structural adaptability and diversity of HOFs for personalized healthcare applications and real-time health monitoring., (© 2025 Wiley‐VCH GmbH.)

Cyclohexane (Cy), commonly produced by the catalytic hydrogenation of benzene (Bz), is used in large quantities as a solvent or feedstock for nylon polymers. Removing trace unreacted Bz from the Cy product is technically difficult due to their similar molecular structures and physical properties. Herein, we report that a metal-organic framework (MOF) adsorbent shows a molecular sieving effect for Bz and Cy with record-high Bz/Cy adsorption selectivities (216, 723, and 1027) in their liquid mixtures (v/v = 1:1, 1:10, and 1:20), and traps Bz molecules effectively even at low partial pressure in the vapor phase (e.g., 2.49 mmol/g at 8.2 Pa) or at low content in liquid-phase Cy (e.g., 128 mg/g at 20 ppm). Over 99% removal of trace Bz (1000 ppm) from liquid Cy could be achieved in one simple stripping step at room temperature using this sorbent, producing a Cy with >99.999% purity. Single-crystal structure analyses for guest-free and Bz-loaded phases of the MOF disclosed that a narrow slit-like pore aperture and the strong uniting of multiple weak host-guest and guest-guest interactions are the co-origin of its distinct adsorption property for Bz and Cy.

Background: Obesity is becoming one of the major non-communicable diseases with increasing incidence and risks that cannot be ignored. However effective and safe clinical treatment strategies still need to be deeply explored. Increased number and volume of adipocytes lead to overweight and obesity. The aim of our work is to identify lncRNAs that have important regulatory in differentiation of human mesenchymal stem cells (MSCs) into adipocytes, and to provide effective targets for clinical prevention and treatment of obesity and related metabolic disorders., Methods: We extracted primary MSCs from human adipose tissue, and conducted expression profile analysis of lncRNAs during adipogenic differentiation of MSCs to screen changed lncRNAs. Characteristics of lncRNA were revealed mainly by RACE and RNA FISH. Loss- and gain-of function experiments in vivo and in vitro were used to analyze effects of lncRNA. Targeted metabolomics was utilized to detect levels of free fatty acids. RNA pull-down, mRNA stability tests, etc. were employed to explore mechanisms of lncRNA., Results: Human-specific lncRNA, we named it MEK6-AS1, was the most up-regulated transcript during adipogenic differentiation of MSCs. MEK6-AS1 was highly expressed in adipose tissue samples from individuals with BMI ≥ 25 and positively correlated with adipogenic marker genes in these samples. Knocking down lncRNA inhibited expression of adipogenic differentiation markers and ectopic adipogenesis, reducing contents of various free fatty acids, as well as promoting osteogenic differentiation. Overexpression of lncRNA had the opposite effects to the above processes. We also found that MEK6-AS1 was elevated during hepatic steatosis organoid generation. Mechanistically, MEK6-AS1 worked partially through stabilization of MEK6 mRNA by NAT10., Conclusions: We have identified a human-specific lncRNA (MEK6-AS1) with position information in the genomic database but has not been extensively reported. We demonstrated that MEK6-AS1 as a novel lncRNA involved in adipogenic differentiation and adipogenesis, fatty acid metabolism, and osteogenic differentiation. We found that MEK6-AS1 may exert its effect by enhancing MEK6 mRNA stability through NAT10. Our study may provide insights into implication of lncRNAs in stem cell biology and offer a new potential therapeutic target for the prevention and treatment of obesity and other related disease., Competing Interests: Declarations. Ethics approval and consent to participate: Human adipose tissues were medical waste obtained from patients undergoing liposuction. The samples are only used for scientific research. The collection of samples does not cause additional harm to the patients and does not infringe their privacy. The informed consent was exempted, which was approved by the Ethics Committee at the Chinese Academy of Medical Sciences and Peking Union Medical College. All animal experiments were carried out in accordance with guidelines of a protocol approved by the Ethics Committee of the Chinese Academy of Medical Sciences and School of Basic Medicine Peking Union Medical College (SB2023048). Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

Traumatic brain injury (TBI) is a significant contributor to global mortality and morbidity, with emerging evidence indicating a heightened risk of developing Alzheimer's disease (AD) following TBI. This study aimed to explore the molecular intersections between TBI and AD, focusing on the role of adipose mesenchymal stem cell (ADMSC)-derived exosomes and hub genes involved in microglial polarization. Transcriptome profiles from TBI (GSE58485) and AD (GSE74614) datasets were analyzed to identify differentially expressed genes (DEGs). The hub genes were validated in independent datasets (GSE180811 for TBI and GSE135999 for AD) and localized to specific cell types using single-cell RNA (scRNA) sequencing data (GSE160763 for TBI and GSE224398 for AD). Experimental validation was conducted to investigate the role of these genes in microglial polarization using cell culture and ADMSC-derived exosomes interventions. Our results identified three hub genes-Bst2, B2m, and Lgals3bp-that were upregulated in both TBI and AD, with strong associations to inflammation, neuronal apoptosis, and tissue repair processes. scRNA sequencing revealed that these genes are predominantly expressed in microglia, with increased expression during M1 polarization. Knockdown of these genes reduced M1 polarization and promoted M2 phenotype in microglia. Additionally, ADMSC-derived exosomes attenuated M1 polarization and downregulated the expression of hub genes. This study provides novel insights into the shared molecular pathways between TBI and AD, highlighting potential therapeutic targets for mitigating neuroinflammation and promoting recovery in both conditions., Competing Interests: Declarations. Ethics approval and consent to participate: None required. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lipid droplets serve as primary storage organelles for neutral lipids in neurons, glial cells, and other cells in the nervous system. Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum. Previously, lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis; however, recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system. In addition to their role in regulating cell metabolism, lipid droplets play a protective role in various cellular stress responses. Furthermore, lipid droplets exhibit specific functions in neurons and glial cells. Dysregulation of lipid droplet formation leads to cellular dysfunction, metabolic abnormalities, and nervous system diseases. This review aims to provide an overview of the role of lipid droplets in the nervous system, covering topics such as biogenesis, cellular specificity, and functions. Additionally, it will explore the association between lipid droplets and neurodegenerative disorders. Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

A major challenge for stem cell therapies, such as using mesenchymal stem cells to treat skin injuries, is the stable engraftment of exogenous cells and the maintenance of their regenerative capacities in the wound areas. DNA-based self-assembly strategies can be used for artificial and multifunctional cell surface engineering to stabilize and enhance their functions for therapeutic applications. Here, we developed DNA nanofiber-decorated stem cells, in which DNA-based, multivalent fiber-like structures were self-assembled in situ on the cell surfaces. These engineered stem cells have demonstrated robust reactive oxygen species (ROS) scavenging effects, specific adhesion to damaged vascular endothelial cells, and the ability to enhance angiogenesis, which were effective and safe for acute or chronic wound healing in a mouse model with excisional skin injury. This DNA nanostructure-engineered stem cell provides a novel therapeutic platform for the treatment of tissue damage.

Cognitive decline and memory impairment are subsequently result in neuronal apoptosis and synaptic damage. Aberrant regulation of microRNAs has been implicated in the pathogenesis of Alzheimer's disease (AD) and may play a pivotal role in the early stages of the disease. In this study, we identified the critical role of miR-4763-3p in AD pathogenesis, focusing on early-stage mild cognitive impairment (AD-MCI). Leveraging fluorescence in situ hybridization, we observed miR-4763-3p upregulation in AD hippocampal tissue, colocalizing with Aβ and Tau. Antagomir-mediated inhibition of miR-4763-3p ameliorated cognitive decline in AD-MCI mice. RNA-seq and functional assays revealed that miR-4763-3p targets ATP11A, and antagomir enhancing inward flipping of the "eat me" phosphatidylserine signal on the surface of neuronal cells, autophagy, and clearance of Aβ/lipofuscin, while reducing neuroinflammation and neuronal apoptosis. Mechanistically, miR-4763-3p modulates the PI3K/AKT/mTOR/Bcl2 pathway, thereby promoting neuronal autophagy and reducing apoptotic crosstalk. These findings underscore miR-4763-3p as a therapeutic target for AD-MCI, offering a novel strategy to enhance neuronal autophagy, alleviate inflammation, and improve cognitive function., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Hydrogen-bonded organic frameworks (HOFs) are emerging as multifunctional materials with exceptional biocompatibility, abundant active sites, and tunable porosity, which are highly beneficial for advanced wound care. However, a significant challenge involves transforming pristine HOFs powders into lightweight, ultrathin, freestanding membranes compatible with soft biological systems. Herein, the study successfully develops shape-adaptive HOF-based matrix membranes (HMMs) using a polymer-assisted liquid-air interface technique. The HMMs conform seamlessly to tissues of different sizes and shapes, effectively stopping bleeding, and provide high water-vapor permeability. Notably, both in vitro and in vivo studies with mice wound models demonstrated that these tissue-conformable HMMs significantly accelerate wound healing by modulating the inflammatory environment of the injured tissue and promoting rapid re-epithelialization. Furthermore, RNA-seq analysis and mechanistic studies revealed that HMMs effectively reduce inflammation and facilitate the tissue transition from the proliferative stage to the remodeling stage of skin development. This work not only opens up new avenues for advanced wound care materials but also establishes a foundation for hybridizing HOFs with polymers for a wide range of potential applications., (© 2024 Wiley‐VCH GmbH.)

UVB radiation induces oxidative stress, DNA damage, and inflammation, leading to skin wrinkling, compromised barrier function, and an increased risk of carcinogenesis. Addressing or preventing photoaging may offer a promising therapeutic avenue for these conditions. Recent research indicated that mesenchymal stem cells (MSCs) exhibit significant therapeutic potential for various skin diseases. Given that extracellular vesicles (EV) can deliver diverse cargo to recipient cells and elicit similar therapeutic effects, we investigated the roles and underlying mechanisms of both adipose-derived MSC-derived EV (AMSC-EV) and umbilical cord-derived MSC-derived EV (HUMSC-EV) in photoaging. Our findings indicated that in vivo, treatment with AMSC-EV and HUMSC-EV resulted in improvements in wrinkles and skin hydration while also mitigating skin inflammation and thickness alterations in both the epidermis and dermis. Additionally, in vitro studies using human keratinocytes (HaCaTs), human dermal fibroblast cells (HDFs), and T-Skin models revealed that AMSC-EV and HUMSC-EV attenuated senescence, reduced levels of reactive oxygen species (ROS) and DNA damage, and alleviated inflammation induced by UVB. Furthermore, EV treatment enhanced cell viability and migration capacity in the epidermis and promoted extracellular matrix (ECM) remodeling in the dermis in photoaged cell models. Mechanistically, proteomics results showed that TIMP1 was highly expressed in both AMSC-EV and HUMSC-EV and could exert similar effects as MSC-EV. In addition, we found that EV and TIMP1 could inhibit Notch1 and downstream targets Hes1, P16, P21, and P53. Collectively, our data suggests that both AMSC-EV and HUMSC-EV attenuate skin photoaging through TIMP1/Notch1., (© 2024. The Author(s).)

Psoriasis (Ps) is one of the most common chronic inflammatory skin disorders with its pathogenesis correlated with dysregulated innate and adaptive system. Even though biological agents have advanced the treatment of psoriasis, however, there are huge limitations, like high adverse reactions and relapse rate. Therefore, it is of great interest in searching clinical resolutions with better safety and efficacy. In the current study, we utilized the adipose-derived mesenchymal stem cell (AD-MSCs) to treat moderate/severe cases of psoriasis in a single-arm clinical study. This AD-MSC treatment has proven to be clinically safe and effective. Interestingly, a trend of adaptome improvement, including increased diversity, elevated uCDR3s and decreased large clone after AD-MSC treatment in a short (2 weeks) and long (12 weeks) terms. In conclusion, allogenic AD-MSC treatment has shown a good safety and efficacy in treating Ps and can effectively improve the compromised adaptive immune system of Ps patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The direct use of mesenchymal stem cells (MSCs) as therapeutics for skin injuries is a promising approach, yet it still faces several obstacles, including limited adhesion, retention, and engraftment of stem cells in the wound area, as well as impaired regenerative and healing functions. Here, DNA-based self-assembled composites are reported that can aid the adhesion of MSCs in skin wounds, enhance MSC viability, and accelerate wound closure and re-epithelialization. Rolling-circle amplification (RCA)-derived DNA flowers, equipped with multiple copies of cyclic Arg-Gly-Asp (cRGD) peptides and anti-von Willebrand factor (vWF) aptamers, act as robust scavengers of reactive oxygen species (ROS) and enable synergistic recognition and adhesion to stem cells and damaged vascular endothelial cells. These DNA structure-aided stem cells are retained at localized wound sites, maintain repair function, and promote angiogenesis and growth factor secretion. In both normal and diabetes-prone db/db mice models with excisional skin injuries, facile topical administration of DNA flower-MSCs elicits rapid blood vessel formation and enhances the sealing of the wound edges in a single dose. DNA composite-engineered stem cells warrant further exploration as a new strategy for the treatment of skin and tissue damage., (© 2024 Wiley‐VCH GmbH.)

The delay in wound healing caused by chronic wounds or pathological scars is a pressing issue in clinical practice, imposing significant economic and psychological burdens on patients. In particular, with the aging of the population and the increasing incidence of diseases such as diabetes, impaired wound healing is one of the growing health problems. MicroRNA (miRNA) plays a crucial role in wound healing and regulates various biological processes. Our results show that miR-618 was significantly upregulated during the inflammatory phase of wound healing.Subsequently, miR-618 promotes the secretion of pro-inflammatory cytokines and regulates the proliferation and migration of keratinocytes. Mechanistically, miR-618 binds to the target gene- Atp11b and inhibits the PI3K-Akt signaling pathway, inhibiting the epithelial-mesenchymal transition (EMT) of keratinocytes. In addition, the PI3K-Akt signaling pathway induces the enrichment of nuclear miR-618, and miR-618 binds to the promoter of Lin7a to regulate gene transcription. Intradermal injection of miR-618 antagomir around full-thickness wounds in peridermal mice effectively accelerates wound closure compared to control. In conclusion, miR-618 antagomir can be a potential therapeutic agent for wound healing.

Psoriasis is an immune-mediated, chronic, relapsing, inflammatory, systemic disease induced by individual-environmental interactions, and is often lifelong because of the difficulty of treatment. In recent years, a variety of targeted therapies, including biologics, have improved the lesions and quality of life of most psoriasis patients, but they still do not address the problem of relapse and may be associated with decreased efficacy or adverse events such as infections over time. Therefore, there is an urgent need for breakthroughs in psoriasis treatment and in relapse-delaying and non-pharmacologic strategies, and stem cell therapy for psoriasis has emerged. In recent years, research on stem cell therapy for psoriasis has received a lot of attention, however, there is no reference standard as well as consensus in this field of research. Therefore, according to the latest consensus and guidelines, combined with relevant literature reports, clinical practice experience and the results of discussions with experts, this consensus specifies the types of stem cells commonly used in the treatment of psoriasis, the methods, dosages, and routes of stem cell therapy for psoriasis, as well as the clinical evaluations (efficacy and safety) of stem cell therapy for psoriasis. In addition, this consensus also provides normative standards for the processes of collection, preparation, preservation and quality control of stem cells and their related products, as well as recommendations for the management of stem cells during infusion for the treatment of psoriasis. This consensus provides the latest specific reference standards and practice guidelines for the field of stem cell therapy for psoriasis.

Rheumatoid arthritis (RA) is an autoimmune disease that affects the living quality of patients, especially the elderly population. RA-related morbidity and mortality increase significantly with age, while current clinical drugs for RA are far from satisfactory and may have serious side effects. Therefore, the development of new drugs with higher biosafety and efficacy is demanding. Black phosphorus nanosheets (BPNSs) have been widely studied because of their excellent biocompatibility. Here, we focus on the inherent bioactivity of BPNSs, report the potential of BPNSs as a therapeutic drug for RA and elucidate the underlying therapeutic mechanism. We find that BPNSs inhibit autophagy at an early stage via the AMPK-mTOR pathway, switch the energy metabolic pathway to oxidative phosphorylation, increase intracellular ATP levels, suppress apoptosis, reduce inflammation and oxidative stress, and down-regulate senescence-associated secretory phenotype (SASP)-related genes in rheumatoid arthritis synovial fibroblasts (RA-SFs). Further, BPNSs induce the apoptosis of macrophages and promote their transition from the M1 to the M2 phenotype by regulating related cytokines. Significantly, the administration of BPNSs can alleviate key pathological features of RA in mice, revealing great therapeutic potential. This study provides a novel option for treating RA, with BPNSs emerging as a promising therapeutic candidate.

Although PD-1 inhibitors have revolutionized the treatment paradigm of non-small cell lung cancer (NSCLC), their efficacy in treating NSCLC has remained unsatisfactory. Targeting cancer-associated fibroblasts (CAFs) is a potential approach for improving the immunotherapy response. Multitarget antiangiogenic tyrosine kinase receptor inhibitors (TKIs) can enhance the efficacy of PD-1 inhibitors in NSCLC patients. However, the effects and mechanisms of antiangiogenic TKIs on CAFs have not been elucidated. In this study, we first compared anlotinib with other antiangiogenic TKIs and confirmed the superior efficacy of anlotinib. Furthermore, we established NSCLC-associated CAF models and found that anlotinib impaired CAF viability and migration capacity and contributed to CAF apoptosis and cell cycle arrest in the G2/M phase. Moreover, anlotinib treatment attenuated the capacity of CAFs to recruit lung cancer cells and macrophages. Experiments in animal models suggested that anlotinib could enhance the efficacy of anti-PD1 therapy in NSCLC and affect CAF proliferation and apoptosis. Anlotinib increased the abundance of tumor-infiltrating CD8 + T cells, and PD-1 inhibitor-induced cytotoxicity to tumor cells was achieved through the transformation of the tumor microenvironment (TME) caused by anlotinib, which may partly explain the synergistic antitumor effect of anlotinib and PD-1 inhibitors. Mechanistically, anlotinib affects CAF apoptosis and cell viability at least in part by inhibiting the AKT pathway. In conclusion, our study suggested that anlotinib could regulate the TME, inhibit the AKT pathway and promote CAF apoptosis, providing new insights into the antitumor effect of anlotinib and improving the efficacy of immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acute lung injury (ALI) is a severe inflammatory lung disease, with high mortality rates. Early intervention by reactive oxygen species (ROS) scavengers could reduce ROS accumulation, break the inflammation expansion chain in alveolar macrophages (AMs), and avoid irreversible damage to alveolar epithelial and endothelial cells. Here, we reported cell-penetrating R9 peptide-modified triangular DNA origami nanostructures (tDONs-R9) as a novel nebulizable drug that could reach the deep alveolar regions and exhibit an enhanced uptake preference of macrophages. tDONs-R9 suppressed the expression of pro-inflammatory cytokines and drove polarization toward the anti-inflammatory M2 phenotype in macrophages. In the LPS-induced ALI mouse model, treatment with nebulized tDONs-R9 alleviated the overwhelming ROS, pro-inflammatory cytokines, and neutrophil infiltration in the lungs. Our study demonstrates that tDONs-R9 has the potential for ALI treatment, and the programmable DNA origami nanostructures provide a new drug delivery platform for pulmonary disease treatment with high delivery efficiency and biosecurity.

Cellular senescence significantly affects the proliferative and differentiation capacities of mesenchymal stem cells (MSCs). Identifying key regulators of senescence and exploring potential intervention strategies, including drug-based approaches, are active areas of research. In this context, S-adenosyl-l-methionine (SAM), a critical intermediate in sulfur amino acid metabolism, emerges as a promising candidate for mitigating MSC senescence. In a hydrogen peroxide-induced MSC aging model (100 μM for 2 hours), SAM (50 and 100 μM) was revealed to alleviate the senescence of MSCs, and also attenuated the level of reactive oxygen species and enhanced the adipogenic and osteogenic differentiation in senescent MSCs. In a premature aging mouse model (subcutaneously injected with 150 mg/kg/day d-galactose in the neck and back for 7 weeks), SAM (30 mg/kg/day by gavage for 5 weeks) was shown to delay the overall aging process while increasing the number and thickness of bone trabeculae in the distal femur. Mechanistically, activation of PI3K/AKT signaling and increased phosphorylation of forkhead box O3 (FOXO3a) was proved to be associated with the antisenescence role of SAM. These findings highlight that the PI3K/AKT/FOXO3a axis in MSCs could play a crucial role in MSCs senescence and suggest that SAM may be a potential therapeutic drug for MSCs senescence and related diseases., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aging-related hypogonadism involves complex mechanisms in humans, predominantly relating to the decline of multiple hormones and senile gonads. Late-onset hypogonadism (LOH) and erectile dysfunction (ED) are the main manifestations in men, while premature ovarian insufficiency (POI) and menopause are the main forms in women. Anti-aging measures include lifestyle modification and resistance training, hormonal supplementation, stem cell therapy, metformin, and rapamycin. In this expert consensus, the mechanisms, efficacy, and side effects of stem cell therapy on aging gonadal function are reviewed. Furthermore, various methods of stem cell therapy, administered intravenously, intracavernously, and intra-ovarially, are exemplified in detail. More clinical trials on aging-related gonadal dysfunction are required to solidify the foundation of this topic.

Background: LncRNAs regulate tumorigenesis and development in a variety of cancers. We substantiate for the first time that LINC00606 is considerably expressed in glioblastoma (GBM) patient specimens and is linked with adverse prognosis. This suggests that LINC00606 may have the potential to regulate glioma genesis and progression, and that the biological functions and molecular mechanisms of LINC00606 in GBM remain largely unknown., Methods: The expression of LINC00606 and ATP11B in glioma and normal brain tissues was evaluated by qPCR, and the biological functions of the LINC00606/miR-486-3p/TCF12/ATP11B axis in GBM were verified through a series of in vitro and in vivo experiments. The molecular mechanism of LINC00606 was elucidated by immunoblotting, FISH, RNA pulldown, CHIP-qPCR, and a dual-luciferase reporter assay., Results: We demonstrated that LINC00606 promotes glioma cell proliferation, clonal expansion and migration, while reducing apoptosis levels. Mechanistically, on the one hand, LINC00606 can sponge miR-486-3p; the target gene TCF12 of miR-486-3p affects the transcriptional initiation of LINC00606, PTEN and KLLN. On the other hand, it can also regulate the PI3K/AKT signaling pathway to mediate glioma cell proliferation, migration and apoptosis by binding to ATP11B protein., Conclusions: Overall, the LINC00606/miR-486-3p/TCF12/ATP11B axis is involved in the regulation of GBM progression and plays a role in tumor regulation at transcriptional and post-transcriptional levels primarily through LINC00606 sponging miR-486-3p and targeted binding to ATP11B. Therefore, our research on the regulatory network LINC00606 could be a novel therapeutic strategy for the treatment of GBM., (© 2024. The Author(s).)

Knee osteoarthritis, a widespread degenerative condition, impacts a younger population and leads to high disability rates. Nature often provides solutions for aging and disease prevention. Mesenchymal stem cells (MSCs) and Radix Achyranthis Bidentatae (AB) are natural substances with potential. MSCs can transform into various tissues, alleviating symptoms by releasing factors and miRNA, potentially slowing osteoarthritis progression. AB's compositions target knee joint cells, enhancing internal conditions and joint function. Both MSCs and AB share mechanisms for immune regulation, reducing cartilage apoptosis, promoting chondrocyte formation, and addressing osteoporosis. They also influence estrogen and gut flora. This article reviews their roles in treating osteoarthritis, discussing apoptosis reduction, chondrocyte growth, bone enhancement, angiogenesis, and regulation of estrogen and intestinal flora. It explores their relationship and suggests AB's potential in stimulating mesenchymal stem cell repair for knee osteoarthritis treatment.

Cyaonoside A (CyA), derived from the natural Chinese medicine, Cyathula officinalis Kuan , which was for a long time used to treat knee injuries and relieve joint pain in traditional Chinese medicine, showed an unclear mechanism for protecting cartilage. In addition, CyA was poorly hydrosoluble and incapable of being injected directly into the joint cavity, which limited its clinical application. This study reveals that CyA resisted IL-1β-mediated chondrogenic inflammation and apoptosis. Next, transcriptome sequencing is used to explore the potential mechanisms underlying CyA regulation of MSC chondrogenic differentiation. Based on these findings, CyA-loaded composite hydrogel microspheres (HLC) were developed and they possessed satisfactory loading efficiency, a suitable degradation rate and good biocompatibility. HLC increased chondrogenic anabolic gene (Acan, COL2A, and SOX9) expression, while downregulating the expression of the catabolic marker MMP13 in vitro . In the osteoarthritis mouse model, HLC demonstrated promising therapeutic capabilities by protecting the integrity of articular cartilage. In conclusion, this study provides insights into the regulatory mechanisms of CyA for chondrocytes and proposes a composite hydrogel microsphere-based advanced therapeutic strategy for osteoarthritis.

Facial nerve (FN) injury seriously affects human social viability and causes a heavy economic and social burden. Although mesenchymal stem cell-derived exosomes (MSC-Exos) promise therapeutic benefits for injury repair, there has been no evaluation of the impact of MSC-Exos administration on FN repair. Herein, we explore the function of MSC-Exos in the immunomodulation of macrophages and their effects in repairing FN injury. An ultracentrifugation technique was used to separate exosomes from the MSC supernatant. Administrating MSC-Exos to SD rats via local injection after FN injury promoted axon regeneration and myelination and alleviated local and systemic inflammation. MSC-Exos facilitated M2 polarization and reduced the M1-M2 polarization ratio. miRNA sequencing of MSC-Exos and previous literature showed that the MAPK/NF-κb pathway was a downstream target of macrophage polarization. We confirmed this hypothesis both in vivo and in vitro. Our findings show that MSC-Exos are a potential candidate for treating FN injury because they may have superior benefits for FN injury recovery and can decrease inflammation by controlling the heterogeneity of macrophages, which is regulated by the p38 MAPK/NF-κb pathway.

Cellular senescence is an irreversible and multifaceted process inducing tissue dysfunction and organismal aging, and thus the clearance of senescent cells can prevent or delay the onset of aging-related pathologies. Herein, we developed an augmented photothermal therapy strategy integrated with an antibody against β2-microglobulin (aB2MG) and an immune adjuvant imiquimod (R837) to effectively accelerate senescent cell apoptosis and clearance under a near-infrared light. With this strategy, the designed CroR@aB2MG enables the targeting of senescent cells and the application of photothermal therapy concomitantly, the initiation of immune clearance subsequently, and finally the realization of protective effects against senescence. Our results showed that the photo-induced heating effect caused senescent cells to quickly undergo apoptosis and the synchronous immune response accelerated the clearance of senescent cells in vitro and in vivo. Therefore, this photoactivated speedy clearing strategy may provide an efficient way for the treatment of senescence-related diseases by eliminating senescent cells with biomaterials.

The emission of volatile organic compounds (VOCs) significantly contributes to air pollution and poses a serious threat to human health. Benzene, one of the most toxic VOCs, is difficult for the human body to metabolize and is classified as a Group 1 carcinogen. The development of efficient adsorbents for removing trace amounts of benzene from ambient air is thus of great importance. In this work, we studied the benzene adsorption properties of four Zr-based metal-organic frameworks (Zr-MOFs) through static volumetric and dynamic breakthrough experiments. Two previously reported Zr-MOFs, BUT-12 and STA-26, were prepared with a tritopic carboxylic acid ligand (H 3 L1) functionalized with three methyl groups, and STA-26 is a 2-fold interpenetrated network of BUT-12. Two new isoreticular Zr-MOFs, BUT-12-Et and STA-26-Et, were synthesized using a similar ligand, H 3 L2, where the methyl groups are replaced with ethyl groups. There are mesopores in BUT-12 and BUT-12-Et and micropores in STA-26 and STA-26-Et. The four Zr-MOFs all showed high stability in liquid water and acidic aqueous solutions. The microporous STA-26 and STA-26-Et showed much higher benzene uptakes than mesoporous BUT-12 and BUT-12-Et at room temperature under low pressures. Particularly, the benzene adsorption capacity of STA-26-Et was high up to 2.21 mmol/g at P / P 0 = 0.001 ( P 0 = 12.78 kPa), higher than those of the other three Zr-MOFs and most reported solid adsorbents. Breakthrough experiments confirmed that STA-26-Et could effectively capture trace benzene (10 ppm) from dry air; however, its benzene capture capacity was reduced by 90% under humid conditions (RH = 50%). Coating of the crystals of STA-26-Et with polydimethylsiloxane (PDMS) increased the hydrophobicity of the exterior MOF surfaces, leading to a more than 2-fold improvement in its benzene capture capacity in the breakthrough experiment under humid condition. PDMS coating of STA-26-Et likely slowed down the water adsorption process, and thus, the adsorbent afforded more efficient capture of benzene. This work demonstrates that modifying both the interior and exterior surfaces of MOFs can effectively enhance their performance in capturing trace benzene from ambient air, even under humid conditions. This finding is meaningful for the development of new adsorbents for effective air purification applications.

Background: Novel therapeutic targets are urgently needed for treating drug-resistant non-small cell lung cancer (NSCLC) and overcoming drug resistance to molecular-targeted therapies. Regulator of G protein signaling 20 (RGS20) is identified as an upregulated factor in many cancers, yet its specific role and the mechanism through which RGS20 functions in NSCLC remain unclear. Our study aimed to identify the role of RGS20 in NSCLC prognosis and delineate associated cellular and molecular pathways., Methods: Immunohistochemistry and lung cancer tissue microarray were used to verify the expression of RGS20 between NSCLC patients. CCK8 and cell cloning were conducted to determine the proliferation ability of H1299 and Anip973 cells in vitro. Furthermore, Transcriptome sequencing was performed to show enrichment genes and pathways. Immunofluorescence was used to detect the translocation changes of YAP to nucleus. Western blotting demonstrated different expressions of autophagy and the Hippo-PKA signal pathway. In vitro and in vivo experiments verified whether overexpression of RGS20 affect the proliferation and autophagy of NSCLC through regulating the Hippo pathway., Results: The higher RGS20 expression was found to be significantly correlated with a poorer five-year survival rate. Further, RGS20 accelerated cell proliferation by increasing autophagy. Transcriptomic sequencing suggested the involvement of the Hippo signaling pathway in the action of RGS20 in NSCLC. RGS20 activation reduced YAP phosphorylation and facilitated its nuclear translocation. Remarkably, inhibiting Hippo signaling with GA-017 promoted cell proliferation and activated autophagy in RGS20 knock-down cells. However, forskolin, a GPCR activator, increased YAP phosphorylation and reversed the promoting effect of RGS20 in RGS20-overexpressing cells. Lastly, in vivo experiments further confirmed role of RGS20 in aggravating tumorigenicity, as its overexpression increased NSCLC cell proliferation., Conclusion: Our findings indicate that RGS20 drives NSCLC cell proliferation by triggering autophagy via the inhibition of PKA-Hippo signaling. These insights support the role of RGS20 as a promising novel molecular marker and a target for future targeted therapies in lung cancer treatment., (© 2024. The Author(s).)

Osteoporotic fractures are the most severe complications of osteoporosis, characterized by poor bone quality, difficult realignment and fixation, slow fracture healing, and a high risk of recurrence. Clinically managing these fractures is relatively challenging, and in the context of rapid aging, they pose significant social hazards. The rapid advancement of disciplines such as biophysics and biochemistry brings new opportunities for future medical diagnosis and treatment. However, there has been limited attention to precision diagnosis and treatment strategies for osteoporotic fractures both domestically and internationally. In response to this, the Chinese Medical Association Orthopaedic Branch Youth Osteoporosis Group, Chinese Geriatrics Society Geriatric Orthopaedics Committee, Chinese Medical Doctor Association Orthopaedic Physicians Branch Youth Committee Osteoporosis Group, and Shanghai Association of Integrated Traditional Chinese and Western Medicine Osteoporosis Professional Committee have collaborated to develop this consensus. It aims to elucidate emerging technologies that may play a pivotal role in both diagnosis and treatment, advocating for clinicians to embrace interdisciplinary approaches and incorporate these new technologies into their practice. Ultimately, the goal is to improve the prognosis and quality of life for elderly patients with osteoporotic fractures.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy.

Background: Hypoxia is a pivotal factor influencing cellular gene expression and contributing to the malignant progression of tumors. Metabolic anomalies under hypoxic conditions are predominantly mediated by mitochondria. Nonetheless, the exploration of hypoxia-induced long noncoding RNAs (lncRNAs) associated with mitochondria remains largely uncharted., Methods: We established hypoxia cell models using primary human hepatocytes (PHH) and hepatocellular carcinoma (HCC) cell lines. We isolated mitochondria for high-throughput sequencing to investigate the roles of candidate lncRNAs in HCC progression. We employed in vitro and in vivo assays to evaluate the functions of solute carrier family 1 member 5 antisense lncRNA ( SLC1A5-AS ). RNA-seq was utilized to scrutinize the comprehensive genome profile regulated by SLC1A5-AS in HCC. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were utilized to validate the expression of alanine-serine-cysteine transporter 2 ( ASCT2 , encoded by the SLC1A5 gene), and a glutamine uptake assay was employed to estimate the glutamine uptake capacity of Huh-7 cells after SLC1A5-AS overexpression. To delve into the mechanisms governing the regulation of SLC1A5 expression by SLC1A5-AS , we employed a biotin-labeled SLC1A5-AS probe in conjunction with a western blot assay to confirm the interactions between SLC1A5-AS and candidate transcription factors. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were utilized to authenticate the effects of the predicted transcription factors on SLC1A5 promoter activity., Results: Following the screening, we identified CTB-147N14.6 , derived from the antisense strand of the SLC1A5 gene, which we have named SLC1A5-AS . SLC1A5-AS exhibited significantly elevated expression levels in HCC tissue and was associated with poor prognosis in HCC patients. In vitro and in vivo assays revealed that the overexpression of SLC1A5-AS significantly heightened cell invasion and metastasis. RNA-seq data unveiled SLC1A5-AS involvement in glutamine metabolism, left-handed amino (L-amino) acid transmembrane transporter activity, and the nuclear factor kappa-B (NF-κB) signaling pathway. Overexpression of SLC1A5-AS markedly increased ASCT2 mRNA/protein levels, thereby enhancing glutamine uptake and promoting the growth and metastasis of HCC cells. Mechanistically, higher RNA levels of SLC1A5-AS directly bound with myeloid zinc finger 1 ( MZF1 ), acting as a transcriptional repressor, thus diminishing its binding to the SLC1A5 promoter region., Conclusions: Our findings unveil a novel role for the lncRNA SLC1A5-AS in glutamine metabolism, suggesting that targeting SLC1A5-AS / MZF1 , in conjunction with ASCT2 inhibitor treatment, could be a potential therapeutic strategy for this disease.

Mesenchymal stem cells (MSCs) play an essential role in multiple physiological processes in vivo and a promising cell-based therapy for various diseases. Nonetheless, MSCs suffer from senescence with expansion culture, leading to a limitation for their clinical application. Recently, it was reported that small extracellular vesicles (sEVs) are involved in regulation of senescence in tumor cells and fibroblasts. However, the biological roles of sEVs in senescent MSCs (Sen MSCs) are poorly understood. In this study, we established a replicative senescence model of MSCs by successive passages and compared the phenotypic changes between presenescent MSCs (Pre-Sen MSCs) and Sen MSCs and found that Sen MSCs exhibited a diminished adipogenic and osteogenic differentiation potential and elevated senescence-associated secretory phenotype levels. In addition, we found that sEV secretion was increased in Sen MSCs, and inhibition of sEV secretion led to apoptosis, DNA damage, and decreased cell viability, suggesting that increased sEV secretion plays an important role in maintaining Sen MSC homeostasis. To further investigate the molecular mechanisms, metabolomic profiling of Pre-Sen MSC-derived sEVs (Pre-Sen-sEVs) and Sen MSC-derived sEVs (Sen-sEVs) was performed. The results showed that lipid metabolites were significantly increased in Sen-sEVs and these significantly upregulated lipid metabolites were shown to be toxic for inducing cellular senescence and apoptosis in previous studies. Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment of differential metabolites between Pre-Sen-sEVs and Sen-sEVs mainly in 25 signaling pathways, of which 21 metabolic pathways have been shown to be closely associated with senescence. Taken together, our findings suggested that increased sEV secretion maintains Sen MSC homeostasis, at least in part, by excreting harmful lipids, thus providing new insights into the regulation of senescence by sEVs.

Propyne/propylene separation is important in the petrochemical industry but challenging due to their similar physical properties and close molecular sizes. Metal-organic frameworks (MOFs) are a class of promising adsorbents for light hydrocarbon separations. Among them, the so-called "flexible-robust" MOFs combine the advantages of flexibility and rigidity in structure and could show enhanced gas separation selectivity as well as improved gas uptake at low pressure. Interpenetrated MOFs offer a platform to explore the "flexible-robust" feature of MOFs based on their subnetwork displacement in the process of gas adsorption. Herein, we present two hydrolytically stable MOFs ( BUT-308 and BUT-309 ) with interpenetrated structures and fascinating propyne/propylene separation performance. BUT-308 is composed of interpenetrated 2D Cu(BDC-NH 2 )BPB layers (H 2 BDC-NH 2 = 2-aminobenzene-1,4-dicarboxylic acid; BPB = 1,4-bis(4-pyridyl)benzene), while BUT-309 consists of twofold interpenetrated 3D pillared-layer Cu 2 (BDC-NH 2 ) 2 (BPB-CF 3 ) nets (BPB-CF 3 = 2-trifluoromethyl-1,4-bis(4-pyridyl)benzene). Gas adsorption measurements showed that BUT-309 was a "flexible-robust" adsorbent with multistep adsorption isotherms for C 3 H 4 rather than C 3 H 6 at a wide temperature range. The guest-dependent pore-opening behavior endows BUT-309 with high potential in the C 3 H 4 /C 3 H 6 separation. The C 3 H 4 adsorption measurements of BUT-309 at 273-323 K showed that the lowering of the temperature induced the pore-opening action at lower pressure. Column breakthrough experiments further confirmed the capability of BUT-309 for the efficient removal of C 3 H 4 from a C 3 H 4 /C 3 H 6 binary gas, and the C 3 H 6 processing capacity at 273 K (15.7 cm 3 g -1 ) was higher than that at 298 K (35.2 cm 3 g -1 ). This work shows a rare example of "flexible-robust" MOFs and demonstrated its high potential for C 3 H 4 /C 3 H 6 separation.

The senescence of mesenchymal stem cells (MSCs) impairs their regenerative capacity to maintain tissue homeostasis. Numerous studies are focusing on the interventions and mechanisms to attenuate the senescence of MSCs. C-phycocyanin (C-PC) is reported to have multiple functions such as antitumor, antioxidation, anti-inflammation and anti-aging roles, but there is little research about the effects of C-PC on the senescence of MSCs. Here we investigated the roles and mechanism of C-PC on MSCs senescence. In vitro results showed that C-PC could reduce senescence, enhance proliferation, promote the adipogenic and osteogenic differentiation in senescent MSCs induced by oxidative stress. In vivo D-Galactose (D-Gal) induced rats aging models showed C-PC also increased the viability and differentiation of intrinsic senescent bone marrow derived MSCs (BMSCs). Furthermore, C-PC also decreased the levels of oxidative stress markers ROS or MDA, elevated the SOD activity, and increased the anti-inflammatory factors. Proteomic chip analysis showed that C-PC interacted with ZDHHC5, and their interaction was verified by pull down assay. Overexpression of ZDHHC5 aggravated the senescence of MSCs and greatly lessened the beneficial effects of C-PC on senescence. In addition, we found ZDHHC5 regulated autophagy by altering LC3, Beclin1 and PI3K/AKT/mTOR pathway. In summary, our data indicated that C-PC ameliorates the senescence of MSCs through zinc finger Asp-His-His-Cys (DHHC) domain-containing protein 5 (ZDHHC5) mediated autophagy via PI3K/AKT/mTOR pathway. The present study uncovered the key role of autophagy in MSCs senescence and PI3K/AKT/mTOR pathway may be a potential target for anti-senescence studies of MSCs.

Background: Alzheimer's disease (AD) is a common neurodegenerative disorder that has a multi-step disease progression. Differences between moderate and advanced stages of AD have not yet been fully characterized., Materials and Methods: Herein, we performed a transcript-resolution analysis in 454 AD-related samples, including 145 non-demented control, 140 asymptomatic AD (AsymAD), and 169 AD samples. We comparatively characterized the transcriptome dysregulation in AsymAD and AD samples at transcript level., Results: We identified 4,056 and 1,200 differentially spliced alternative splicing events (ASEs) that might play roles in the disease progression of AsymAD and AD, respectively. Our further analysis revealed 287 and 222 isoform switching events in AsymAD and AD, respectively. In particular, a total of 163 and 119 transcripts showed increased usage, while 124 and 103 transcripts exhibited decreased usage in AsymAD and AD, respectively. For example, gene APOA2 showed no expression changes between AD and non-demented control samples, but expressed higher proportion of transcript ENST00000367990.3 and lower proportion of transcript ENST00000463812.1 in AD compared to non-demented control samples. Furthermore, we constructed RNA binding protein (RBP)-ASE regulatory networks to reveal potential RBP-mediated isoform switch in AsymAD and AD., Conclusion: In summary, our study provided transcript-resolution insights into the transcriptome disturbance of AsymAD and AD, which will promote the discovery of early diagnosis biomarkers and the development of new therapeutic strategies for patients with AD., 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 Wu, Wang, Hu, Zhuang, Zhou, Wu, Li and Zhao.)

Biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC) with NF2 gene mutations is a newly described provisional category of renal cell carcinoma (RCC). Here we described three additional cases of BHP RCC with CYP2A6 gene mutation besides NF2 gene. The carcinomas were predominantly unencapsulated, and two of them had a rounded, nodular interface with the native kidney while one had perirenal adipose tissue invasion. Histopathologically, all neoplasms had a characteristic biphasic appearance of smaller cells clustering around basement membrane material within larger acini, forming pseudorosettes or a glomeruloid pattern. The smaller cells were focally spindle-shaped in two carcinomas. Psammoma bodies were shown in two carcinomas. Cellular necrosis and perineural invasion was identified in one case. Immunohistochemically, Vimentin, EMA, P504s were extensively expressed while RCC and CD10 were only expressed in larger cells. CK7 was positive in one tumor. CYP2A6 gene mutation (CYP2A6 NM_000762.6: exon4:c.A580G:p.K194E) was revealed in three tumors by Whole-genome exome sequencing, which was further confirmed by Sanger sequencing. Only one case harbored a somatic termination mutation in NF2 gene. NF2 promoter methylation was observed in the other two cases. Clinically, one patient died of disease with widespread bone metastases confirmed by biopsy at the ninth month after surgery but the other two patients had no evidence of recurrence or metastases (follow-up period 9-90 months). Our findings validated previously described clinicopathological features and NF2 gene mutation or promoter methylation of BHP RCC. In addition, we reported different IHC pattern of BHP RCC and further revealed the recurrent CYP2A6 genetic alteration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Purpose: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI)., Patients and Methods: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety., Results: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups., Conclusion: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

Adult-derived mesenchymal stem cells (MSCs) can be used in therapies for the treatment of various diseases. The MSCs derived from aging tissues or long-term MSC cultures could have diminished therapeutic effects compared with MSCs derived from younger tissues, but the underlying mechanism has not been completely established. Dysfunction of energy metabolism is one of the main mechanisms underlying cell senescence. Although cyclic adenosine monophosphate (cAMP) is known to inhibit cell division and proliferation in vitro, its impact on MSC senescence has not been described. In this study, we used forskolin, an adenylate cyclase agonist and cAMP inducer, to disrupt metabolism in human adipose-derived MSCs and investigate the effects of metabolic dysfunction on MSC senescence. Treatment of human MSCs with forskolin resulted in senescence phenotypes, including reduced proliferation, cell-cycle arrest, and enhanced expression of the cell aging markers p16 and p21. Further, the senescent MSCs exhibited increased adipogenesis capacity and decreased osteogenesis capacity as well as a senescence-associated secretory phenotype characterized by increased expression of several inflammatory factors. Forskolin-associated MSC senescence was mainly caused by oxidative stress-induced disruption of mitochondrial metabolism, and the senescent MSCs had high levels of reactive oxygen species and reduced sirtuin gene expression. Lastly, we found that cAMP inhibitor SQ22536 protects MSCs from forskolin-induced senescence and senescence-related inflammatory phenotype. Our results indicate that forskolin can cause senescence of human MSCs through oxidative stress-induced mitochondrial metabolic dysfunction, and thus the results provide a basis for developing strategies for improving the quality and efficacy of cultured MSCs for clinical use.

Declining global DNA methylation and cognitive impairment are reported to occur in the normal aging process. It is not known if DNA methylation plays a role in the efficacy of memory-enhancing therapies. In this study, aged animals were administered prelimbic cortical deep brain stimulation (PrL DBS) and/or L-methionine (MET) treatment. We found that PrL DBS and MET (MET-PrL DBS) co-administration resulted in hippocampal-dependent spatial memory enhancements in aged animals. Molecular data suggested MET-PrL DBS induced DNA methyltransferase DNMT3a-dependent methylation, robust synergistic upregulation of neuroplasticity-related genes, and simultaneous inhibition of the memory-suppressing gene calcineurin in the hippocampus. We further found that MET-PrL DBS also activated the PKA-CaMKIIα-BDNF pathway, increased hippocampal neurogenesis, and enhanced dopaminergic and serotonergic neurotransmission. We next inhibited the activity of DNA methyltransferase (DNMT) by RG108 infusion in the hippocampus of young animals to establish a causal relationship between DNMT activity and the effects of PrL DBS. Hippocampal DNMT inhibition in young animals was sufficient to recapitulate the behavioral deficits observed in aged animals and abolished the memory-enhancing and molecular effects of PrL DBS. Our findings implicate hippocampal DNMT as a therapeutic target for PrL DBS and pave way for the potential use of non-invasive neuromodulation modalities against dementia., Competing Interests: Competing interests The authors declare no competing financial interests., (copyright: © 2022 Poon et al.)

Senescence is a cellular response characterized by cells irreversibly stopping dividing and entering a state of permanent growth arrest. One of the underlying pathophysiological causes of senescence is the oxidative stress-induced damage, indicating that eliminating the reactive oxygen and nitrogen species (RONS) may be beneficial to prevent and/or alleviate senescence. Herein, we developed ultra-small polydopamine nanoparticles (UPDA NPs) with superoxide dismutase (SOD)/catalase (CAT) enzyme-mimic activities, featuring broad-spectrum RONS-scavenging capability for inducing cytoprotective effects against RONS-mediated damage. The engineered UPDA NPs can restore senescence-related renal function, tissue homeostasis, fur density, and motor ability in mice, potentially associated with the regulation of multiple genes involved in lipid metabolism, mitochondrial function, energy homeostasis, telomerase activity, neuroprotection, and inflammatory responses. Importantly, the dietary UPDA NPs can enhance the antioxidant capacity, improve the climbing ability, and prolong the lifespan of Drosophila . Notably, UPDA NPs possess excellent biocompatibility stemming from the ultra-small size, ensuring quick clearance out of the body. These findings reveal that UPDA NPs can delay aging through reducing oxidative stress and provide a paradigm and practical strategy for treating senescence and senescence-related diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Nucleic acid drugs have the advantages of rich target selection, simple in design, good and enduring effect. They have been demonstrated to have irreplaceable superiority in brain disease treatment, while vectors are a decisive factor in therapeutic efficacy. Strict physiological barriers, such as degradation and clearance in circulation, blood-brain barrier, cellular uptake, endosome/lysosome barriers, release, obstruct the delivery of nucleic acid drugs to the brain by the vectors. Nucleic acid drugs against a single target are inefficient in treating brain diseases of complex pathogenesis. Differences between individual patients lead to severe uncertainties in brain disease treatment with nucleic acid drugs. In this Review, we briefly summarize the classification of nucleic acid drugs. Next, we discuss physiological barriers during drug delivery and universal coping strategies and introduce the application methods of these universal strategies to nucleic acid drug vectors. Subsequently, we explore nucleic acid drug-based multidrug regimens for the combination treatment of brain diseases and the construction of the corresponding vectors. In the following, we address the feasibility of patient stratification and personalized therapy through diagnostic information from medical imaging and the manner of introducing contrast agents into vectors. Finally, we take a perspective on the future feasibility and remaining challenges of vector-based integrated diagnosis and gene therapy for brain diseases., (© 2023. The Author(s).)

Background: Although autologous fat grafting is a feasible surgical technique to improve facial deformity in patients with localized scleroderma, its success is limited by the low graft retention induced by the local inflammatory environment. This study investigated the potential effect of adipose-derived stem cells (ASCs) on skin fibrosis and fat retention in a localized scleroderma mouse model., Methods: BALB/C nude mice that were induced by bleomycin to establish a localized scleroderma model were divided randomly into five groups: blank control; fat grafting; and low, moderate, and high doses of ASC-assisted fat grafting. The backs of the mice were subcutaneously injected with phosphate-buffered saline or fat, or fat with low, moderate, and high doses of ASCs (1 × 10 5 /mL, 5 × 10 5 /mL, and 25 × 10 5 /mL, respectively). The skin fibrosis and fat retention were analyzed after 1 month or 3 months, respectively., Results: Compared to the disease model group, the fat-grafting group, and the low- and moderate-dose ASC-enriched groups, the high-dose ASCs significantly attenuated skin fibrosis, inhibited the production of type III collagen and transforming growth factor-β1, increased fat graft retention, enhanced the expression of angiogenesis-related cytokines and angiogenesis, and increased the expression of adipogenesis-related cytokines., Conclusions: The results demonstrated that high-dose ASCs attenuated skin fibrosis and improved fat retention in a localized scleroderma model by reducing inflammation and by promoting angiogenesis and adipogenesis. The authors further demonstrated that ASCs enhanced adipogenesis through the AKT/ERK signaling pathway., Clinical Relevance Statement: Fat grafting has been used to treat localized scleroderma patients but with low fat retention. In this study, ASC attenuated skin fibrosis and improved fat retention in the localized scleroderma model, providing evidence for cell therapy in future application of localized scleroderma treatment., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Diabetic foot ulcer (DFU) is a multifactorial complication of diabetes, mainly manifested as infection, ulcer, or destruction of deep tissue, and there is currently no effective treatment. Several preclinical and clinical studies have proved that the transplantation of mesenchymal stem cells (MSCs) improved wound healing. In this study, we evaluated the therapeutic efficacy of human umbilical cord (hUC-MSCs) in DFU rat model. One dose of hUC-MSCs (1 × 10 6 cells) was subcutaneously injected around wounds in male Sprague-Dawley rats. Wound healing was evaluated macroscopically (wound closure) every 3 days. In addition, we measured growth factors and specific proteins [matrix metalloproteinases (MMPs)-9 and MMP-8] on Day 14 post hUC-MSC transplantation. Results showed significant differences in the wound healing kinetics of lesions that received hUC-MSCs compared to lesions that received vehicle (phosphate buffered saline; P  < 0.05). Enzyme-linked immunosorbent assay analyses indicated that MMP-9 protein contents were significantly upregulated in DFU animals, while MMP-8 was downregulated compared to the diabetic rats ( P  < 0.05). After MSC treatment, the level of MMP-9 and MMP-8 decreased and increased compared to the vehicle group, respectively. These findings suggest that hUC-MSC transplantation can ameliorate the healing process of DFU rats and a potential mechanism through which MSCs enhance DFU wound healing by decreasing MMP-9 expression and increasing MMP-8 expression. This study represents a promising opportunity to gain insight into how MSCs mediate wound healing.

Obesity is a chronic metabolic disorder characterized by the accumulation of excess fat in the body. Preventing and controlling obesity by inhibiting the adipogenic differentiation of mesenchymal stem cells (MSCs) and thereby avoiding the increase of white adipose tissue is safe and effective. Recent studies have demonstrated that Sprouty proteins (SPRYs) are involved in cell differentiation and related diseases. However, the role and mechanism of SPRY4 in MSC adipogenic differentiation remain to be explored. Here, we found that SPRY4 positively correlates with the adipogenic differentiation of human adipose-derived MSCs (hAMSCs). Via gain- and loss-of-function experiments, we demonstrated that SPRY4 promotes hAMSC adipogenesis both in vitro and in vivo. Mechanistically, SPRY4 functioned by activating the MEK-ERK1/2 pathway. Our findings provide new insights into a critical role for SPRY4 as a regulator of adipogenic differentiation, which may illuminate the underlying mechanisms of obesity and suggest the potential of SPRY4 as a novel treatment option.

Mesenchymal stromal/stem cells (MSCs) have been considered an attractive source of cytotherapy due to their promising effects on treating various diseases. Allogeneic MSCs (allo-MSCs) are extensively used in clinical trials due to their convenient preparation and credible performance. Traditionally, allo-MSCs are considered immunoprivileged with minimal immunogenicity and potent immunomodulatory capacity. However, growing evidence has suggested that allo-MSCs also induce immune response and cause rejection after transplantation, but the underlying cellular and molecular mechanisms remain to be elucidated. Here, we demonstrated that allografted MSCs upregulated MHC-II upon stimulation of IFN-γ in hepatic inflammatory environment by using mouse model of CCl 4 -induced liver injury. MHC-II upregulation enhanced the immunogenicity of allo-MSCs, leading to the activation of alloreactive T cells and rejection of allo-MSCs. However, MHC-II deficiency impaired the allogenic reactivity, thereby rescuing the loss of allo-MSCs. Mechanistically, CD4 + cytotoxic T lymphocytes (CTLs), rather than CD8 + CTLs, acted as the major effector for allo-MSC rejection. Under liver injury condition, the transplanted allo-MSCs upregulated CD80 and PD-L1, and CD8 + CTLs highly expressed CTLA-4 and PD-1, thereby inducing immune tolerance of CD8 + T cells to allo-MSCs. On the contrary, CD4 + CTLs minimally expressed CTLA-4 and PD-1; thus, they remain cytotoxic to allo-MSCs. Consequently, transplantation of MHC-II-deficient allo-MSCs substantially promoted their therapeutic effects in treating liver injury. This study revealed a novel mechanism of MSC allograft rejection mediated by CD4 + CTLs in injured liver, which provided new strategies for improving clinical performance of allo-MSCs in benefiting hepatic injury repair., Competing Interests: Conflict of Interest The authors declare that they have no conflicts of interest with the contents of this article., (copyright: © 2022 Shen et al.)

Increasing evidence has demonstrated the important roles of exosomes during pancreatic cancer development. However, the effects of pancreatic cancer exosomes (PC-exos) on adipocytes remain largely unknown. Here, we used mass-spectrometry-based lipidomics to identify lipids that were changed in adipocytes after exposure to PC-exos, and we found that triglyceride (TG) reduction was the most significant, which might be induced by increased lipolysis because the number of large lipid droplets increased while small ones decreased. Additionally, abdominal adipocytes in mice injected with PC-exos had a relatively smaller size. Mechanistically, we found that genes involved in metabolism and inflammation were up-regulated, among which increase of IL-6 was significant, and we then found IL-6 promoted lipolysis. To our knowledge, this is the first study on the lipidomics changes of adipocytes after PC-exos treatment.

The high occurrence rate and difficulties in symptom control are listed as the major problems of oral mucosal disease by medical professionals. Following the development of oral mucosal lesions, the oral microenvironment changes, immunity declines, and continuous bacterial stimulation causes wound infection. Traditional antibacterial drugs are ineffective for oral mucosal lesions. To overcome this problem, a light-responsive antibacterial hydrogel containing sustained-release BMSCs was inspired by the trauma environment in the oral cavity, which is different from that on the body surface since it mostly remains under dark conditions. In the absence of light, the hydrogel seals the wound to form a barrier, exerts a natural bacteriostatic effect, and prevents invasion by foreign bacteria. Simultaneously, mesenchymal stem cells are presented, and the released growth factors and other substances have excellent anti-inflammatory and angiogenic effects, which result in rapid repair of the damaged site. Under light conditions, after photo-induced shedding of the hydrogel, RuB 2 A exerts an antibacterial effect accompanied by degradation of the hydrogel. Results in a rat oral mucosal repair model demonstrate that DCS-RuB 2 A 2 -BMSCs could rapidly repair the oral mucosa within 4 days. Sequencing data provide ideas for further analysis of the intrinsic molecular mechanisms and signaling pathways. Taken together, our results suggest that this light-responsive antibacterial hydrogel loaded with BMSCs can be used for rapid wound repair and may advance the development of therapeutic strategies for the treatment of clinical oral mucosal defects., (© 2022 The Authors.)