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In the design of photoharvesting and photoresponsive supramolecular systems in aqueous medium, the fabrication of amphiphilic photoswitches enables a noninvasive functional response through photoirradiation. Although most aqueous supramolecular assemblies are driven by high-energy and biodamaging UV light, we have previously reported a design of amphiphilic donor-acceptor Stenhouse adducts (DASAs) controlled by white light. Herein, we present a series of DASA amphiphiles (DAs) with minor structural modifications on the alkyl linker chain length connecting the DASA motif with the hydrophilic moiety. The excellent photoswitchability in organic medium and the photoresponsiveness in aqueous medium, driven by visible light, were investigated by UV-vis absorption spectroscopy. The assembled supramolecular nanostructures were confirmed by electron microscopy, while the supramolecular packing was revealed by X-ray diffraction analysis. Upon visible-light irradiation, significant transformations of the DA geometry enabled transformations of the supramolecular assemblies on a microscopic scale, subsequently disassembling macroscopic soft scaffolds of DAs. The current work shows promising use for the fabrication of visible-light-controlled macroscopic scaffolds, offering the next generation of biomedical materials with visible-light-controlled microenvironments and future soft-robotic systems., (Copyright © 2024, Hung et al.)

Molecular motor amphiphiles have already been widely attempted for dynamic nanosystems across multiple length-scale for developments of small functional materials, including controlling macroscopic foam properties, amplifying motion as artificial molecular muscles, and serving as extracellular matrix mimicking cell scaffolds. However, limiting examples of bola-type molecular motor amphiphiles are considered for constructing macroscopic biomaterials. Herein, this work presents the designed two second generation molecular motor amphiphiles, motor bola-amphiphiles (MBAs). Aside from the photoinduced motor rotation of MBAs achieved in both organic and aqueous media, the rate of recovering thermal helix inversion step can be controlled by the rotor part with different steric hindrances. Dynamic assembled structures of MBAs are observed under (cryo)-transmission electron microscopy (TEM). This dynamicity assists MBAs in further assembling as macroscopic soft scaffolds by applying a shear-flow method. Upon photoirradiation, the phototropic bending function of MBA scaffolds is observed, demonstrating the amplification of molecular motion into macroscopic phototropic bending functions at the macroscopic length-scale. Since MBAs are confirmed with low cytotoxicity, human bone marrow-derived mesenchymal stem cells (hBM-MSCs) can grow on the surface of MBA scaffolds. These results clearly demonstrate the concept of designing MBAs for developing photoresponsive dynamic functional materials to create new-generation soft robotic systems and cell-material interfaces., (© 2024 Wiley‐VCH GmbH.)

Amphiphilic molecules functionalized with photoresponsive motifs have attractive prospects for applications in smart functional bio-material ranging from cell-material interfaces to drug delivery systems owing to the precisely controllable functionality of self-assembled hierarchical supramolecular structures in aqueous media by a non-invasive light stimulation with high temporal- and spatial-resolution. However, most of reported photoresponsive amphiphiles are triggered by bio-damaging UV-light, which greatly limits the potential in bio-related applications. Herein, we present newly designed red-light controlled N,N'-diaryl-substituted indigo amphiphiles (IA), exhibiting excellent photoswitchablity and photostability with dual red-/green-light in organic media. Meanwhile, aqueous solutions of IA assembled into supramolecular structures in both microscopic and macroscopic length-scale, though the photoresponsiveness of IA is slightly compromised in aqueous media. At macroscopic length-scale, morphological changes of IA macroscopic scaffold prepared by a shear-flow method can be fine adjusted upon red-light irradiation. Moreover, the preferential attachment of live h-MSCs to IA macroscopic scaffold surface also indicates a good biocompatibility of IA macroscopic scaffold. These results provide the potential for developing the next generation of red-light controlled soft functional materials with good biocompatibility., 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 Inc. All rights reserved.)

Gold (III) cyclometalated based amphiphiles in aqueous media have been revealed with excellent supramolecular transformations to external stimuli to open new pathways for soft functional material fabrications. Herein, we report a new chiral cyclometalated gold (III) amphiphile (GA) assembling into lamellar nanostructures in aqueous media confirmed with transmission electron microscopy (TEM). Counterion exchange with D-, L-, or racemic-camphorsulfonates features the significant supramolecular helicity enhancements, enabling transformations of GA from lamellar structure to vesicles and to nanotubes with multi-equivalents of counterion. The limited cytotoxicity of GA in aqueous media exhibits good biocompatibility., (© 2023 Wiley-VCH GmbH.)

Invited for this month's cover are the collaborating groups of Prof. Man-Kin Wong and Dr. Franco King-Chi Leung from The Hong Kong Polytechnic University. The cover picture illustrates chiral gold (III) amphiphiles assemble into tubular supramolecular structures in aqueous media through counterion controlled pathway. The nanostructures were further demonstrated with good cytocompatibility in aqueous media. More information can be found in the Research Article by Man-Kin Wong, Franco King-Chi Leung, and co-workers., (© 2024 Wiley-VCH GmbH.)

Herein, we disclose a visible-light-induced oxy-alkynylation of diazo compounds with ethynylbenziodoxolones. The efficient protocol provides a mild and metal-free methodology to synthesize propargylic esters in moderate to good yields. Notably, this metal-free carbene transfer reaction appears to involve an oxonium ylide intermediate, followed by intramolecular ligand exchange and reductive elimination.

Neuroinflammation is tightly associated with onset of depression. The nuclear receptor related 1 protein (Nurr1, also called Nr4a2), its roles in dopaminergic neurons is well understood, which can alleviate inflammation. Nevertheless, potential effects of Nr4a2 on neuroinflammation associated with depression still remains unclear. Chronic lipopolysaccharides (LPS) stress induced depressive-behaviors were confirmed via behavioral tests. Differentially expressed genes were detected by using RNA-sequencing. The anterior cingulate cortex (ACC) tissues were collected for biochemical experiments. The Golgi-Cox staining and virus labeling were used to evaluate the dendritic spines. We applied fluoxetine (FLX) and amodiaquine dihydrochloride (AQ, a highly selective agonist of Nr4a2) in mice. Overexpression experiments were performed by injecting with AAV-Nr4a2-EGFP into ACC. Chemogenetic activation of CamkII neurons via injecting the hM3Dq virus. Mice treated with LPS displayed depressive- and anxiety-like behaviors. The reduction of Nr4a2 and FosB induced by LPS were rescued by pretreatment with FLX or AQ. More importantly, LPS-induced behavior deficits in mice were also alleviated via fluoxetine treatment and pharmacological activation the expression of Nr4a2. Meanwhile, enhancing the level of Nr4a2 could improve dendritic spines loss of neuron and morphological changes in microglia. Overexpression of Nr4a2 in ACC reversed the depressive- and anxiety-like behaviors caused by LPS administration. Activation of CamkII neurons in ACC could robustly increase the expression of Nr4a2 and improve LPS-induced behavior deficits. Our findings demonstrate that the Nr4a2 may regulate depressive-like behaviors via alleviating the impairment of morphology and function on microglia and CamkII neurons induced by chronic neuroinflammation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A visible light-induced carbene reactivity of acceptor diazoalkanes has been developed for the synthesis of difunctionalized ethers from cyclic ethers and various N/O/S nucleophiles.

Oxidative stress caused by the overexpression of reactive oxygen species (ROS) plays an important role in the pathogenesis of traumatic brain injury (TBI). Accumulation of ROS can lead to cell death, neurodegeneration, and neurological deficit. Therefore, the design and application of functional materials with ROS scavenging ability is of great significance for neural repair. Herein, an injectable and antioxidant hydrogel was developed for TBI treatment based on the Schiff base reaction of gallic acid-conjugated gelatin (GGA) and oxidized dextran (Odex). The resulting GGA/Odex hydrogel could effectively scavenge DPPH and ABTS radicals, as well as protect cells from the oxidative damage in vitro. Moreover, GGA/Odex hydrogel possessed well biocompatible features. In a moderate TBI mouse model, in situ implantation of GGA 6 Odex hydrogel efficiently facilitated neurogenesis and promoted the motor, learning and memory abilities. Also, this composite hydrogel suppressed oxidative stress and inflammation via the activation of Nrf2/HO-1 pathway and the regulating of inflammatory factors secretion and macrophage/microglia polarization. Therefore, this injectable and ROS-scavenging GGA 6 Odex hydrogel is a promising biomaterial for tissue regenerative medicine, including TBI and other tissue repair relevant to raised ROS circumstance., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Engineered wound dressing materials with excellent injectability, self-healing ability, tissue-adhesiveness, especially the ones possessing potential therapeutic effects have great practical significance in healthcare. Herein, an injectable quaternary ammonium chitosan (QCS)/tannic acid (TA) hydrogel based on QCS and TA was designed and fabricated by facile mixing of the two ingredients under physiological conditions. In this system, hydrogels were mainly cross-linked by dynamic ionic bonds and hydrogen bonds between QCS and TA, which endows the hydrogel with excellent injectable, self-healing, and adhesive properties. Benefitting from the inherent antioxidative, antibacterial, and hemostatic abilities of TA and QCS, this hydrogel showed superior reactive oxygen species scavenging activity, broad-spectrum antibacterial ability, as well as rapid hemostatic capability. Moreover, the QCS/TA 2.5 hydrogel (containing 2.5% TA) exhibited excellent biocompatibility. The in vivo experiments also showed that QCS/TA 2.5 hydrogel dressing not only rapidly stopped the bleeding of arterial and deep incompressible wounds in mouse tail amputation, femoral artery hemorrhage, and liver incision models but also significantly accelerated wound healing in a full-thickness skin wound model. For the great potentials listed above, this multifunctional QCS/TA 2.5 hydrogel offers a promising network as a dressing material for both rapid hemostasis and skin wound repair.

Hydrogel-based antibacterial materials with multi-functions are of great significance for healthcare. Herein, a facile and one-step method was developed to fabricate an injectable hydrogel (named CMCS/OPC hydrogel) based on carboxymethyl chitosan (CMCS) and oligomeric procyanidin (OPC). In this hydrogel system, OPC serves as the dynamic crosslinker to bridge CMCS macromolecules mainly through dynamical hydrogen bonds, which endows this hydrogel with excellent injectable, self-healing, and adhesive abilities. In addition, due to the inherent antibacterial properties of CMCS and OPC, this hydrogel shows excellent antibacterial activity. Therefore, the well-designed CMCS/OPC hydrogel has great prospects as an antibacterial material in the biomedical field., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Infected wound healing has always been a challenge in clinic. Effective and economic wound dressings with combined antibacterial activity and pro-healing function are highly desirable, especially in the context of infected wounds. An obvious advantage of antibacterial wound dressing is to avoid the overuse of antibiotics and the occurrence of drug resistance. Herein, an injectable hyaluronic acid hydrogel with antioxidative and photothermal antibacterial activity as a functional dressing was prepared, characterized and evaluated in an experimental infected wound model. This hydrogel was developed by loading graphene oxide (GO) in a natural polymer network consisting of hyaluronic acid grafted with tyramine (HT) and gelatin grafted with gallic acid (GGA). The HT/GGA/GO hydrogels have a porous cross-linked network structure and demonstrate a good stability, biocompatibility, antioxidant, hemostatic and photothermal antibacterial activity against Escherichia coli and Staphylococcus aureus. In addition, in vivo studies have shown that HT 1 /GGA 2 /GO 0.1 hydrogel dressing combined with photothermal therapy can effectively prevent early infection and accelerate wound healing. These results indicated this functionalized injectable hydrogel HT 1 /GGA 2 /GO 0.1 has a great potential in wound dressing application., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The efficacy of neural repair and regeneration strategies for traumatic brain injury (TBI) treatment is greatly hampered by the harsh brain lesion microenvironment including oxidative stress and hyper-inflammatory response. Functionalized hydrogel with the capability of oxidative stress suppression and neuroinflammation inhibition will greatly contribute to the repairment of TBI. Herein, antioxidant gallic acid-grafted hyaluronic acid (HGA) was combined with hyaluronic acid-tyramine (HT) polymer to develop an injectable hydrogel by dual-enzymatically crosslinking method. The resulting HT/HGA hydrogel is biocompatible and possesses effective scavenging activity against DPPH and hydroxyl radicals. Meanwhile, this hydrogel improved cell viability and reduced intracellular reactive oxygen species (ROS) production under H 2 O 2 insult. The in vivo study showed that in situ injection of HT/HGA hydrogel significantly reduced malondialdehyde (MDA) production and increased glutathione (GSH) expression in lesion area after treatment for 3 or 21 days, which might be associated with the activation of Nrf2/HO-1 pathway. Furthermore, this hydrogel promoted the microglia polarization to M2 (Arg1) phenotype, it also decreased the level of proinflammatory factors including TNF-α and IL-6 and increased anti-inflammatory factor expression of IL-4. Finally, blood-brain barrier (BBB) was protected, neurogenesis in hippocampus was promoted, and the motor, learning and memory ability was enhanced. Therefore, this injectable, biocompatible, and antioxidant hydrogel exhibits a huge potential for treating TBI and allows us to recognize the great value of this novel biomaterial for remodeling brain structure and function., 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., (© 2022 The Authors.)

Multifunctional hydrogel as a sealant or wound dressing with high adhesiveness and excellent antibacterial activity is highly desirable in clinical applications. In this contribution, one-step synthetic hydrogel based on quaternized chitosan (QCS), tannic acid (TA), and ferric iron (Fe(III)) is developed for skin incision closure and Staphylococcus aureus (S. aureus)-infected wound healing. In this hydrogel system, the ionic bonds and hydrogen bonds between QCS and TA form the main backbone of hydrogel, the metal coordination bonds between TA and Fe(III) (catechol-Fe) endow hydrogel with excellent adhesiveness and (near-infrared light) NIR-responsive photothermal property, and these multiple dynamic physical crosslinks enable QCS/TA/Fe hydrogel with flexible self-healing ability and injectability. Moreover, QCS/TA/Fe hydrogel possesses superior antioxidant, anti-inflammatory, hemostasis, and biocompatibility. Also, it is safe for vital organs. The data from the mouse skin incision model and infected full-thickness skin wound model presented the high wound closure effectiveness and acceleration of the wound healing process by this multifunctional hydrogel, highlighting its great potential in wound management., (© 2021 Wiley-VCH GmbH.)

Background: NUT (nuclear protein in testis) midline carcinoma (NMC) is a rapidly progressive tumor arising from midline structures. Recent cases have reported that the poor prognosis with a median survival of 6.7 months and a 2 years overall survival of 19% due to limited treatment. Based on the effect of arotinib on inhibiting tumor growth and angiogenesis. We present one patient case treated with anlotinib and radiotherapy., Case Presentation: Here, we describe a 33-year old patient who complained of cough and chest pain and was diagnosed as a pulmonary NMC through CT scan, FISH and immunohistochemistry. In addition, we initially demonstrated that anlotinib combined with palliative radiotherapy could significantly prevent the tumor growth in a pulmonary NMC., Conclusion: The report indicated that anlotinib combined with palliative radiotherapy could inhibit the tumor progression in a pulmonary NMC, which may provide a combined therapy to pulmonary NMC in the future., (© 2021. The Author(s).)

Injectable hydrogel has the advantage to fill the defective area and thereby shows promise as therapeutic implant or cell/drug delivery vehicle for tissue repair. In this study, an injectable hyaluronic acid hydrogel in situ dual-enzymatically cross-linked by galactose oxidase (GalOx) and horseradish peroxidase (HRP) was synthesized and optimized, and the therapeutic effect of this hydrogel encapsulated with bone mesenchymal stem cells (BMSC) and nerve growth factors (NGF) for traumatic brain injury (TBI) mice was investigated. Results from in vitro experiments showed that either tyramine-modified hyaluronic acid hydrogels (HT) or NGF loaded HT hydrogels (HT/NGF) possessed good biocompatibility. More importantly, the HT hydrogels loaded with BMSC and NGF could facilitate the survival and proliferation of endogenous neural cells probably by neurotrophic factors release and neuroinflammation regulation, and consequently improved the neurological function recovery and accelerated the repair process in a C57BL/6 TBI mice model. All these findings highlight that this injectable, BMSC and NGF-laden HT hydrogel has enormous potential for TBI and other tissue repair therapy., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors.)

Hydrogels have gained a niche in the market as wound dressings due to their high water content and plasticity. However, traditional hydrogel wound dressings are difficult to fully adapt to irregular-shaped wound areas. Additionally, excessive reactive oxygen species (ROS) accumulated in the damaged area impede the wound healing process. Therefore, hydrogels with injectable and antioxidant properties offer promising qualities for wound healing, but their design and development remain challenges. In this study, HT/QGA (tyramine-grafted hyaluronic acid/gallic acid-grafted quaternized chitosan) hydrogels with injectable and antioxidant properties were prepared and characterized. This hydrogel exhibited excellent injectability, favorable antioxidant activity, and good biocompatibility. Moreover, we evaluated the therapeutic effect of HT/QGA hydrogel in a full-thickness skin injury model. These results suggested that HT/QGA hydrogel may offer a great potential application in wound healing.

Brain inflammation induced by ischemic stroke is an important cause of secondary brain injury. The nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and NLRP3 inflammasome signaling are believed to drive the progression of brain inflammation. Spermatogenesis-associated protein2 (SPATA2) functions as a partner protein that recruits CYLD, a negative regulator of NF-κB signaling, to signaling complexes. However, the role of SPATA2 in the central nervous system remains unclear and whether it is involved in regulating inflammatory responses remains controversial. Rats were subjected to transient middle cerebral artery occlusion followed by reperfusion (tMCAO/R) surgery. The expression and localization of SPATA2 in the brain were investigated. The lentivirus-mediated shRNA was employed to inhibit SPATA2 expression. The inflammatory responses and outcomes of Spata2 knockdown were investigated. SPATA2 was co-localized with CYLD in neurons. SPATA2 expression was reduced in tMCAO/R rats. Spata2 knockdown resulted in increased microglia, increased expression of Tnfa, Il-1β, and Il-18, decreased Garcia score, and increased infarct volume. Spata2 knockdown resulted in the activation of P38MAPK and NLRP3 inflammasome and the increased activation of NF-κB signaling. These results suggest that SPATA2 plays a protective role against brain inflammation induced by ischemia/reperfusion injury. Therefore, SPATA2 could be a potential therapeutic target for treating ischemic stroke., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Activated microglia are polarized into the M1 or M2 phenotype. We previously reported that electroacupuncture (EA) effectively prevented nuclear factor-κB (NF-κB) nuclear translocation and improved neuronal C-X-C motif 3 chemokine ligand 1 (CX3CL1) expression, repressing microglial activation by upregulating neuronal cylindromatosis (CYLD) expression in the periischemic cortex. However, the potential mechanisms are unclear. Therefore, we explored whether EA improved CYLD protein expression to regulate microglial polarization-mediated neuroinflammation and the potential mechanisms in an ischemic stroke model., Methods: A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in male Sprague-Dawley (SD) rats. The rats were treated with EA at the Baihui, Hegu and Taichong acupoints once daily beginning 2 h after focal cerebral ischemia. CYLD gene interference was used to investigate the role of CYLD in microglial polarization. We used neurobehavioral evaluations and TTC staining to examine the neuroprotective effect of EA via CYLD upregulation. Immunofluorescence and RT-qPCR were used to measure NLRP3 activation, M1/M2 microglial activation, pro-/anti-inflammatory gene mRNA expression and crosstalk (CX3CL1/CX3CR1 axis) between neurons and microglia. Western blotting was used to assess the underlying molecular mechanism., Results: CYLD inhibited M1 microglial activation and improved M2 microglial activation after 72 h of reperfusion. CYLD overexpression decreased the NLRP3 mRNA level. CYLD suppressed microglial overactivation by inhibiting NLRP3 activation. CYLD gene silencing partially weakened EA improvement of neurological function deficits and reduction of infarct volumes after 72 h reperfusion. In addition, EA inhibited M1-like phenotypic microglial activation and promoted M2-like phenotypic microglia through upregulating CYLD expression. Finally, EA-mediated modulation of the CX3CL1/CX3CR1 axis and NLRP3 inflammasome was reversed by CYLD gene silencing in the periischemic cortex., Conclusion: EA-induced upregulation of neuronal CYLD expression plays anti-inflammatory and neuroprotective roles and regulates the interaction between neurons and microglia, thereby suppressing M1 and improving M2 microglial activation in the periischemic cortex., Competing Interests: Jin Jiang is the correspondence author, and Yikun Ren is the co-correspondence author in this study. The authors report no conflicts of interest in this work., (© 2021 Lin et al.)

Background: The pathogenesis of post-stroke depression (PSD) remains largely unknown. There is growing evidence indicating that gut microbiota participates in the development of brain diseases through the gut-brain axis. Here, we aim to determine whether and how microbial composition and function altered among control, stroke and PSD rats., Materials and Methods: After the PSD rat model was successfully established, gut microbiome combined with fecal metabolome approach were performed to identify potentially PSD-related gut microbes and their functional metabolites. Then, correlations between behavior indices and altered gut microbes, as well as correlations between altered gut microbial operational taxonomic units (OTUs) with differential metabolites in PSD rats were explored. Enrichment analysis was also conducted to uncover the crucial metabolic pathways related to PSD., Results: Although there were some alterations in the microbiome and metabolism of the control and stroke rats, we found that the microbial and metabolic phenotypes of PSD rats were significantly different. The microbial composition of PSD showed a decreased species richness indices, characterized by 22 depleted OTUs mainly belonging to phylum Firmicutes , genus Blautia and Streptococcus . In addition, PSD was associated with disturbances of fecal metabolomics, among them Glutamate, Maleic acid, 5-Methyluridine, Gallocatechin, 1,5-Anhydroglucitol, L-Kynurenine, Daidzein, Cyanoalanine, Acetyl Alanine and 5-Methoxytryptamine were significantly related to disturbed gut microbiome (P ≤ 0.01). Disordered fecal metabolomics in PSD rats mainly assigned to lipid, amino acid, carbohydrate and nucleotide metabolism. The steroid biosynthesis was particularly enriched in PSD., Conclusions: Our findings suggest that gut microbiome may participate in the development of PSD, the mechanism may be related to the regulation of lipid metabolism., 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 © 2021 Jiang, Gong, Liu, Ren and Mu.)

Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence. Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.