Search

For most well-known companies, in addition to the pursuit of brand sales, brands also focus on brand culture and brand image building so that a company can be sustainable in development and gain a competitive advantage. For sports brands, showing themselves in significant events is a moment that can reflect their brand image. The Olympic Games are arguably the most important among many sporting events. This article focuses on the strategies adopted by Chinese sports brands during the Olympics and how to maximize the benefits of the Olympics for their brands. Through the analysis of different case studies, we find that the Olympics is an excellent marketing opportunity for Chinese sports brands to promote their products, increase their sales, build their brand image, and make their brands more visible to more people. At the same time, they also found the limitations of marketing with the help of the Olympic Games, which may need external help to solve or internal self-coordination of the company.

Fried Mugil cephalus was investigated under optimal vacuum and atmospheric conditions. The water distribution, texture, and color properties of vacuum-fried samples were enhanced compared with atmospheric-fried samples. Meanwhile, vacuum frying (VF) reduced the total oil content, protein oxidation, and degradation. The molecular weight and amino acid content suggested that protein was well-preserved during VF. In addition, the total carbonyl, free thiol groups, thiobarbituric acid reactive substances (TBARS), and Schiff base values were all significantly improved by the VF method compared to atmospheric frying (AF). VF inhibited the shift of amide bands to a higher frequency and the disordering of protein secondary structure. The sample surface morphology shrank under vacuum conditions, likely resulting in the lower fat content of vacuum-fried M. cephalus. Thus, VF improved the quality, water distribution, and microstructure and decreased the protein oxidation and degradation of M. cephalus and was considered a potential method for frying processing.

Runjie Sun,1 Jiang Liu,2 Manya Yu,1 Mengting Xia,3 Yanyu Zhang,1 Xiaoqi Sun,1 Yunsheng Xu,4 Xing Cui4 1College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 2Department of Foreign Affairs Office, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 3First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 4Second School of Clinical Medicine, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, People’s Republic of ChinaCorrespondence: Yunsheng Xu; Xing Cui, Second School of Clinical Medicine, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 1 Jingba Road, Jinan, 250001, People’s Republic of China, Email xys65@126.com; cdz45@foxmail.comBackground: Bortezomib-induced peripheral neuropathy (BiPN) is a common complication of multiple myeloma (MM) treatment that seriously affects the quality of life of patients. The purpose of the present study was to explore the therapeutic effect of paeoniflorin on BiPN and its possible mechanism.Methods: ELISA was used to measure the level of interleukin-6 (IL6) in the plasma of MM patients, and bioinformatics analysis was used to predict the mechanism underlying the effect of paeoniflorin on peripheral neuropathy. Cell and animal models of BiPN were constructed to evaluate mitochondrial function by measuring cell viability and mitochondrial quality and labeling mitochondria with MitoTracker Green. Nerve injury in mice with BiPN was assessed by behavioral tests, evaluation of motor nerve conduction velocity, hematoxylin-eosin (HE) staining, electron microscopy and analysis of the levels of reactive oxygen species (ROS). Western blotting and immunohistochemistry (IHC) were used to assess the expression of autophagy-related proteins.Results: In MM patients, IL6 levels were positively correlated with the degree of PN. The results of bioinformatics analysis suggested that paeoniflorin ameliorated PN by altering inflammation levels and mitochondrial autophagy. Paeoniflorin increased PC12 cell viability and mitochondrial autophagy levels, alleviated mitochondrial damage, and reduced IL6 levels. In addition, paeoniflorin effectively improved the behavior of mice with BiPN, relieved sciatic nerve injury in mice, increased the expression of LC3II/I, beclin-1, and Parkin in sciatic nerve cells, and increased the expression of LC3B and Parkin in the nerve tissue.Conclusion: The present study confirmed that paeoniflorin significantly ameliorated peripheral neuropathy (PN) caused by bortezomib, possibly by reducing IL6 levels to regulate PARKIN-mediated mitochondrial autophagy and mitochondrial damage.Keywords: multiple myeloma, paeoniflorin, peripheral neuropathy, mitochondria, autophagy

Background Skin cutaneous melanoma (SKCM) is an extremely malignant tumor and accounts for the majority of skin cancer deaths. Aspartate beta-hydroxylase domain containing 1 (ASPHD1) may participate in cancer progression through controlling α-ketoglutarate-dependent dioxygenases. However, its role in skin cutaneous melanoma (SKCM) has not been well studied. Methods The gene expression data of ASPDH1 and differentially expressed genes (DEGs) from TCGA and GTEx were evaluated, and verified via the GEO database. Then, we performed GO/KEGG, GSEA, PPI network analysis to analyze the functional implications of the DEGs related to ASPHD1. Then, the association between the ASPHD1 expression and clinical parameters was investigated by Cox regression analysis. Subsequently, the survival time of SKCM patients was evaluated by plotting Kaplan-Meier curves. Moreover, we investigated the correlation between the ASPHD1 expression and lymphocytic infiltration by using the data from TISIDB and TIMER 2.0. Next, we explored the association between ASPHD1 expression and drug sensitivity. Finally, we validate the expression differences by analyzing the results of qPCR, Western blot from human normal epidermal melanocytes and melanoma cells, and immunohistochemistry (IHC) from non-tumor skin as well as melanoma tissues. Results The ASPHD1 expression level was significantly upregulated in several cancers, including SKCM especially SKCM-metastasis tissues, and patients with an increased ASPHD1 expression had longer overall survival time than low expression ones. The functional enrichment analysis of ASPHD1-related DEGs showed an association with cell development regulation and tumorigenic pathways. Furthermore, the increased ASPHD1 expression level was associated with the level of immunostimulors, immunoinhibitors, chemokines, and TILs, such as CD4+, CD8+ T cell, mast cell, Th2 cell, and dendritic cell. More interesting, we found that ASPHD1 expression was tightly associated with CTLA4 and CD276 which are immune checkpoint markers. Moreover, the upregulated expression of ASPHD1 exhibited higher IC50 values for 24 chemotherapy drugs, including doxorubicin, and masitinib. Finally, the differential expression of ASPHD1 in SKCM was validated by the results of qPCR, Western blot, and IHC. Conclusion The expression of ASPHD1 in SKCM patients is closely related to patient survival. ASPHD1 may participate in the regulation of tumor immune microenvironment. Additionally, it may serve as a prognostic biomarker for SKCM and future in-depth studies are necessary to explore its value.

Cuproptosis, a newly identified form of regulated cell death that is copper-dependent, offers great opportunities for exploring the use of copper-based nanomaterials inducing cuproptosis for cancer treatment. Here, a glucose oxidase (GOx)-engineered nonporous copper(I) 1,2,4-triazolate ([Cu(tz)]) coordination polymer (CP) nanoplatform, denoted as GOx@[Cu(tz)], for starvation-augmented cuproptosis and photodynamic synergistic therapy is developed. Importantly, the catalytic activity of GOx is shielded in the nonporous scaffold but can be "turned on" for efficient glucose depletion only upon glutathione (GSH) stimulation in cancer cells, thereby proceeding cancer starvation therapy. The depletion of glucose and GSH sensitizes cancer cells to the GOx@[Cu(tz)]-mediated cuproptosis, producing aggregation of lipoylated mitochondrial proteins, the target of copper-induced toxicity. The increased intracellular hydrogen peroxide (H

Melanoma is one of the most aggressive skin cancers and a major cause of cancer-linked deaths worldwide. As the morbidity and mortality of melanoma are increasing, it is necessary to elucidate the potential mechanism influencing melanoma progression. Tumor tissues and adjacent normal tissues (5 cm away from tumors) from 22 melanoma patients at the I-II stage and 39 patients at the III-VI stage were acquired. The expression of LINC01063 in melanoma was estimated by quantitative PCR. Functional assays were employed to investigate the function of LINC01063 in melanoma. Mechanism assays were adopted to explore the mechanism of LINC01063. LINC01063 knockdown impeded melanoma cell proliferation, migration, invasion, and epithelial-mesenchymal transition as well as melanoma tumor growth. Mechanistically, LINC01063 acted as an miR-5194 sponge to upregulate SOX12 expression. Finally, LINC01063 was tested to facilitate the malignant behaviors of melanoma cells via targeting miR-5194/SOX12. LINC01063 was significantly upregulated in melanoma. Specifically, LINC01063 displayed a higher level in patients at an advanced stage or with metastasis than those at an early stage or without metastasis. Our study revealed the oncogenic effects of LINC01063 on melanoma cell/tumor growth and its molecular mechanism involving miR-5194/SOX12, which might support LINC01063 to be the potential prognostic or therapeutic biomarker against melanoma.

A series of hydroxy-terminated oxalamide segments (OXA-n, HO-(CH2)n-NHCOCONH-(CH2)n-OH, n = 2, 4 and 6) were designed as initiators for ring-opening polymerization and then poly(l-lactide) with OXA-n in the middle (PLLAOXA-n) were synthesized.

Melanoma is one of the most aggressive and life‐threatening skin cancers, and in this research, we aimed to explore the functional role of circular RNA VANGL1 (circVANGL1) in melanoma progression. The expression levels of circVANGL1 were observed to be significantly increased in clinical melanoma tissues and cell lines. Moreover, circVANGL1 knockdown suppressed, while circVANGL1 overexpression promoted the proliferation, migration and invasion abilities of melanoma cells. Further investigations confirmed the direct binding relation between circVANGL1 and miR‐150‐5p in melanoma, and restoration of miR‐150‐5p blocked the effects of circVANGL1 overexpression in melanoma cells. We further found that circVANGL1 was up‐regulated by TGF‐β treatment, and the enhanced EMT of TGF‐β‐treated melanoma cells was blocked by circVANGL1 knockdown. In conclusion, these results indicated that circVANGL1 might serve as a promising therapeutic target for melanoma.

COVID-19 has seriously threatened public health and transdermal vaccination is an effective way to prevent pathogen infection. Microneedles (MN) can damage the stratum corneum for passive diffusion of vaccine macromolecules but the delivery efficiency is low, while iontophoresis can actively promote transdermal delivery but fails to transport vaccine macromolecules due to the barrier of stratum corneum. Herein, we developed a wearable iontophoresis-driven MN patch and its iontophoresis-driven device for active and efficient transdermal vaccine macromolecules delivery. Polyacrylamide/chitosan hydrogels with good biocompatibility, excellent conductivity, high elasticity and large loading capacity were prepared as the key component for vaccine storage and active iontophoresis. The transdermal vaccine delivery strategy of the iontophoresis-driven MN patch is: “press and poke, iontophoresis-driven delivery, and immune response”. We demonstrated that the synergistic effect of MN puncture and iontophoresis could significantly promote the transdermal vaccine delivery efficiency. In vitro experiments showed that the transdermal delivery amount of ovalbumin using iontophoresis-driven MN patch could be controlled by the iontophoresis current. In vivo immunization studies of Balb/c mice demonstrated that transdermal inoculation of ovalbumin using iontophoresis-driven MN patch induced an effective immune response, which was even stronger than that traditional intramuscular injection. Moreover, the iontophoresis-driven MN patch had little biosafety concern. This delivery system is low-cost, user-friendly, and active delivery that shows a great potential in vaccine self-administration at home.

Melanoma, the most aggressive skin cancer that originated from genetic mutations in the melanocytes, is still a troublesome medical problem under the current therapeutic approaches, which include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy and targeted therapy. Nanotechnology has significantly contributed to the development of cancer treatment in the past few years, among which extracellular vesicles (EVs) are nanosized lipid bilayer vesicles secreted from almost all cells that play essential roles in many physiological and pathological processes. In terms of melanoma therapy, the unique physicochemical properties of EVs make them promising nanocarriers for drug transportation compared to other synthetic nanocarriers. Moreover, EVs can be further engineered to maximize their drug delivery potential. Herein, in this minireview, we gave a brief overview of EV-based drug delivery strategies for melanoma therapy, in which different therapeutics delivered via EVs were summarized. We also highlighted the current progress of the EV-based delivery platform for melanoma therapy in clinical trials. The obstacles to applying exosomes in clinical practice toward further translation of EVs melanoma therapy were also discussed at the end. In summary, EVs offer promising prospects for melanoma therapy, whilst the ways for unlocking EVs’ full potential in melanoma therapies should be further investigated by solving relevant issues which hamper EVs-based melanoma therapy translation in the future.

Background Acerola cherry is a famous functional fruit containing plentiful antioxidants and other nutrients. However, studies on the variations among nutrients during the ripening process of acerola fruit are scare. Results Comparative metabolomic and transcriptomic analyses were performed and identified 31 331 unigenes and 1896 annotated metabolite features in acerola cherry fruit. K Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that several antioxidant and nutrient-related metabolic pathways, such as the flavonoids, vitamins, carotenoids, amino acids, and fatty acids metabolic pathways, were significantly changed during the ripening process. The metabolites related to the vitamin, carotenoid, and fatty acid metabolic pathways were downregulated during the ripening process. Several flavonoid biosynthesis-related genes (including dihydroflavonol 4-reductase, chalcone synthase, flavanone 3-hydroxylase, and anthocyanidin synthase), were significantly upregulated, suggesting their essential functions in the accumulation of flavonoids in mature fruit. Conclusion Most of the vitamin and carotenoid metabolism-related metabolites significantly accumulated in immature fruit, suggesting that immature acerola fruit is a good material for the extraction of vitamins and carotenoids. For macronutrients, most of the amino acids accumulated in mature fruit and most of the fatty acids greatly accumulated in immature fruit. Our data revealed the differential accumulation of antioxidants and nutrients during the ripening process of acerola cherry fruit. © 2021 Society of Chemical Industry.

Reactive oxygen species (ROS) at supraphysiological concentration have a determinate role in contributing to immuno-metabolic disorders in the epithelial immune microenvironment (EIME) of psoriatic lesions. With an exclusive focus on the gene-oxidative stress environment interaction in the EIME, a comprehensive strategy based on ROS-regulating nanomedicines is greatly anticipated to become the mainstay of anti-psoriasis treatment. This potential therapeutic modality could inhibit the acceleration of psoriasis via remodeling the redox equilibrium and reshaping the EIME. Herein, we present a marked overview of the current progress in the pathomechanisms of psoriasis, with particular concerns on the potential pathogenic role of ROS, which significantly dysregulates redox metabolism of keratinocytes (KCs) and skin-resident or -infiltrating cells. Meanwhile, the emergence of versatile nanomaterial-guided evolution for transdermal drug delivery has been attractive for the percutaneous administration of antipsoriatic therapies in recent years. We emphasize the underlying molecular mechanism of ROS-based nanoreactors for improved therapeutic outcomes against psoriasis and summarize up-to-date progress relating to the advantages and limitations of nanotherapeutic application for transdermal administration, as well as update an insight into potential future directions for nanotherapies in ROS-related skin diseases. Graphical Abstract

Background: To explore the underlying mechanism of the regulatory effect of HPV-associated cancer cells on immune cells of the cervical cancer microenvironment. Methods: Immature dendritic cells (imDCs) were obtained from primary mouse bone marrow cells, which were induced in 500 ng/mL LPS for 18 h to get mature dendritic cells (mDCs). DCs were then identified by measuring CD11c, CD80 and CD86 by flow cytometry. Protein levels of TLR3, TLR4 and TLR7 in imDCs and mDCs were examined by Western blot. H8 cells transfected with shHPV18-E6 or Hela cells transfected with HPV18-E6 siRNA were co-cultured with mDCs for 24 h, followed by protein levels of TLR3, TLR4 and TLR7, cell apoptosis and migration. Results: Protein levels of TLR3, TLR4 and TLR7 were significantly higher in mDCs than in imDCs. A higher migratory rate and higher protein levels of TLR3, TLR4 and TLR7 were detected in H8 cells transfected with shHPV18-E6 co-cultured with mDCs than those of controls; While the opposite results were detected in Hela cells transfected with HPV18-E6 siRNA that were co-cultured with mDCs. Conclusion: TLR3, TLR4 and TLR7 are upregulated in mDCs. HPV18-E6 mediates immune cells in the cervical cancer microenvironment via regulating Toll-like receptors (TLRs), thereby achieving immune escape and promoting the migration of cervical cancer cells.

Although circular RNAs (circRNAs) are known to play key roles in non-alcoholic fatty liver disease, much about their targets and mechanisms remains unknown. We therefore investigated the actions and mechanisms of hsa_circ_0048179 in an in vitro model of NAFLD. HepG2 cells were exposed to oleate/palmitate (2:1 ratio) for 24 h to induce intracellular lipid accumulation. Using CCK-8 assays, flow cytometry, fluorescence microscopy, western blotting, RT-qPCR, and Oil red O staining, we found that oleate/palmitate treatment reduced cell viability while increasing apoptosis and lipid accumulation in HepG2 cells. Levels of the antioxidant enzyme GPX4 were decreased in oleate/palmitate-treated HepG2 cells, and there were corresponding increases in reactive oxygen species and damage to mitochondrial cristae. Levels of hsa_circ_0048179 expression were also suppressed by oleate/palmitate treatment, and GPX4 levels were markedly increased in HepG2 cells following transfection with hsa_circ_0048179. Analysis of its mechanism revealed that hsa_circ_0048179 upregulated GPX4 levels by acting as a competitive “sponge” of miR-188-3p and that hsa_circ_0048179 attenuated oleate/palmitate-induced lipid accumulation in HepG2 cells by sponging miR-188-3p. Collectively, our findings suggest that hsa_circ_0048179 may play a key role in the pathogenesis of steatosis and may thus be a useful target for drug development.

Two vanillin-based photocurable, thermally reprocessable, and chemically recyclable imine thermosets were successfully designed. The vanillin vitrimer resins were synthesized through a protocol wit...

Slow crystallization rates and poor storage stability of mechanical properties limit the widespread use of biosynthesized poly(hydroxyalkanoate)s (PHA). Hydrazide compounds (HC

Wound management remains a worldwide challenge. It is undeniable that patients with problems such as difficulties in wound healing, metabolic disorder of the wound microenvironment and even severely infected wounds etc. always suffer great pain that affected their quality of lives. The selection of appropriate wound dressings is vital for the healing process. With the advances of technology, hydrogels dressings have been showing great potentials for the treatment of both acute wounds (e.g., burn injuries, hemorrhage, rupturing of internal organs/aorta) and chronic wounds such as diabetic foot and pressure ulcer. Particularly, in the past decade, polysaccharide-based hydrogels which are made up with abundant and reproducible natural materials that are biocompatible and biodegradable present unique features and huge flexibilities for modifications as wound dressings and are widely applicable in clinical practices. They share not only common characteristics of hydrogels such as excellent tissue adhesion, swelling, water absorption, etc., but also other properties (e.g., anti-inflammatory, bactericidal and immune regulation), to accelerate wound re-epithelialization, mimic skin structure and induce skin regeneration. Herein, in this review, we highlighted the importance of tailoring the physicochemical performance and biological functions of polysaccharide-based hydrogel wound dressings. We also summarized and discussed their clinical states of, aiming to provide valuable hints and references for the future development of more intelligent and multifunctional wound dressings of polysaccharide hydrogels.

BackgroundA number of studies have demonstrated that circular RNA (circRNA) plays a critical role in tumorigenesis and tumor progression. However, the biological effects of most circRNAs on cervical cancer remain unclear. Hsa_circ_0021087 (thereafter named circLMO1) is a circRNA generated from the circularization of exon 2 and exon 3 of LIM Domain Only 1 (LMO1) and first identified as a tumor suppressor in gastric cancer. We aimed to identify the role of circLMO1 in cervical cancer progression.MethodsCircLMO1 was verified through qPCR and Sanger sequencing. The biological role of circLMO1 in regulating cervical cancer growth and metastasis was investigated both in vitro and in the nude mouse xenograft tumor model. The dual luciferase reporter assay and rescue experiment were conducted to evaluate the interactions among circLMO1, microRNA (miR)-4291, and acyl-CoA synthetase long chain family member 4 (ACSL4). The role of circLMO1 in regulating ferroptosis was assessed by analyzing lipid reactive oxygen species (ROS), and malonyl dialdehyde (MDA), and glutathione (GSH) content.ResultsThe level of circLMO1 was down-regulated in cervical cancer tissues and was associated with the International Federation of Gynecology and Obstetrics (FIGO) staging. Functionally, circLMO1 overexpression inhibited cervical cancer growth and metastasis both in vitro and in vivo, whereas circLMO1 depletion promoted cervical cancer cell proliferation and invasion. Mechanistically, circLMO1 acted as a competing endogenous RNA (ceRNA) by sponging miR-4192 to repress target gene ACSL4. CircLMO1 promoted cervical cancer cell ferroptosis through up-regulating ACSL4 expression. Overexpression of miR-4291 or knockdown of ACSL4 reversed the effect of circLMO1 on facilitating ferroptosis and repressing cervical cancer cell proliferation and invasion.ConclusionCircLMO1 acted as a tumor suppressor of cervical cancer by regulating miR-4291/ACSL4-mediated ferroptosis, and could be a promising biomarker for the clinical management of cervical cancer.

Polyhydroxyalkanoates (PHAs), produced by the microbial fermentation, is a promising green polymer and has attracted much attention due to its excellent biocompatibility, complete biodegradability, and non-cytotoxicity. The physical properties of PHAs are closely related to their chemical and crystalline structure. Therefore, deep understanding and regulating the structure and crystallization of PHAs are the key factors to improve the performance of PHAs. This review first provides a brief overview of the development history, chemical structure, and basic properties of PHAs. Then, the crystal structure, crystal morphology, kinetics theories and crystallization behavior of nucleation-induced PHAs are systematically summarized to provide a theoretical foundation for improving PHAs crystallization rate and physical properties. In the end, the outlook on the crystallization and application prospects of PHAs is also addressed.

Sea urchin Mesocentrotus nudus, Glyptocidaris crenularis, and Strongylocentrotus intermedius gonad protein isolates (mnGPIs, gcGPIs, and siGPIs) were extracted by isoelectric solubilization/precipitation (ISP) from the defatted gonads, and their functional properties were compared. Sodium dodecyl sulfate polyacrylamide gel electrophoresis results showed the similar protein pattern between each protein isolate and defatted gonad, indicating the high efficiency of ISP processing for protein recovery. Amino acid profileconfirmed that the mnGPIs and siGPIs could be potential sources of essential amino acid in nature. As regard to functional properties, mnGPIs showed higher water- and oil- holding capacities followed bysiGPIs and gcGPIs and all protein isolates presented great foaming property. As for emulsifying activity index (EAI), mnGPIs, gcGPIs, and siGPIs showed the minimum solubility and EAI at pH 5, 3, and 4, respectively, and behaved a pH-dependent manner. The gcGPIs revealed the highest EAI from pH 6 to 8 among the samples. In addition, circular dichroism showed increased content of β-sheet at the expense of α-helix and β-turn, suggesting the structure denaturation of the protein isolates. Indeed, no statistical difference was observed between secondary structure of mnGPIs and siGPIs. Moreover, ISP processing increased free sulfhydryl content of sea urchin protein isolates, but no difference was observed among the samples. Furthermore, siGPIs revealed the highest amount of total sulfhydryl and disulfide bonds, whereas both defatted gonads and protein isolates from G. crenularis presented the maximum surface hydrophobicity. These results suggest that gonad protein isolates from three species of sea urchin possess various functionalities and therefore can be potentially applied in food system. PRACTICAL APPLICATION: Sea urchin M. nudus, G. crenularis, and S. intermedius gonads are edible, whereas the functional properties of protein isolates from sea urchin gonad remain unknown. In this case, the extraction and comparison of three species of sea urchin gonad protein isolates will not only confirm functional properties but also screen food ingredients with suitable functions. In this study, functionalities of protein isolates derived from M. nudus, G. crenularis, and S. intermedius gonads would provide potential application in bakery food and meat products or as emulsifier candidates in food system.

Commercial Kraft lignin was successfully valorized into recyclable and flexible polyester thermosets. Kraft lignin was first processed into more well-defined lignin fractions via liquid-solid extra ...

Internal N6-methyladenosine (m6A) modification is one of the most common and abundant modifications of RNA. However, the biological roles of viral RNA m6A remain elusive. Here, using human metapneumovirus (HMPV) as a model, we demonstrate that m6A serves as a molecular marker for innate immune discrimination of self from non-self RNAs. We show that HMPV RNAs are m6A methylated and that viral m6A methylation promotes HMPV replication and gene expression. Inactivating m6A addition sites with synonymous mutations or demethylase resulted in m6A-deficient recombinant HMPVs and virion RNAs that induced increased expression of type I interferon, which was dependent on the cytoplasmic RNA sensor RIG-I, and not on melanoma differentiation-associated protein 5 (MDA5). Mechanistically, m6A-deficient virion RNA induces higher expression of RIG-I, binds more efficiently to RIG-I and facilitates the conformational change of RIG-I, leading to enhanced interferon expression. Furthermore, m6A-deficient recombinant HMPVs triggered increased interferon in vivo and were attenuated in cotton rats but retained high immunogenicity. Collectively, our results highlight that (1) viruses acquire m6A in their RNA as a means of mimicking cellular RNA to avoid detection by innate immunity and (2) viral RNA m6A can serve as a target to attenuate HMPV for vaccine purposes. This study reports a novel function for the N6-methyladenosine RNA modification in allowing RIG-I to discriminate self from non-self RNA and shows that human metapneumovirus induces this modification of its RNA to evade recognition in vivo.

A number of studies have demonstrated that circular RNA (circRNA) plays a critical role in tumorigenesis and tumor progression. However, the biological effects of most circRNAs on cervical cancer remain unclear. Hsa_circ_0021087 (thereafter named circLMO1) is a circRNA generated from the circularization of exon 2 and exon 3 of LIM Domain Only 1 (CircLMO1 was verified through qPCR and Sanger sequencing. The biological role of circLMO1 in regulating cervical cancer growth and metastasis was investigated bothThe level of circLMO1 was down-regulated in cervical cancer tissues and was associated with the International Federation of Gynecology and Obstetrics (FIGO) staging. Functionally, circLMO1 overexpression inhibited cervical cancer growth and metastasis bothCircLMO1 acted as a tumor suppressor of cervical cancer by regulating miR-4291/

Background Psoriasis is a chronic relapsing immunological skin disease characterized by multiple cross-talk inflammatory circuits which are relevantly associated with abnormal cross-reactivity between immune cells and keratinocytes (KCs). It may be inadequate to eradicate complicated pathogenesis only via single-mode therapy. To provide optimal combinatory therapeutics, a nanocomposite-based hydrogel was constructed by loading methotrexate (MTX) into ZnO/Ag to realize combined multiple target therapy of psoriasis. Results In this composite hydrogel, ZnO hybrid mesoporous microspheres were utilized both as drug carriers and reactive oxygen species (ROS)-scavenging nanoparticles. A proper amount of Ag nanoparticle-anchored ZnO nanoparticles (ZnO/Ag) was functionalized with inherent immunoregulatory property. The experiments showed that ZnO/Ag nanoparticles could exhibit a self-therapeutic effect that was attributed to reducing innate cytokine profiles by inactivating p65 in proinflammatory macrophages and abrogating secretion of adaptive cytokines in KCs by downregulating ROS-mediated STAT3-cyclin D1 signaling. A preferable antipsoriatic efficacy was achieved via topical administration of this hydrogel on the imiquimod (IMQ)-induced psoriasis mice model, demonstrating the superior transdermal delivery and combined enhancement of therapeutic efficacy caused by intrinsic nanoparticles and extrinsic MTX. Conclusion This composite hydrogel could serve as a multifunctional, nonirritating, noninvasive and effective transcutaneous nanoagent against psoriasis. Graphical Abstract

HPV16 infections promote the development and progression of cervical cancer. We investigated Fms-like Tyrosine Kinase 3 Ligand and granulocyte macrophage colony-stimulating factor as new adjuvants to an HPV16 vaccine. C57BL/6 mice were immunized by intramuscular injections of HPV16 E6/E7 plasmids every two weeks, three times in all. An in vivo imaging system was used to observe tumor growth and metastasis. Pathological changes to the heart, liver, spleen, lungs, brain and kidneys were recorded, and the survival rate of the mice was determined. The constructed HPV16 E6/E7 vaccine had no notable side effects in terms of physiological or biochemical indexes. Fms-like Tyrosine Kinase 3 Ligand and granulocyte macrophage colony-stimulating factor increased the inhibitory effects of the HPV16 E6/E7 vaccine on tumor growth and metastasis in vivo. The HPV16 E6/E7 vaccine enhanced the survival of mice and increased their serum-specific antibody and interferon-γ levels. Fms-like Tyrosine Kinase 3 Ligand and granulocyte macrophage colony-stimulating factor augmented these effects. In a cytotoxic lymphocyte killing test, Fms-like Tyrosine Kinase 3 Ligand and granulocyte macrophage colony-stimulating factor improved the ability of splenic lymphocytes from HPV16 E6/E7-vaccinated mice to kill B16 cells. As Fms-like Tyrosine Kinase 3 Ligand and granulocyte macrophage colony-stimulating factor enhanced the anti-tumor and immune effects of the HPV16 vaccine, these adjuvants should be considered for the treatment of cervical cancer.

OBJECTIVE In recent years, many studies have tried to prove whether Helicobacter pylori (H. pylori) can promote the progression of atherosclerosis (AS), but the reported results are conflicting. Carotid intima-media thickness (CIMT), flow-mediated dilation (FMD), or pulse wave velocity (PWV) are the most commonly used indicators to evaluate the progress of AS. So, we collected and evaluated these three indicators to provide evidence-based medicine for the clinic. MATERIALS AND METHODS We included and evaluated studies on H. pylori infection and CIMT, FMD, or PWV from PubMed, Cochrane trials, and Embase databases before September 1, 2021, and language restrictions: English. Research types include cross-sectional studies, cohort studies, and case-control studies. The MINORS scale was used to evaluate the quality of these studies. For all studies, we choose a random-effects model and calculate the weighted mean difference (WMD) for analysis, and all our analyses use STATA software. RESULTS Meta-analysis shows that H. pylori infection can significantly increase CIMT (WMD = 0.059, 95% CI: 0.039, 0.079, p

Emerging evidence suggests heterologous prime-boost COVID-19 vaccination as a superior strategy than homologous schedules. Animal experiments and clinical observations have shown enhanced antibody response against influenza variants after heterologous vaccination; however, whether the inoculation order of COVID-19 vaccines in a prime-boost schedule affects antibody response against SARS-CoV-2 variants is not clear.We conducted immunological analyses in a cohort of health care workers (n = 486) recently vaccinated by three types of inactivated COVID-19 vaccines under homologous or heterologous prime-boost schedules. Antibody response against ancestral SARS-CoV-2 (Wuhan-Hu-1) was assessed by total antibody measurements, surrogate virus neutralization tests, and pseudovirus neutralization assays (PNA). Furthermore, serum neutralization activity against SARS-CoV-2 variants of concern was also measured by PNA.We observed strongest serum neutralization activity against the widely circulating SARS-CoV-2 variant B.1.617.2 among recipients of heterologous BBIBP-CorV/CoronaVac and WIBP-CorV/CoronaVac. In contrast, recipients of CoronaVac/BBIBP-CorV and CoronaVac/WIBP-CorV showed significantly lower B.1.617.2 neutralization titers than recipients of reverse schedules. Laboratory tests revealed that neutralizing activity against common variants but not the ancestral SARS-CoV-2 was associated with the inoculation order of heterologous prime-boost vaccines. Multivariable regression analyses confirmed this association after adjusting for known confounders.Our data provide clinical evidence of inoculation order-dependent expansion of neutralizing breadth against SARS-CoV-2 in recipients of heterologous prime-boost vaccination and call for further studies into its underlying mechanism.National Key RD Program of China, National Development and Re-form Commission of China, National Natural Science Foundation of China, Shenzhen Science and Technology Innovation Commission, and US Department of Veterans Affairs.

Immunotherapy has emerged as a promising strategy for cancer treatment, in which durable immune responses were generated in patients with malignant tumors. In the past decade, biomaterials have played vital roles as smart drug delivery systems for cancer immunotherapy to achieve both enhanced therapeutic benefits and reduced side effects. Hydrogels as one of the most biocompatible and versatile biomaterials have been widely applied in localized drug delivery systems due to their unique properties, such as loadable, implantable, injectable, degradable and stimulus responsible. Herein, we have briefly summarized the recent advances on hydrogel-by-design delivery systems including the design of hydrogels and their applications for delivering of immunomodulatory molecules (e.g., cytokine, adjuvant, checkpoint inhibitor, antigen), immune cells and environmental regulatory substances in cancer immunotherapy. We have also discussed the challenges and future perspectives of hydrogels in the development of cancer immunotherapy for precision medicine at the end.

Qiuyue Guo,1 Yunsheng Xu,2 Jie Li,3 Wenrong An,3 Dan Luo,4 Chengcheng Huang,4 Yanqin Huang4 1Department of Endocrinology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, People’s Republic of China; 3First Clinical Medical College, Jingshi Rd. Campus, Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 4Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of ChinaCorrespondence: Yanqin Huang Email huangyanqin2020@126.com; 20137125@sdutcm.deu.cnPurpose: To analyze the effect and potential therapeutic targets of liraglutide in type 2 diabetes through miRNA expression profiling.Methods: Ten of 30 SPF Wistar rats, males at 4 weeks old, were randomly selected as the control group and given conventional feed, the other rats adopted high-sugar and high-fat diet combined with an intraperitoneal injection of streptozotocin to establish a T2DM model. One unsuccessful rat was excluded, and the remaining rats were randomized to the model and the liraglutide group. Liraglutide group was subcutaneously injected with liraglutide 0.11 mg/kg for 8 weeks. The biochemical indicators and staining HE were detected. The expression of miRNA in pancreatic tissue was detected by miRNA sequencing. The intersection of miRNA difference was used to predict the target gene, then functional enrichment was performed to identify its possible biological functions and signal transduction paths. Finally, qRT-PCR was used to verify the results.Results: Compared to the model group, the level of fasting blood glucose (FBG), glucagon and insulin resistance index (HOMA-IR) in the liraglutide group were significantly decreased, fasting insulin (FINS) and insulin sensitivity index (ISI) were increased. Nine differential miRNAs (miR-135a-5p, miR-144-5p, miR-21-3p, miR-215, miR-451-5p, miR-486, miR-122-5p, miR-181d-5p and miR-345-5p) were identified at the intersection through two miRNA sequencing. A total of 3359 related target gene predictions were obtained. GO and pathway analyses demonstrated that differentially expressed genes were closely related to cell proliferation, angiogenesis, and proteolysis. Significant signaling pathways included PI signaling system, autophagy, FoxO and HIF-1 signaling pathway.Conclusion: Liraglutide could improve islet function by regulating nine miRNAs, and the related signaling pathways included PI signaling system, autophagy, FoxO and HIF-1 signaling pathway. Our study provided the basis and direction for further exploring the molecular mechanism of liraglutide on T2DM.Keywords: liraglutide, type 2 diabetes, miRNA expression profile, target gene, signaling pathway

A series of kraft lignin based thermosets were successfully synthesized by a one-pot heat curing method composed of lignin, PEG400, and citric acid through esterification reactions with water as th...

Background Cervical cancer is the second most common malignant cancer in women worldwide. Evidence indicated that miR-664 was significantly downregulated in cervical cancer. However, the mechanisms by which miR-664 regulates the tumorigenesis of cervical cancer remain unclear. Thus, this study aimed to investigate the role of miR-664 in cervical cancer. Methods Quantitative reverse transcription polymerase chain reaction was used to detect the level of miR-664 in tumor tissues and cell line. The dual luciferase reporter system assay and Western blotting were used to explore the interaction of miR-664 and c-Kit in cervical cancer. Results The expression of miR-664 in patients with cervical cancer was dramatically decreased compared with that in adjacent tissues. MiR-664 mimics significantly inhibited proliferation in SiHa cells via inducing apoptosis. In addition, miR-664 mimics induced apoptosis in SiHa cells via increasing the expressions of Bax and active caspase 3 and decreasing the level of Bcl-2. Moreover, dual-luciferase assay showed that c-Kit was the directly binding target of miR-664 in SiHa cells; overexpression of miR-664 downregulated the expression of c-Kit. Meanwhile, upregulation of miR-664 significantly decreased the levels of c-Myc and Cyclin D in cells. Furthermore, miR-664 markedly inhibited tumor growth of cervical cancer in xenograft. Conclusion Our data indicated that miR-664 exerted antitumor effects on SiHa cells by directly targeting c-Kit in vitro and in vivo. Therefore, miR-664 might be a potential therapeutic target for the treatment of patients with cervical cancer.

Myelin-laden macrophages (mye-MΦ), resulting primarily from internalization of myelin debris by infiltrating bone marrow-derived macrophages in spinal cord injury (SCI), trigger inflammatory responses that largely contribute to secondary injury. Adiponectin, which is secreted from adipose tissue, is an important hormone that modulates macrophage inflammation. In the present study, we examined the role of adiponectin on macrophage-mediated neuroinflammation after SCI. We found that in vitro activation of adiponectin receptors (AdipoRs) by their agonist AdipoRon suppressed myelin lipid accumulation in mye-MΦ through APPL1/PPARγ/LXRα/ABCA1-mediated lipid efflux, subsequently inhibiting inflammation and restoring normal function to mye-MΦ. In vivo data further confirmed that intravenous administration of AdipoRon after SCI dampened recruitment of macrophages and reduced myelin lipid accumulation. Accordingly, AdipoRon treatment ameliorated post-SCI tissue damage and astrogliosis, resulting in improved motor function. Although there was no significant pathological exacerbation in adiponectin-null mice subjected to SCI, our work reveals a functional link between adiponectin and hematogenous macrophages in the context of SCI, suggesting that activation of adiponectin signaling is a promising therapeutic approach to mitigate mye-MΦ-mediated neuroinflammation in neurological disorders involving demyelination.

Rational structure design benefits the development of new classes of contrast agents (CAs) with excellent magnetic resonance imaging performance. In this work, hydrogenated silica with a net nanostructure (HSiO2) was fabricated and used to modify gadolinium-doped iron oxide nanoclusters (GdIONCs) to form a core-shell nanoplatform (HSiO2@GdIONC) with enhanced T1 and T2 contrast ability. In this nanoplatform, the HSiO2 shell showed a strong binding capacity for water molecules because of the presence of hydrogen bonds, oxygen vacancies, and high specific surface areas, and the strong binding capacity significantly improved the spin-spin (T2) and spin-lattice (T1) imaging of the GdIONC core. In addition, the T1 relaxation rate of the GdIONC core dramatically increased from 30.8 mM−1 s−1 to 38.2 mM−1 s−1 after being coated with the HSiO2 shell, and the r2 to r1 ratio decreased from 10.9 to 8.3, which is an appropriate ratio (r2/r1: 5–10) for dual-mode contrast. Cell and animal experiments suggested that HSiO2@GdIONC exhibited a better T1- and T2-weighted MR imaging effect than the bare GdIONC core, confirming that this strategy for modifying GdIONCs is a beneficial and promising approach for obtaining highly efficient dual-mode CAs.

The development of non-invasive biosensor for monitoring glucose in interstitial fluid (ISF) is still challenging, because ISF extraction through classical reverse iontophoresis (RI) is limited by low extraction flux and consistency. Here, we developed a touch-actuated biosensor for monitoring glucose in ISF. The biosensor is composed of three main components: 1) the solid microneedle array (MA) for painless skin penetration; 2) the RI unit for ISF extraction through the MA-created microchannels; and 3) the sensing unit for glucose monitoring. The sensing strategy of this biosensor is "skin penetration-RI extraction-electrochemical detection". Compared with RI extraction only, the reported skin penetration-RI extraction sampling strategy obviously increased the glucose extraction flux by ∼1.6 times not only in vitro but also in vivo. Moreover, we developed a wearable glucose monitoring system by incorporating this touch-actuated biosensor, a wireless electrochemical detector, and a smartphone application. In vivo experiments using healthy and diabetic rats revealed a high correlation between the results measured by the reported wearable system and commercially blood glucometer. This sampling strategy which combined skin penetration and RI extraction paves the way to develop wearable platforms for not only glucose monitoring but also various ISF biomarkers without the need of painful finger-stick blood sampling.

Ethnopharmacological relevance Allium macrostemon Bunge. is an edible Chinese herb traditionally used for the treatment of thoracic pain, stenocardia, heart asthma and diarrhea. Although its biological potential has been extensively proven such as antioxidant activity, antiplatelet aggregation, vasodilation and antidepressant-like activity, there are no reports in the literature regarding its pharmacological analgesic activity. Aim of the study The study was carried out to examine the anti-nociceptive activity of the crude extract of A. macrostemon bulbs and interpret its likely molecular target. Materials and methods The bulbs of A. macrostemon were gathered, dried-up , and extracted with water (AMWD). AMWD was subjected to activity testing, using chemical-induced (acetic acid and formalin test) and heat-induced (hot plate) pain models. To evaluate the likely mechanistic strategy involved in the analgesic effect of AMWD, whole-cell patch clamp recordings were conducted in acutely dissociated dorsal root ganglion (DRG) neurons and human embryonic kidney 293T (HEK293T) cells expressing pain-related receptors. Electrophysiological methods were employed to detect the action potentials of DRG neurons and potential targets of A. macrostemon. Results AMWD showed significant palliative effect in all heat and chemical induced pain assays. Moreover, AMWD significantly reduces the excitability of dorsal root ganglion neurons by reducing the firing frequency of action potentials. Further analysis revealed that voltage-gated sodium channel Nav1.7 is the potential target of A. macrostemon for its analgesic activity. Conclusion This study has brought new scientific evidence of preclinical efficacy of A. macrostemon as an anti-nociceptive agent. Apparently, these effects are involved with the inhibition of the voltage-sensitive Nav1.7 channel contributing to the reduction of peripheral neuronal excitability. Our present study justifies the folkloric usage of A. macrostemon as a remedy for several pain states. Furthermore, A. macrostemon is a good resource for the development of analgesic drugs targeting Nav1.7 channel.

Though widely used in the treatment of coronary heart disease (CHD), the mechanism of traditional Chinese medicine (TCM) is still unclear because of its complex prescription rules. This study prospectively collected 715 prescriptions of TCM for the treatment of CHD. The characteristics of TCM in prescriptions were described and analyzed, and the rules of prescriptions were analyzed by using association rules. Frequency statistics showed that the high-frequency herbs with a frequency of more than 60% were Gan-cao, Huang-qi, Dang-gui, Chuan-xiong, Yan-hu-suo, and San-qi. The high-frequency herb combinations were summarized by using association rules. By using the method of the “Top N groups” to excavate the empirical prescriptions, the basic prescriptions for treating CHD were summarized. We named the intersection herbs of the basic prescriptions and the high frequency herbs as the core herbal prescription. To explore the possible mechanisms underlying the anti-CHD effect of the core herbal prescription, the bioactive components of core herbal prescription and their targets were screened out by using network pharmacology. Molecular docking was performed between the bioactive components and core targets. A total of 28 potential active ingredients and 5 core targets were identified for the treatment of CHD with core herbal prescription. The enrichment analysis results indicated that the mechanism of action mainly involved neuroactive ligand-receptor interaction and calcium signaling pathway. The commonly used herbal pairs for CHD with qi deficiency and blood stasis syndrome were Huang-qi and Dang-gui. The mechanism of action of common herbal pairs was also studied by network pharmacology. This study summarized the prescription rule of TCM in the treatment of CHD and may provide a new idea for the treatment of CHD.

Tryptophan 2,3‑dioxygenase (TDO2) is a key rate‑limiting enzyme in the kynurenine pathway and promotes tumor growth and escape from immune surveillance in different types of cancer. The present study aimed to investigate whether TDO2 serves a role in the development of ovarian cancer. Reverse transcription‑quantitative PCR and western blotting were used to detect the expression of TDO2 in different cell lines. The effects of TDO2 overexpression, TDO2 knockdown and TDO2 inhibitor on ovarian cancer cell proliferation, migration and invasion were determined by MTS, colony formation and Transwell assays. The expression of TDO2 in ovarian cancer tissues, normal ovarian tissues and fallopian tube tissues were analyzed using the gene expression data from The Cancer Genome Atlas and Genotype‑Tissue Expression project. Immune cell infiltration in cancer tissues was evaluated using the single sample gene set enrichment analysis algorithm. The present study found that RasV12‑mediated oncogenic transformation was accompanied by the upregulation of TDO2. In addition, it was demonstrated that TDO2 was upregulated in ovarian cancer tissues compared with normal ovarian tissues. TDO2 overexpression promoted proliferation, migration and invasion of ovarian cancer cells, whereas TDO2 knockdown repressed these phenotypes. Treatment with LM10, a TDO2 inhibitor, also repressed the proliferation, migration and invasion of ovarian cancer cells. The present study indicated that TDO2 can be used as a new target for the treatment of ovarian cancer.

Synthetic glucocorticoid dexamethasone is the first trial-proven drug that reduces COVID-19 mortality by suppressing immune system. In contrast, interferons are a crucial component of host antiviral immunity and can be directly suppressed by glucocorticoids. To investigate whether therapeutic interferons can compensate glucocorticoids-induced loss of antiviral immunity, we retrospectively analyzed a cohort of 387 PCR-confirmed COVID-19 patients with quasi-random exposure to interferons and conditional exposure to glucocorticoids. Among patients receiving glucocorticoids, early interferon therapy was associated with earlier hospital discharge (adjusted HR 1.68, 95% CI 1.19–2.37) and symptom relief (adjusted HR 1.48, 95% CI 1.06–2.08), while these associations were insignificant among glucocorticoids nonusers. Early interferon therapy was also associated with lower prevalence of prolonged viral shedding (adjusted OR 0.24, 95% CI 0.10–0.57) only among glucocorticoids users. Additionally, these associations were glucocorticoid cumulative dose- and timing-dependent. These findings reveal potential therapeutic synergy between interferons and glucocorticoids in COVID-19 that warrants further investigation.

Previous studies evaluating the association of dietary fat and risk of age-related macular degeneration (AMD) yield discrepant results. The objective of this systematic review (SR) and meta-analysis is to establish whether an association exists between dietary fat and AMD. This protocol was developed in line with the quality requirements of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement. PubMed and EMBASE will be searched for randomized controlled trials (RCTs), non-randomized trials (NRTs), cross-sectional studies, cohort studies, and case-control studies that evaluate the total incidence of AMD. The data extraction content and quantitative analysis will be carried out systematically. Newcastle-Ottawa Scale (NOS), the Cochrane risk of bias tool, and quality assessment tools will be used for quality assessment. This SR will synthesize evidence to determine if there is an association between dietary fat and AMD. The evidence would provide rationale for future research and serve as a basis for the development of future guidelines. Results are expected to be publicly available in mid 2020. PROSPERO registration number: CRD42019137086.