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Cachexia, which affects 50-80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75-ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with withanone, a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention., (© 2024. The Author(s).)

Physalis pubescens and Physalis alkekengi , members of the Physalis genus, are valued for their delicious and medicinal fruits as well as their different ripened fruit colors-golden for P. pubescens and scarlet for P. alkekengi . This study aimed to elucidate the pigment composition and genetic mechanisms during fruit maturation in these species. Fruit samples were collected at four development stages, analyzed using spectrophotometry and high-performance liquid chromatography (HPLC), and complemented with transcriptome sequencing to assess gene expression related to pigment biosynthesis. β-carotene was identified as the dominant pigment in P. pubescens , contrasting with P. alkekengi , which contained both lycopene and β-carotene. The carotenoid biosynthesis pathway was central to fruit pigmentation in both species. Key genes pf02G043370 and pf06G178980 in P. pubescens , and TRINITY_DN20150_c1_g3 , TRINITY_DN10183_c0_g1 , and TRINITY_DN23805_c0_g3 in P. alkekengi were associated with carotenoid production. Notably, the MYB-related and bHLH transcription factors (TFs) regulated zeta-carotene isomerase and β-hydroxylase activities in P. pubescens with the MYB-related TF showing dual regulatory roles. In P. alkekengi , six TF families-bHLH, HSF, WRKY, M-type MADS, AP2, and NAC-were implicated in controlling carotenoid synthesis enzymes. Our findings highlight the intricate regulatory network governing pigmentation and provide insights into Physalis germplasm's genetic improvement and conservation.

A smart dendritic cell (DC)-derived whole cell cytokine (DWC) nano-regulator of TCPs was developed for tumor cytokine-immunotherapy. The DWCs were purified from activated DC-cultured media and applied as a nano-dosage form. It was found that TCPs could remodel extracellular matrices via the elimination of fibronectin and type I collagen (Col-I) in tumor tissues, as well as the inhibition of α-SMA expression in cancer associated fibroblasts (CAFs). Furthermore, after local TCP treatment, significant tumor inhibition could be achieved combined with radiotherapy., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Broad cellular components-initiated efficient chemical reactions that occur in malignant cells may contribute to exploring emerging strategies for cancer treatment. Herein, an ozonated oleogel (OG (O) ) was developed to achieve cancer ozone therapy (O 3 -T) based on intracellular Criegee's reaction. By integrating the chemo-drug, the ozone-loaded oleogel (Dox@OG (O) ) was prepared as a chemotherapeutic agent for local O 3 -T, associated with chemotherapy (CT)/radiotherapy (RT)/immunotherapy and wound healing. The in vitro results showed that, Dox@OG (O) could achieve high ozone loading efficiency and ensure its stability. This Oleogel-mediated O 3 -T could directly destroy tumor cells via intracellular Criegee's reaction occurred on cell membranes, as well as the effects of tumor microenvironment (TME) regulation by the generation of oxygen/reactive oxygen species (ROS) and depletion of glutathione (GSH). Meanwhile, under the stimulation of X-ray, an accelerated free radical's production was observed, further combined with the radio-sensitivity after TME regulation, an effective anti-tumor effect would be achieved. Further on, in vivo results demonstrated that the locally implanted Dox@OG (O) could effectively inhibit the growth of both primary and secondary tumors. Considering these results above, it will serve as inspiration for future studies investigating of O 3 -T, especially for postoperative skin diseases., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Enlightened by the great success of the drug repurposing strategy in the pharmaceutical industry, in the current study, material repurposing is proposed where the performance of carbonyl iron powder (CIP), a nutritional intervention agent of iron supplement approved by the US FDA for iron deficiency anemia in clinic, was explored in anti-cancer treatment. Besides the abnormal iron metabolic characteristics of tumors, serving as potential targets for CIP-based cancer therapy under the repurposing paradigm, the efficacy of CIP as a catalyst in the Fenton reaction, activator for dihydroartemisinin (DHA), thus increasing the chemo-sensitivity of tumors, as well as a potent agent for NIR-II photothermal therapy (PTT) was fully evaluated in an injectable alginate hydrogel form. The CIP-ALG gel caused a rapid temperature rise in the tumor site under NIR-II laser irradiation, leading to complete ablation in the primary tumor. Further, this photothermal-ablation led to the significant release of ATP, and in the bilateral tumor model, both primary tumor ablation and inhibition of secondary tumor were observed simultaneously under the synergistic tumor treatment of nutritional-photothermal therapy (NT/PTT). Thus, material repurposing was confirmed by our pioneering trial and CIP-ALG-meditated NT/PTT/immunotherapy provides a new choice for safe and efficient tumor therapy.

Objectives: The majority of esophageal squamous dysplasia (ESD) patients progress slowly, while a subset of patients can undergo recurrence rapidly or progress to invasive cancer even after proper treatment. However, the molecular mechanisms underlying these clinical observations are still largely unknown., Methods: By sequencing the genomic data of 160 clinical samples from 49 tumor-free ESD patients and 88 esophageal squamous cell carcinoma (ESCC) patients, we demonstrated lower somatic mutation and copy number alteration (CNA) burden in ESD compared with ESCC., Results: Cross-species screening and functional assays identified ACSM5 as a novel driver gene for ESD progression. Furthermore, we revealed that miR-4292 promoted ESD progression and could serve as a non-invasive diagnostic marker for ESD., Conclusions: These findings largely expanded our understanding of ESD genetics and tumorigenesis, which possessed promising significance for improving early diagnosis, reducing overtreatment, and identifying high-risk ESD patients., Competing Interests: Competing interests: Authors state no conflict of interest. Professor Qimin Zhan is a member of Medical Review editorial board and is not involved in the peer review and decision process of this article., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Herein, we introduce a novel composite hydrogel scaffold designed for addressing infectious jaw defects, a significant challenge in clinical settings caused by the inherent limited self-regenerative capacity of bone tissues. The scaffold was engineered from a blend of carboxymethyl chitosan (CMCS)/sodium alginate (SA) hydrogel (CSH), β-cyclodextrin/chlorhexidine clathrate (β-CD-CHX), and strontium-nanohydroxyapatite nanoparticles (Sr-nHA). The β-CD-CHX and Sr-nHA components were synthesized using a saturated aqueous solution and a coprecipitation method, respectively. Subsequently, these elements were encapsulated within the CSH matrix. Comprehensive characterization of the CMCS/SA/β-CD-CHX/Sr-nHA composite hydrogel scaffold via scanning electron microscopy, X-ray photoelectron spectroscopy, and Fourier-transform infrared spectroscopy validated the successful synthesis. The swelling and in vitro degradation behaviors proved that the composite hydrogel had good physical properties, while in vitro evaluations demonstrated favorable biocompatibility and osteoinductive properties. Additionally, antibacterial assessments revealed its effectiveness against common pathogens, Staphylococcus aureus and Escherichia coli . Overall, our results indicate that the CMCS/SA/β-CD-CHX/Sr-nHA composite hydrogel scaffolds exhibit significant potential for effectively treating infection-prone jaw defects., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Jaw defects, which can result from a multitude of causes, significantly affect the physical well-being and psychological health of patients. The repair of these infected defects presents a formidable challenge in the clinical and research fields, owing to their intricate and diverse nature. This study aims to develop a personalized bone tissue engineering scaffold that synergistically offers antibacterial and osteogenic properties for treating infected maxillary defects. This study engineered a novel temperature-sensitive, sustained-release hydrogel by amalgamating β-cyclodextrin (β-CD) with chlorhexidine (CHX) and a decellularized extracellular matrix (dECM). This hydrogel was further integrated with a polylactic acid (PLA)-nano hydroxyapatite (nHA) scaffold, fabricated through 3D printing, to form a multifaceted composite scaffold (nHA/PLA/dECM/β-CD-CHX). Drug release assays revealed that this composite scaffold ensures prolonged and sustained release. Bacteriological studies confirmed that the β-CD-CHX loaded scaffold exhibits persistent antibacterial efficacy, thus effectively inhibiting bacterial growth. Moreover, the scaffold demonstrated robust mechanical strength. Cellular assays validated its superior biocompatibility, attributed to dECM and nHA components, significantly enhancing the proliferation, adhesion, and osteogenic differentiation of osteogenic precursor cells (MC3T3-E1). Consequently, the nHA/PLA/dECM/β-CD-CHX composite scaffold, synthesized via 3D printing technology, shows promise in inducing bone regeneration, preventing infection, and facilitating the repair of jaw defects, positioning itself as a potential breakthrough in bone tissue engineering., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Regarded as one of the hallmarks of tumorigenesis and tumor progression, the evasion of apoptotic cell death would also account for treatment resistance or failure during cancer therapy. In this study, a Ca 2+ /Cu 2+ dual-ion "nano trap" to effectively avoid cell apoptosis evasion by synchronously inducing paraptosis together with apoptosis was successfully designed and fabricated for breast cancer treatment. In brief, disulfiram (DSF)-loaded amorphous calcium carbonate nanoparticles (NPs) were fabricated via a gas diffusion method. Further on, the Cu 2+ -tannic acid metal phenolic network was embedded onto the NPs surface by self-assembling, followed by mDSPE-PEG/lipid capping to form the DSF-loaded Ca 2+ /Cu 2+ dual-ions "nano trap". The as-prepared nanotrap would undergo acid-triggered biodegradation upon being endocytosed by tumor cells within the lysosome for Ca 2+ , Cu 2+ , and DSF releasing simultaneously. The released Ca 2+ could cause mitochondrial calcium overload and lead to hydrogen peroxide (H 2 O 2 ) overexpression. Meanwhile, Ca 2+ /reactive oxygen species-associated mitochondrial dysfunction would lead to paraptosis cell death. Most importantly, cell paraptosis could be further induced and strengthened by the toxic dithiocarbamate (DTC)-copper complexes formed by the Cu 2+ combined with the DTC, the metabolic products of DSF. Additionally, the released Cu 2+ will be reduced by intracellular glutathione to generate Cu + , which can catalyze the H 2 O 2 to produce a toxic hydroxyl radical by a Cu + -mediated Fenton-like reaction for inducing cell apoptosis. Both in vitro cellular assays and in vivo antitumor evaluations confirmed the cancer therapeutic efficiency by the dual ion nano trap. This study can broaden the cognition scope of dual-ion-mediated paraptosis together with apoptosis via a multifunctional nanoplatform.

Cancer immunotherapy has attracted considerable attention due to its advantages of persistence, targeting, and ability to kill tumor cells. However, the efficacy of tumor immunotherapy in practical applications is limited by tumor heterogeneity and complex tumor immunosuppressive microenvironments in which abundant of M2 macrophages and immune checkpoints (ICs) are present. Herein, two type-I aggregation-induced emission (AIE)-active photosensitizers with various reactive oxygen species (ROS)-generating efficiencies are designed and synthesized. Engineered extracellular vesicles (EVs) that express ICs Siglec-10 are first obtained from 4T1 tumor cells. The engineered EVs are then fused with the AIE photosensitizer-loaded lipidic nanosystem to form SEx@Fc-NPs. The ROS generated by the inner type-I AIE photosensitizer of the SEx@Fc-NPs through photodynamic therapy (PDT) can convert M2 macrophages into M1 macrophages to improve tumor immunosuppressive microenvironment. The outer EV-antigens that carry 4T1 tumor-associated antigens directly stimulate dendritic cells maturation to activate different types of tumor-specific T cells in overcoming tumor heterogeneity. In addition, blocking Siglec-10 reversed macrophage exhaustion for enhanced antitumor ability. This study presents that a combination of PDT, immune checkpoints, and EV-antigens can greatly improve the efficiency of tumor immunotherapy and is expected to serve as an emerging strategy to improve tumor immunosuppressive microenvironment and overcome immune escape., (© 2023 Wiley‐VCH GmbH.)

Hypoxia may enhance the chemoresistance of cancer cells and can significantly compromise the effectiveness of chemotherapy. Many efforts have been made to relieve or reverse hypoxia by introducing more oxygen into the tumor microenvironment (TME). Acting in a diametrically opposite way, in the current study, a novel nanocarrier was designed to further exhaust the oxygen level of the hypoxic TME. By creating such an oxygen depleted TME, the hypoxia-selective cytotoxin can work effectively, and oxygen exhaustion triggered chemotherapy can be achieved. Herein, deoxygenation agent, FDA-approved perfluorocarbon (PFC) and photosensitizer indocyanine green (ICG) for oxygen depletion, along with the hypoxia-activating drug tirapazamine (TPZ), were coincorporated within the poly(lactic- co -glycolic acid) (PLGA) nanoemulsion (ICG/TPZ@PPs) for the treatment of hypoxic tumors. Following hypoxia amplifying through physical oxygen dissolution and photodynamic depletion in tumors, hypoxic chemotherapy could be effectively activated to improve multitreatment synergy. After achieving local tumor enrichment, PFC-mediated oxygen dissolution combined with further ICG-mediated photodynamic therapy (PDT) under near-infrared (NIR) laser irradiation could induce enhanced hypoxia, which would activate the antitumor activity of codelivered TPZ to synergize cytotoxicity. Remarkably, in vivo experimental results exhibited that deoxygenated ICG/TPZ@PPs-based photothermal therapy (PTT), PDT, and hypoxia activated chemotherapy have an excellent synergistic ablation of tumors without obvious side effects, and therefore, a broad prospect of application of this nanocarrier could be expected.

Since the nonspecificity and nonselectivity of traditional treatment models lead to the difficulty of cancer treatment, nanobased strategies are needed to fill in the gaps of current approaches. Herein, a tumor microenvironment (TME)-responsive chemo-photothermal treatment model was developed based on dihydroartemisinin (DHA)-loaded conjugated polymers (DHA@PLGA-PANI). The synthesized DHA@PLGA-PANI exhibited enhanced photothermal properties under mild-acidic conditions and thus triggered local heat at the tumor site. Meanwhile, these iron-doped conjugated polymers of PLGA-PANI were used as the source of Fe, and benefiting from the Fe-dependent cytotoxicity of DHA, the burst of free radicals could be generated in tumors. Therefore, the combination of TME-responsive chemo-photothermal therapy could achieve effective tumor efficacy.

Nanoheterostructures with exquisite interface and heterostructure design find numerous applications in catalysis, plasmonics, electronics, and biomedicine. In the current study, series core-shell metal or metal oxide-based heterogeneous nanocomposite have been successfully fabricated by employing sandwiched liquid metal (LM) layer (i.e., LM oxide/LM/LM oxide) as interfacial galvanic replacement reaction environment. A self-limiting thin oxide layer, which would naturally occur at the metal-air interface under ambient conditions, could be readily delaminated onto the surface of core metal (Fe, Bi, carbonyl iron, Zn, Mo) or metal oxide (Fe 3 O 4 , Fe 2 O 3 , MoO 3 , ZrO 2 , TiO 2 ) nano- or micro-particles by van der Waals (vdW) exfoliation. Further on, the sandwiched LM layer could be formed immediately and acted as the reaction site of galvanic replacement where metals (Au, Ag, and Cu) or metal oxide (MnO 2 ) with higher reduction potential could be deposited as shell structure. Such strategy provides facile and versatile approaches to design and fabricate nanoheterostructures. As a model, nanocomposite of Fe@Sandwiched-GaIn-Au (Fe@SW-GaIn-Au) is constructed and their application in targeted magnetic resonance imaging (MRI) guided photothermal tumor ablation and chemodynamic therapy (CDT), as well as the enhanced radiotherapy (RT) against tumors, have been systematically investigated., (© 2023 Wiley-VCH GmbH.)

In clinical practice, challenges remain in the treatment of large infected bone defects. Bone tissue engineering scaffolds with good mechanical properties and antibiotic-controlled release are powerful strategies for infection treatment. In this study, we prepared polylactic acid (PLA)/nano-hydroxyapatite (nHA) scaffolds with vertical orthogonal and staggered orthogonal structures by applying 3D printing technology. In addition, vancomycin (Van)-based chitosan (CS) hydrogel (Gel@Van) was loaded on the scaffold (PLA/nHA/CS-Van) to form a local antibiotic release system. The microstructure of the composite scaffold had high porosity with interconnected three-dimensional networks. The mechanical properties of the PLA/nHA/CS-Van composite scaffold were enhanced by the addition of CS-Van. The results of the water contact angle analysis showed that the hydrophilicity of the drug-loaded scaffold improved. In addition, the composite scaffold could produce sustained release in vitro for more than 8 weeks without adverse effects on the proliferation and differentiation of mouse embryonic osteoblasts (MC3T3-E1), which confirmed its good biocompatibility. During the in vitro antimicrobial study, the composite scaffold effectively inhibited the growth of Staphylococcus aureus ( S. aureus ). Therefore, our results suggest that the PLA/nHA/CS-Van composite scaffold is a promising strategy for treating infected bone defects., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Immunogenic cell death (ICD) induced by treatment modalities like chemotherapy, radiotherapy, and photothermal and photodynamic therapy has shown great potential to improve the low response rate of various solid tumors in cancer immunotherapy. However, extensive studies have revealed that the efficacy of cancer treatment is limited by the hypoxia and immunosuppression in the tumor microenvironment (TME). To address these challenges, a hypoxia alleviated and one phototriggered thermal/dynamic nanoplatform based on MnO 2 @PDA/ICG-BSA (MPIB) is developed for oxygen (O 2 ) self-supply enhanced cancer phototherapy (PT). First, MnO 2 transfers intracellular overexpression H 2 O 2 into O 2 in the acidic TME through its catalase-like activity to improve the hypoxia and also provide O 2 for the following photodynamic therapy. Then, under single NIR-808 nm light irradiation (called the "phototherapeutic window"), excellent photothermal and photodynamic performance of the MPIB is activated for combined PT. Finally, assisted with immune adjuvant cytosine-phospho-guanine, obvious ICD and systemic antitumor immunity was elicited in PT-treated mice and demonstrated significant growth inhibition on distant tumors. This MPIB-based nanoplatform highlights the promise to overcome the limitations of hypoxia and also challenges of immunosuppressive tumor microenvironments for improved cancer immunotherapy.

Bimetallic nanozymes have been emerging as essential catalysts due to their unique physicochemical properties from the monometallics. However, the access to optimize catalytic performance is often limited by the thermodynamic immiscibility and also heterogeneity. Thus, we present a one-step coreduction strategy to prepare the miscible Cu-Pd bimetallic nanozymes with controllable shape and homogeneously alloyed structure. The homogeneity is systematically explored and luckily, the homogeneous introduction of Cu successfully endows Cu-Pd bimetallic nanozymes with enhanced Fenton-like efficiency. Density functional theory (DFT) theoretical calculation reveals that Cu-Pd bimetallic nanozymes exhibit smaller d-band center compared with Pd nanozymes. Easier adsorption of H 2 O 2 molecular contributed by the electronic structure of Cu significantly accelerate the catalytic process together with the strong repulsive interaction between H atom and Pd atom. In vitro cytotoxicity and intracellular ROS generation performance reveal the potential for in vivo biocatalysis. The strategy to construct kinetically miscible Cu-Pd bimetallic nanozymes will guide the development of bimetallic catalysts with excellent Fenton-like efficiency for biocatalytic nanomedicine., 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 Published by Elsevier Ltd.)

Porous bone scaffolds based on high-precision 3D printing technology gave recently been developed for use in bone defect repair. However, conventional scaffold materials have poor mechanical properties and low osteogenic activity, limiting their clinical use. In this study, a porous composite tissue-engineered bone scaffold was prepared using polylactic acid, nano-hydroxyapatite, and nano-magnesium oxide as raw materials for high-precision 3D printing. The composite scaffold takes full advantage of the personalized manufacturing features of 3D printers and can be used to repair complex bone defects in clinical settings. The composite scaffold combines the advantages of nano-hydroxyapatite, which improves the formability of scaffold printing, and of nano-magnesium oxide, which regulates pH during degradation and provide a good environment for cell growth. Additionally, nano-magnesium oxide and nano-hydroxyapatite have a bidirectional effect on promoting the compressive strength and osteogenic activity of the scaffolds. The prepared composite porous scaffolds based on 3D printing technology show promise for bone defect repair., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Low-dose radioresistance continues to be one of the major limitations for clinical curative treatment of cancer. Luckily, nanotechnology mediated by multifunctional nanomaterials provides potential opportunity to relieve the radioresistance via increasing the radiosensitivity of cancer cells. Herein, an ultrafast fabrication strategy is reported to prepare iron/manganese co-doped bismuth trimetallic nanoparticles (pFMBi NPs) as a multifunctional radiosensitizer for combined therapy. The bismuth matrix provides the intrinsic radiosensitization effect under the low and safe radiation dose via Auger electrons, photoelectrons, and Rayleigh scattering. Meanwhile, co-doping of iron and manganese ions endows pFMBi NPs with both the Fenton reaction property for reactive oxygen species (ROS) generation and photothermal conversion performance for heat production. Additional ROS generation enhances the radiosensitization effect by collaborating with Rayleigh scattering-mediated water radiolysis, and endogenous heat production under near-infrared 808 nm laser irradiation makes DNA more sensitive to radiation and ROS damage. Both in vitro and in vivo evaluations demonstrate the effective antitumor and radiosensitization effects via thermally aided chemodynamic/radiotreatment with a low radiation dose (6 Gy). Therefore, this work provides a potential strategy for overcoming the low-dose radioresistance in cancer therapy.

Adhesion to many kinds of surfaces, including biological tissues, is important in many fields but has been proved to be extremely challenging. Furthermore, peeling from strong adhesion is needed in many conditions, but is sometimes painful. Herein, a mussel inspired hydrogel is developed to achieve both strong adhesion and trigger-detachment. The former is actualized by electrostatic interactions, covalent bonds, and physical interpenetration, while the latter is triggered, on-demand, through combining a thixotropic supramolecular network and polymer double network. The results of the experiments show that the hydrogel can adhere to various material surfaces and tissues. Moreover, triggered by shear force, non-covalent interactions of the supramolecular network are destroyed. This adhesion can be peeled easily. The possible mechanism involved is discussed and proved. This work will bring new insight into electronic engineering and tissue repair like skin care for premature infants and burn victims., (© 2022 Wiley-VCH GmbH.)

Immunotherapy has established a new paradigm for cancer treatment and made many breakthroughs in clinical practice. However, the rarity of immune response suggests that additional intervention is necessary. In recent years, it has been reported that local tumor destruction (LTD) can cause cancer cell death and induce an immunologic response. Thus, the combination of immunotherapy and LTD methods will be a promising approach to improve immune efficiency for cancer treatment. Herein, a nanobiotechnology platform to achieve high-precision LTD for systemic cancer immunotherapy has been successfully constructed. Possessing radio-sensitizing and photothermal properties, the engineered immunoadjuvant-loaded nanoplatform, which could precisely induce radiotherapy (RT)/photothermal therapy (PTT) to eliminate local tumor and meanwhile lead to the release of tumor-derived protein antigens (TDPAs), has been facilely fabricated by commercialized SPG membrane emulsification technology. Further on, the TDPAs could be captured and form personal nanovaccines in situ to serve as both reservoirs of antigen and carriers of immunoadjuvant, which can effectively improve the immune response. The investigations suggest that the combination of RT/PTT and improved immunotherapy using adjuvant-encapsulated antigen-capturing nanoparticles holds tremendous promise in cancer treatments.

Radial glia (RG) cells that align in parallel in the embryonic brain are found to be able to guide the directed migration of neurons in response to brain injury. Therefore, biomaterials with aligned architectures are supposed to have positive effects on neural migration and neurogenic differentiation for brain injury repair that are rarely addressed, although they have been widely demonstrated in spinal cord and peripheral nerve system. Here, we present a highly biomimetic scaffold of aligned fibrin hydrogel (AFG) that mimics the oriented structure of RG fibers. Through a combination of histological, behavioral, imaging, and transcriptomic analyses, we demonstrated that transplanting the AFG scaffold into injured cortical brains promotes effective migration, differentiation, and maturation of endogenous neural stem cells, resulting in neurological functional recovery. Therefore, this study will light up a new perspective on applying an aligned scaffold to promote cortical regeneration after injury by inducing endogenous neurogenesis., (Copyright © 2021. Published by Elsevier Ltd.)

Chitosan oligosaccharide (COS), hydrolyzed and deacetylated from chitosan, has been reported to possess varieties of biological activities. Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by cognitive decline and memory loss, where oxidative stress was reported to be an overwhelming cause of the occurrence of AD. We have previously reported that COS could significantly decrease cell death, ROS generation, and lipid peroxidation, though the potential mechanism was yet to be determined. This study was designed to investigate the neuroprotective effect of COS against hydrogen peroxide (H 2 O 2 )-induced oxidative stress and apoptosis in neuronal SH-SY5Y cells. Our results indicated that COS could dose-dependently scavenge H 2 O 2 in the cell-free systems. Accordingly, COS markedly decreased H 2 O 2 -induced cell apoptosis and intracellular ROS generation, while increased antioxidant capacity in SH-SY5Y cells. Further, COS significantly reduced the expression of Bax and upregulated Bcl-2. The mRNA and protein expression levels of nuclear Nrf2, heme oxygenase 1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO1) were significantly increased upon COS treatment. Moreover, Nrf2-siRNA evidently reversed the promotive effect of COS on expression levels of HO-1 and NQO1, and ARE-driven transcriptional activity as determined by double-luciferase reporter gene assay. Besides, COS reversed H 2 O 2 -mediated increased phosphorylation of ERK1/2 and p38 MAPK. In conclusion, our findings indicate that COS could protect SH-SY5Y cells from oxidative damage and apoptosis via regulating Nrf2/ARE signaling pathway, which may provide new applications for the prevention and treatment of AD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

For the purpose of improving the quality of life and minimizing the psychological morbidity of a mastectomy, breast-conserving treatment (BCT) has become the more preferable choice in breast cancer patients. Meanwhile, tumor hypoxia has been increasingly recognized as a major deleterious factor in cancer therapies. In the current study, a novel, effective, and noninvasive magnetothermodynamic strategy based on an oxygen-independent free-radical burst for hypoxia-overcoming BCT is proposed. Radical precursor (AIPH) and iron oxide nanoparticles (IONPs) are coincorporated within the alginate (ALG) hydrogel, which is formed in situ within the tumor tissue by leveraging the cross-linking effect induced by the local physiological Ca 2+ with ALG solution. Inductive heating is mediated by IONPs under AMF exposure, and consequently, regardless of the tumor hypoxia condition, a local free-radical burst is achieved by thermal decomposition of AIPH via AMF responsivity. The combination of magnetic hyperthermia and oxygen-irrelevant free-radical production effectively enhances the in vitro cytotoxic effect and also remarkably inhibits tumor proliferation. This study provides a valuable protocol for an hypoxia-overcoming strategy and also an alternative formulation candidate for noninvasive BCT.

Tumor tissue imaging and drug release imaging are both crucial for tumor imaging and image-guided drug delivery. It is urgent to develop a multileveled tumor imaging platform to realize the multiple imaging applications. In this work, we synthesized an albumin-based fluorescence resonance energy transfer (FRET) probe Cy5/7@HSA NPs containing two near-infrared cyanine dyes (CyBI5 and CyBI7) with high FRET efficiency (97 %). Excellent brightness and efficient FRET inside Cy5/7@HSA NPs enabled high-sensitive cell imaging and tumor imaging. This unique nanoprobe imaged 4T1 tumor-bearing mice with high sensitivity (TBR = 5.2) at 24 h post-injection and the dyes penetrated the tumor interior around 4 h post-injection. The release of dyes from nanoprobes was also tracked. This result shows the strong potential of this albumin-based FRET nanoprobe as multileveled tumor imaging platform for in vivo tumor imaging, drug delivery and image-guided surgery., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cachexia, characterized by loss of skeletal muscle mass and function, is estimated to inflict the majority of patients with oesophageal squamous cell carcinoma (ESCC) and associated with their poor prognosis. However, its underlying mechanisms remain elusive. Here, we developed an ESCC-induced cachexia mouse model using human xenograft ESCC cell lines and found that ESCC-derived extracellular vesicles (EVs) containing prolyl 4-hydroxylase subunit beta (P4HB) induced apoptosis of skeletal muscle cells. We further identified that P4HB promoted apoptotic response through activating ubiquitin-dependent proteolytic pathway and regulated the stability of phosphoglycerate dehydrogenase (PHGDH) and subsequent antiapoptotic protein Bcl-2. Additionally, we proved that the P4HB inhibitor, CCF642, not only rescued apoptosis of muscle cells in vitro, but also prevented body weight loss and muscle wasting in ESCC-induced cachexia mouse model. Overall, these findings demonstrate a novel pathway for ESCC-induced muscle wasting and advocate for the development of P4HB as a potential intervention target for cachexia in patients with ESCC., Competing Interests: No potential conflicts of interest were disclosed., (© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly diseases. In our previous comprehensive genomics study, we found that family with sequence similarity 135 member B ( FAM135B ) was a novel cancer-related gene, yet its biological functions and molecular mechanisms remain unclear. In this study, we demonstrate that the protein levels of FAM135B are significantly higher in ESCC tissues than in precancerous tissues, and high expression of FAM135B correlates with poorer clinical prognosis. Ectopic expression of FAM135B promoted ESCC cell proliferation in vitro and in vivo , likely through its direct interaction with growth factor GRN, thus forming a feedforward loop with AKT/mTOR signaling. Patients with ESCC with overexpression of both FAM135B and GRN had worse prognosis; multivariate Cox model analysis indicated that high expression of both FAM135B and GRN was an independent prognostic factor for patients with ESCC. FAM135B transgenic mice bore heavier tumor burden than wild-type mice and survived a relatively shorter lifespan after 4-nitroquinoline 1-oxide treatment. In addition, serum level of GRN in transgenic mice was higher than in wild-type mice, suggesting that serum GRN levels might provide diagnostic discrimination for patients with ESCC. These findings suggest that the interaction between FAM135B and GRN plays critical roles in the regulation of ESCC progression and both FAM135B and GRN might be potential therapeutic targets and prognostic factors in ESCC. SIGNIFICANCE: These findings investigate the mechanisms of FAM135B in promoting ESCC progression and suggest new potential prognostic biomarkers and therapeutic targets in patients with ESCC., (©2020 American Association for Cancer Research.)

A series of Cu@Pd/C with different Pd contents was prepared using the galvanic reduction method to disperse Pd on the surface of Cu nanoparticles on Cu/C. The dispersion of Pd was regulated by the Cu(I) on the surface, which was introduced by pulse oxidation. The Cu 2 O did not react during the galvanic reduction process and restricted the Pd atoms to a specific area. The pulse oxidation method was demonstrated to be an effective process to control the oxidization degree of Cu on Cu/C and then to govern the dispersion of Pd. The catalysts were characterized by transmission electron microscopy (TEM), high-resolution transmission electron microscope (HRTEM), high angular annular dark field scanning TEM (HAADF-STEM), energy-dispersive spectroscopy (EDS) mapping, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), auger electron spectroscopy (AES), and inductively coupled plasma optical emission spectrometer (ICP-OES), which were used to catalyze the hydrogen evolution from ammonia borane. The Cu@Pd/C had much higher activity than the PdCu/C, which was prepared by the impregnation method. The TOF increased as the Cu 2 O in Cu/C used for the preparation of Cu@Pd/C increased, and the maximum TOF was 465 mol H2 min -1 mol Pd -1 at 298 K on Cu@Pd 0.5 /C-640 (0.5 wt % of Pd, 640 mL of air was pulsed during the preparation of Cu/C-640). The activity could be maintained in five continuous processes, showing the strong stability of the catalysts.

Cadmium (Cd) is an important toxic chemical due to its increasing levels in the environment and bioaccumulation in humans and animals. The present study was performed to evaluate the effects of long-term exposure to 1, 10, or 100 μg/L Cd in drinking water on the development, reproduction and neurotoxicity of offspring when administered to mice from parental puberty to postnatal 10 weeks in offspring. The development parameters measured in offspring included physical development, reflex ontogeny, body weight and body size. The reproductive indices measured consisted of anogenital distances (AGDs), estrous cycle, sperm quality, specific gene expression in Leydig or Sertoli cells, seminiferous epithelium cycle, sex hormone levels, histological morphology and apoptosis in testis or ovary, and the levels of oxidative stress. The determination of neurotoxicity included learning and memory ability, anxiety, and related serum indicators. In addition, blood lipid level, liver and kidney function were also determined by serum biochemical assays. The results showed that exposure to Cd in the present model had no adverse effects on development, but had some reproductive toxicity and neurotoxicity, including alteration of spermatogenic epithelial staging in testis and inducing anxiety in offspring. Furthermore, the levels of total protein, globulins, total bile acid and direct bilirubin were also significantly altered, especially in female offspring. The present study suggested that long-term exposure to low doses of Cd had adverse effects on the health of the next generation, and some harmful effects showed gender differences in offspring. The present study demonstrated that attention should be paid to Cd pollution in the environment, especially before pregnancy., (Copyright © 2019. Published by Elsevier B.V.)

N , N -Dimethylformamide hydrochloric acid/XMCl n ([HDMF]Cl/XMCl n , M = Zn or Fe, n = 2 or 3) was synthesized by stirring the mixture of [HDMF]Cl and metal chloride. [HDMF]Cl-based DES was characterized by FT-IR spectroscopy, ESI-MS and 1 H-NMR spectroscopy. The oxidative desulfurization activity was investigated using [HDMF]Cl/0.2FeCl 3 and [HDMF]Cl/ZnCl 2 as the extractant and catalyst, and hydrogen peroxide (H 2 O 2 ) as the oxidant. The desulfurization rate can reach up to 98.08% and 99.2% for DBT using [HDMF]Cl/0.2FeCl 3 and [HDMF]Cl/ZnCl 2 , respectively. After recycling for 7 times, the removal rate of DBT still can reach more than 97%., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Importance: Nomogram prognostic models can facilitate cancer patient treatment plans and patient enrollment in clinical trials., Objective: The primary objective is to provide an updated and accurate prognostic model for predicting the survival of advanced non-small-cell lung cancer (NSCLC) patients, and the secondary objective is to validate a published nomogram prognostic model for NSCLC using an independent patient cohort., Design: 1817 patients with advanced NSCLC from the control arms of 4 Phase III randomized clinical trials were included in this study. Data from 524 NSCLC patients from one of these trials were used to validate a previously published nomogram and then used to develop an updated nomogram. Patients from the other 3 trials were used as independent validation cohorts of the new nomogram. The prognostic performances were comprehensively evaluated using hazard ratios, integrated area under the curve (AUC), concordance index, and calibration plots., Setting: General community., Main Outcome: A nomogram model was developed to predict overall survival in NSCLC patients., Results: We demonstrated the prognostic power of the previously published model in an independent cohort. The updated prognostic model contains the following variables: sex, histology, performance status, liver metastasis, hemoglobin level, white blood cell counts, peritoneal metastasis, skin metastasis, and lymphocyte percentage. This model was validated using various evaluation criteria on the 3 independent cohorts with heterogeneous NSCLC populations. In the SUN1087 patient cohort, the continuous risk score output by the nomogram achieved an integrated area under the receiver operating characteristics (ROC) curve of 0.83, a log-rank P -value of 3.87e-11, and a concordance index of 0.717. In the SAVEONCO patient cohort, the integrated area under the ROC curve was 0.755, the log-rank P -value was 4.94e-6 and the concordance index was 0.678. In the VITAL patient cohort, the integrated area under the ROC curve was 0.723, the log-rank P -value was 1.36e-11, and the concordance index was 0.654. We implemented the proposed nomogram and several previously published prognostic models on an online Web server for easy user access., Conclusions: This nomogram model based on basic clinical features and routine lab testing predicts individual survival probabilities for advanced NSCLC and exhibits cross-study robustness., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background/aims: The effects of exposure to radiofrequency electromagnetic fields (RF-EMFs) on the male reproductive system have raised public concern and studies have shown that exposure to RF-EMFs can induce DNA damage and autophagy. However, there are no related reports on the role of autophagy in DNA damage in spermatocytes, especially after exposure to RF-EMFs. The aim of the present study was to determine the mechanism and role of autophagy induced by RF-EMFs in spermatozoa cells., Methods: Mouse spermatocyte-derived cells (GC-2) were exposed to RF-EMFs 4 W/kg for 24 h. The level of reactive oxygen species (ROS) was determined by ROS assay kit. Comet assay was utilized to detect DNA damage. Autophagy was detected by three indicators: LC3II/LC3I, autophagic vacuoles, and GFP-LC3 dots, which were measured by western blot, transmission electron microscopy, and transfection with GFP-LC3, respectively. The expression of the molecular signaling pathway AMP-activated protein kinase (AMPK)/mTOR was determined by western blot., Results: The results showed that RF-EMFs induced autophagy and DNA damage in GC-2 cells via ROS generation, and the autophagy signaling pathway AMPK/mTOR was activated by ROS generation. Furthermore, following inhibition of autophagy by knockdown of AMPKα, increased DNA damage was observed in GC-2 cells following RF-EMFs exposure, and overexpression of AMPKα promoted autophagy and attenuated DNA damage., Conclusions: These findings demonstrated that the autophagy which was induced by RF-EMFs via the AMPK/mTOR signaling pathway could prevent DNA damage in spermatozoa cells., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

The protein α-hemolysin (α-HL) is a self-assembling exotoxin that binds to the membrane of a susceptible host cell. In this paper, experimental studies show that cyrtominetin (CTM) can inhibit the hemolytic activity of α-HL. To understand how CTM can affect hemolytic activity, molecular dynamics simulations were carried out for α-HL-CTM complex and these results were compared with the crystal structure of monomeric α-HL. With this approach, the analysis revealed that the inhibition of CTM involves CTM directly binding to α-HL. Due to the binding of CTM, the conformation of the critical "Loop" region was restrained. This mechanism was confirmed by the experimental data. These findings indicate that CTM hinders the lysis activity of α-HL through a novel mechanism., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

In this study, the binding of Bovine serum albumin (BSA) with three flavonoids, kaempferol-3-O-a-L-rhamnopyranosyl-(1-3)-a-L-rhamnopyranosyl-(1-6)-b-D-galacto- pyranoside (drug 1),kaempfol-7-O-rhamnosyl-3-O-rutinoside (drug 2)andkaempferide-7-O-(4"-O-acetylrhamnosyl)-3-O-ruti- noside (drug 3) is investigated by molecular docking, molecular dynamics (MD) simulation, and binding free energy calculation. The free energies are consistent with available experimental results and suggest that the binding site of BSA-drug1 is more stable than those of BSA-drug2 and BSA-drug3. The energy decomposition analysis is performed and reveals that the electrostatic interactions play an important role in the stabilization of the binding site of BSA-drug1 while the van der Waals interactions contribute largely to stabilization of the binding site of BSA-drug2 and BSA-drug3. The key residues stabilizing the binding sites of BSA-drug1, BSA-drug2 and BSA-drug3 are identified based on the residue decomposition analysis.

In this study, hemolysis, Western blot, and real-time RT-PCR assays were performed to evaluate silibinin's activity against S. aureus α-toxin secretion. In addition, live/dead cell staining and lactate dehydrogenase activity assays were introduced to examine the influence of silibinin on α-toxin-induced cell injury in human alveolar epithelial cells. Furthermore, we tested the influence of silibinin on S. aureus pneumonia in a mouse model. We show that silibinin inhibits the expression of α-toxin in a dose-dependent manner and alleviates α-toxin-induced lung cell injury. The IC50 of silibinin that inhibits the hemolytic activity of S. aureus was 14.33 µg/mL for strain 8325-4. Moreover, this compound provides effective protection on the lung injury of staphylococcal pneumonia., (Georg Thieme Verlag KG Stuttgart · New York.)