Identification of a marine-derived sesquiterpenoid, Compound-8, that inhibits tumour necrosis factor-induced cell death by blocking complex II assembly.

BACKGROUND AND PURPOSE: Tumour necrosis factor (TNF) is a pleiotropic inflammatory cytokine that not only directly induces inflammatory gene expression but also triggers apoptotic and necroptotic cell death, which leads to tissue damage and indirectly exacerbates inflammation. Thus, identification of inhibitors for TNF-induced cell death has broad therapeutic relevance for TNF-related inflammatory diseases. In the present study, we isolated and identified a marine fungus-derived sesquiterpenoid, 9α,14-dihydroxy-6ß-p-nitrobenzoylcinnamolide (named as Cpd-8), that inhibits TNF receptor superfamily-induced cell death by preventing the formation of cytosolic death complex II. EXPERIMENTAL APPROACH: Marine sponge-associated fungi were cultured and the secondary metabolites were extracted to yield pure compounds. Cell viability was measured by ATP-Glo cell viability assay. The effects of Cpd-8 on TNF signalling pathway were investigated by western blotting, immunoprecipitation, and immunofluorescence assays. A mouse model of acute liver injury (ALI) was employed to explore the protection effect of Cpd-8, in vivo. KEY RESULTS: Cpd-8 selectively inhibits TNF receptor superfamily-induced apoptosis and necroptosis. Cpd-8 prevents the formation of cytosolic death complex II and subsequent RIPK1-RIPK3 necrosome, while it has no effect on TNF receptor I (TNFR1) internalization and the formation of complex I in TNF signalling pathway. In vivo, Cpd-8 protects mice against TNF-α/D-GalN-induced ALI. CONCLUSION AND IMPLICATIONS: A marine fungus-derived sesquiterpenoid, Cpd-8, inhibits TNF receptor superfamily-induced cell death, both in vitro and in vivo. This study not only provides a useful research tool to investigate the regulatory mechanisms of TNF-induced cell death but also identifies a promising lead compound for future drug development.

Analysis of Bifidobacterium animalis subsp. lactis BB-12 ® and Lactobacillus rhamnosus GG on underweight and malabsorption in premature infants.

OBJECTIVE: This study aimed to explore and analyze the therapeutic effect of the combination of Bifidobacterium animalis subsp. lactis BB-12® and Lactobacillus rhamnosus GG on underweight and malabsorption in premature infants. METHODS: This is a retrospective study. The clinical data of 68 premature infants admitted to Beijing United Family Hospital (Private Secondary Comprehensive Hospital, Chaoyang District, Beijing, China) from January 2016 to January 2022 were analyzed retrospectively. Preterm infants less than 37 weeks of gestational age admitted to the neonatal intensive care unit were included in the study. Patients with intestinal malformations, necrotizing enterocolitis, etc., who require long-term fasting were excluded. A telephone follow-up was performed 3-6 months after discharge. They were classified as treatment groups A and B according to the treatment plan. The treatment group A included parenteral nutrition, enteral nutrition, etc. In treatment group B, based on treatment group A, the premature infants were treated with Bifidobacterium animalis subsp. lactis BB-12® and Lactobacillus rhamnosus GG. The time to regain birthweight and the weight on day 30 were compared between the two groups, as was the duration of transition from parenteral nutrition to total enteral nutrition. RESULTS: The time of weight regain birthweight in group B was shorter than that in group A (t=-2.560; t=-4.287; p<0.05). The increase of weight on day 30 in group B was significantly higher than that in group A (t=2.591; t=2.651; p<0.05). The time from parenteral nutrition to total enteral nutrition in group B was shorter than that in group A (z=-2.145; z=-2.236; p<0.05). CONCLUSION: In the treatment of premature infants, the combination of Bifidobacterium animalis subsp. lactis BB-12® and Lactobacillus rhamnosus GG can have a better therapeutic effect on the underweight and malabsorption of premature infants, and this treatment method can be popularized in clinics.

GelMA/PEDOT:PSS Composite Conductive Hydrogel-Based Generation and Protection of Cochlear Hair Cells through Multiple Signaling Pathways.

Recent advances in cochlear implantology are exemplified by novel functional strategies such as bimodal electroacoustic stimulation, in which the patient has intact low-frequency hearing and profound high-frequency hearing pre-operatively. Therefore, the synergistic restoration of dysfunctional cochlear hair cells and the protection of hair cells from ototoxic insults have become a persistent target pursued for this hybrid system. In this study, we developed a composite GelMA/PEDOT:PSS conductive hydrogel that is suitable as a coating for the cochlear implant electrode for the potential local delivery of otoregenerative and otoprotective drugs. Various material characterization methods (e.g., 1H NMR spectroscopy, FT-IR, EIS, and SEM), experimental models (e.g., murine cochlear organoid and aminoglycoside-induced ototoxic HEI-OC1 cellular model), and biological analyses (e.g., confocal laser scanning microscopy, real time qPCR, flow cytometry, and bioinformatic sequencing) were used. The results demonstrated decent material properties of the hydrogel, such as mechanical (e.g., high tensile stress and Young's modulus), electrochemical (e.g., low impedance and high conductivity), biocompatibility (e.g., satisfactory cochlear cell interaction and free of systemic toxicity), and biosafety (e.g., minimal hemolysis and cell death) features. In addition, the CDR medicinal cocktail sustainably released by the hydrogel not only promoted the expansion of the cochlear stem cells but also boosted the trans-differentiation from cochlear supporting cells into hair cells. Furthermore, hydrogel-based drug delivery protected the hair cells from oxidative stress and various forms of programmed cell death (e.g., apoptosis and ferroptosis). Finally, using large-scale sequencing, we enriched a complex network of signaling pathways that are potentially downstream to various metabolic processes and abundant metabolites. In conclusion, we present a conductive hydrogel-based local delivery of bifunctional drug cocktails, thereby serving as a potential solution to intracochlear therapy of bimodal auditory rehabilitation and diseases beyond.

Clinical applications of stem cell-derived exosomes.

Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.

Analysis of Bifidobacterium animalis subsp. lactis BB-12 ® and Lactobacillus rhamnosus GG on underweight and malabsorption in premature infants

SUMMARY OBJECTIVE: This study aimed to explore and analyze the therapeutic effect of the combination of Bifidobacterium animalis subsp. lactis BB-12® and Lactobacillus rhamnosus GG on underweight and malabsorption in premature infants. METHODS: This is a retrospective study. The clinical data of 68 premature infants admitted to Beijing United Family Hospital (Private Secondary Comprehensive Hospital, Chaoyang District, Beijing, China) from January 2016 to January 2022 were analyzed retrospectively. Preterm infants less than 37 weeks of gestational age admitted to the neonatal intensive care unit were included in the study. Patients with intestinal malformations, necrotizing enterocolitis, etc., who require long-term fasting were excluded. A telephone follow-up was performed 3-6 months after discharge. They were classified as treatment groups A and B according to the treatment plan. The treatment group A included parenteral nutrition, enteral nutrition, etc. In treatment group B, based on treatment group A, the premature infants were treated with Bifidobacterium animalis subsp. lactis BB-12® and Lactobacillus rhamnosus GG. The time to regain birthweight and the weight on day 30 were compared between the two groups, as was the duration of transition from parenteral nutrition to total enteral nutrition. RESULTS: The time of weight regain birthweight in group B was shorter than that in group A (t=-2.560; t=-4.287; p<0.05). The increase of weight on day 30 in group B was significantly higher than that in group A (t=2.591; t=2.651; p<0.05). The time from parenteral nutrition to total enteral nutrition in group B was shorter than that in group A (z=-2.145; z=-2.236; p<0.05). CONCLUSION: In the treatment of premature infants, the combination of Bifidobacterium animalis subsp. lactis BB-12® and Lactobacillus rhamnosus GG can have a better therapeutic effect on the underweight and malabsorption of premature infants, and this treatment method can be popularized in clinics.

Development of a fibroblast activation protein-targeted PET/NIR dual-modality probe and its application in head and neck cancer.

Purpose: The combination of near-infrared (NIR) and positron emission tomography (PET) imaging presents an opportunity to utilize the benefits of dual-modality imaging for tumor visualization. Based on the observation that fibroblast activation protein (FAP) is upregulated in cancer-associated fibroblasts (CAFs) infiltrating all solid tumors, including head and neck squamous cell carcinoma (HNSCC), we developed the novel PET/NIR probe [68Ga]Ga-FAP-2286-ICG. Preclinically, the specificity, biodistribution and diagnostic properties were evaluated. Methods: Cell uptake assays were completed with the U87MG cell to evaluate the specificity of the [68Ga]Ga-FAP-2286-ICG. The tumor-targeting efficiency, biodistribution and optimal imaging time window of the [68Ga]Ga-FAP-2286-ICG were studied in mice bearing U87MG xenografts. HNSCC tumor-bearing mice were used to evaluate the feasibility of [68Ga]Ga-FAP-2286-ICG for tumor localization and guided surgical resection of HNSCC tumors. Results: The in vitro experiments confirmed that [68Ga]Ga-FAP-2286-ICG showed good stability, specific targeting of the probe to FAP, and the durable retention effect in high-expressing FAP tumors U87MG cell. Good imaging properties such as good tumor uptake, high tumor-to-background ratios (5.44 ± 0.74) and specificity, and tumor contouring were confirmed in studies with mice bearing the U87MG xenograft. PET/CT imaging of the probe in head and neck cancer-bearing mice demonstrated specific uptake of the probe in the tumor with a clear background. Fluorescence imaging further validated the value of the probe in guiding surgical resection and achieving precise removal of the tumor and residual lesions. Conclusion: In a preclinical model, these attractive [68Ga]Ga-FAP-2286-ICG PET/NIR imaging acquired in head and neck cancer make it a promising FAP-targeted multimodal probe for clinical translation.

A Prognostic Model of Head and Neck Cancer Based on Amino Acid Metabolism-Related Signature and Its Implication for Immunosuppressive Microenvironment.

Amino acid metabolism has been implicated in tumorigenesis and tumor progression. Alterations in intracellular and extracellular metabolites associated with metabolic reprogramming in cancer have profound effects on gene expression, cell differentiation, and tumor immune microenvironment. However, the prognostic significance of amino acid metabolism in head and neck cancer remains to be further investigated. In this study, we identified 98 differentially expressed genes related to amino acid metabolism in head and neck cancer in The Cancer Genome Atlas. Using batch univariate Cox regression and Lasso regression, we extracted nine amino acid metabolism-related genes. Based on that, we developed the amino acid metabolism index. The prognostic value of this index was validated in two Gene Expression Omnibus cohorts. The results show that this model can help predict tumor recurrence and prognosis. The infiltration of immune cells in the tumor microenvironment was analyzed, and it was discovered that the high index is associated with an immunosuppressive microenvironment. In addition, this study demonstrated the impact of the amino acid metabolism index on clinical indicators, survival of patients with head and neck cancer, and the prediction of treatment response to immune checkpoint inhibitors. We conducted several cell experiments and demonstrated that epigenetic drugs could affect the index and enhance tumor immunity. In conclusion, our study demonstrates that the index not only has important prognostic value in head and neck cancer patients but also facilitates patient stratification for immunotherapy.

Double-network hydrogel enhanced by SS31-loaded mesoporous polydopamine nanoparticles: Symphonic collaboration of near-infrared photothermal antibacterial effect and mitochondrial maintenance for full-thickness wound healing in diabetes mellitus.

Diabetic wound healing has become a serious healthcare challenge. The high-glucose environment leads to persistent bacterial infection and mitochondrial dysfunction, resulting in chronic inflammation, abnormal vascular function, and tissue necrosis. To solve these issues, we developed a double-network hydrogel, constructed with pluronic F127 diacrylate (F127DA) and hyaluronic acid methacrylate (HAMA), and enhanced by SS31-loaded mesoporous polydopamine nanoparticles (MPDA NPs). As components, SS31, a mitochondria-targeted peptide, maintains mitochondrial function, reduces mitochondrial reactive oxygen species (ROS) and thus regulates macrophage polarization, as well as promoting cell proliferation and migration, while MPDA NPs not only scavenge ROS and exert an anti-bacterial effect by photothermal treatment under near-infrared light irradiation, but also control release of SS31 in response to ROS. This F127DA/HAMA-MPDA@SS31 (FH-M@S) hydrogel has characteristics of adhesion, superior biocompatibility and mechanical properties which can adapt to irregular wounds at different body sites and provide sustained release of MPDA@SS31 (M@S) NPs. In addition, in a diabetic rat full thickness skin defect model, the FH-M@S hydrogel promoted macrophage M2 polarization, collagen deposition, neovascularization and wound healing. Therefore, the FH-M@S hydrogel exhibits promising therapeutic potential for skin regeneration.

Flexible Piezoelectric and Pyroelectric Nanogenerators Based on PAN/TMAB Nanocomposite Fiber Mats for Self-Power Multifunctional Sensors.

Self-powered wearable electronics to convert mechanical and thermal energy into electrical energy are important for biomedical monitoring, which highly require good flexibility, comfortability, signal sensitivity, and accuracy. In this work, composite nanofiber mats of polyacrylonitrile (PAN) and trimethylamine borane (TMAB) were prepared by electrospinning, which exhibited excellent piezoelectric and pyroelectric abilities in harvesting mechanical and thermal energy. The PAN/TMAB-4 nanofiber mats not only generated a high voltage of up to 2.56 V and a high power of 0.19 µW upon shape deformation but also exhibited linear voltage response to thermal gradient. The hybrid piezoelectric and pyroelectric output signals were successfully integrated together and have been applied to precisely monitor human vital signs, including elbow bending angles, foot posture, and breathing status, in real time by attaching the flexible sensors to proper human body parts. Overall, good flexibility, bifunctional sensing ability, and self-power make PAN-/TMAB-type sensors very attractive in fabricating high-performance electronics for detecting motion, monitoring health, and making portable microelectronics.

Plasma oncology: Adjuvant therapy for head and neck cancer using cold atmospheric plasma.

The worldwide incidence of head and neck cancer (HNC) exceeds half a million cases annually, and up to half of the patients with HNC present with advanced disease. Surgical resection remains the mainstay of treatment for many HNCs, although radiation therapy, chemotherapy, targeted therapy, and immunotherapy might contribute to individual patient's treatment plan. Irrespective of which modality is chosen, disease prognosis remains suboptimal, especially for higher staging tumors. Cold atmospheric plasma (CAP) has recently demonstrated a substantial anti-tumor effect. After a thorough literature search, we provide a comprehensive review depicting the oncological potential of CAP in HNC treatment. We discovered that CAP applies to almost all categories of HNC, including upper aerodigestive tract cancers, head and neck glandular cancers and skin cancers. In addition, CAP is truly versatile, as it can be applied not only directly for superficial or luminal tumors but also indirectly for deep solid organ tumors. Most importantly, CAP can work collaboratively with existing clinical oncotherapies with synergistic effect. After our attempts to elaborate the conceivable molecular mechanism of CAP's anti-neoplastic effect for HNC, we provide a brief synopsis of recent clinical and preclinical trials emphasizing CAP's applicability in head and neck oncology. In conclusion, we have enunciated our vision of plasma oncology using CAP for near future HNC treatment.

Hemoglobin-binding α-synuclein levels in erythrocytes are elevated in patients with multiple system atrophy.

Previous studies have shown that α-synuclein (α-syn) accumulation in the normal aging brain is associated with a parallel increase in hemoglobin-binding α-syn (Hb-α-syn) in the brain and peripheral erythrocytes (ERCs), indicating that Hb-α-syn levels in ERCs may reflect the α-syn changes in the brain. However, if there is any change in ERC Hb-α-syn levels in disease condition is unclear. In this study, Hb-α-syn levels in ERCs from 149 Patients with multiple system atrophy (MSA) and 149 healthy controls (HCs) were measured by enzyme linked immunosorbent assay (ELISA). The results showed that Hb-α-syn levels in ERCs were significantly increased in MSA patients in comparison with those in HCs (777.84 ± 240.82 ng/mg vs 508.84 ± 162.57 ng/mg, P < 0.001). Receiver operating characteristic curve (ROC) indicated that increased Hb-α-syn in ERCs could discriminate MSA patients from HCs, with a sensitivity of 71.8%, a specificity of 80.5%, and an area under the curve (AUC) of 0.837. The positive and negative predictive values at a cut-off value of 616.12 ng/mg were 78.7% and 74.1%, respectively. However, the increase in Hb-α-syn levels did not show any association with the age of onset and consultation, disease duration, and UMSARS (I-IV) score. This pilot study suggests that ERC Hb-α-syn is increased in MSA patients and could evaluate α-syn accumulation in the brain of patients.

Cold atmospheric plasma induces apoptosis in human colon and lung cancer cells through modulating mitochondrial pathway.

Cold atmospheric plasma (CAP) is an emerging and promising oncotherapy with considerable potential and advantages that traditional treatment modalities lack. The objective of this study was to investigate the effect and mechanism of plasma-inhibited proliferation and plasma-induced apoptosis on human lung cancer and colon cancer cells in vitro and in vivo. Piezobrush® PZ2, a handheld CAP unit based on the piezoelectric direct discharge technology, was used to generate and deliver non-thermal plasma. Firstly, CAPPZ2 treatment inhibited the proliferation of HT29 colorectal cancer cells and A549 lung cancer cells using CCK8 assay, caused morphological changes at the cellular and subcellular levels using transmission electron microscopy, and suppressed both types of tumor cell migration and invasion using the Transwell migration and Matrigel invasion assay. Secondly, we confirmed plasma-induced apoptosis in the HT29 and A549 cells using the AO/EB staining coupled with flow cytometry, and verified the production of apoptosis-related proteins, such as cytochrome c, PARP, cleaved caspase-3 and caspase-9, Bcl-2 and Bax, using western blotting. Finally, the aforementioned in vitro results were tested in vivo using cell-derived xenograft mouse models, and the anticancer effect was confirmed and attributed to CAP-mediated apoptosis. The immunohistochemical analysis revealed that the expression of cleaved caspase-9, caspase-3, PARP and Bax were upregulated whereas that of Bcl-2 downregulated after CAP treatment. These findings collectively suggest that the activation of the mitochondrial pathway is involved during CAPPZ2-induced apoptosis of human colon and lung cancer cells in vitro and in vivo.

Advances in nuclear medicine-based molecular imaging in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) are often aggressive, making advanced disease very difficult to treat using contemporary modalities, such as surgery, radiation therapy, and chemotherapy. However, targeted therapy, e.g., cetuximab, an epidermal growth factor receptor inhibitor, has demonstrated survival benefit in HNSCC patients with locoregional failure or distant metastasis. Molecular imaging aims at various biomarkers used in targeted therapy, and nuclear medicine-based molecular imaging is a real-time and non-invasive modality with the potential to identify tumor in an earlier and more treatable stage, before anatomic-based imaging reveals diseases. The objective of this comprehensive review is to summarize recent advances in nuclear medicine-based molecular imaging for HNSCC focusing on several commonly radiolabeled biomarkers. The preclinical and clinical applications of these candidate imaging strategies are divided into three categories: those targeting tumor cells, tumor microenvironment, and tumor angiogenesis. This review endeavors to expand the knowledge of molecular biology of HNSCC and help realizing diagnostic potential of molecular imaging in clinical nuclear medicine.

The seasonal variations and potential sources of nitrous acid (HONO) in the rural North China Plain.

Nitrous acid (HONO), an essential precursor of hydroxyl radicals (OH) in the troposphere, plays an integral role in atmospheric photochemistry. However, potential HONO sources remain unclear, particularly in rural areas, where long-term (including seasonal) measurements are scarce. HONO and related parameters were measured at a rural site in the North China Plain (NCP) during the winter of 2017 and summer and autumn of 2020. The mean HONO level was higher in winter (1.79 ± 1.44 ppbv) than in summer (0.67 ± 0.50 ppbv) and autumn (0.83 ± 0.62 ppbv). Source analysis revealed that the heterogeneous conversion (including photo-enhanced conversion) of NO2 on the ground surface dominated the daytime HONO production in the three seasons (43.1% in winter, 54.3% in summer, and 62.0% in autumn), and the homogeneous reaction of NO and OH contributed 37.8, 12.2, and 28.4% of the daytime HONO production during winter, summer, and autumn, respectively. In addition, the total contributions of other sources (direct vehicle emissions, particulate nitrate photolysis, NO2 uptake and its photo-enhanced reaction on the aerosol surface) to daytime HONO production were less than 5% in summer and autumn and 12.0% in winter. Unlike winter and autumn, an additional HONO source was found in summer (0.45 ± 0.21 ppbv h-1, 31.4% to the daytime HONO formation), which might be attributed to the HONO emission from the fertilized field. Among the primary radical sources (photolysis of HONO, O3, and formaldehyde), HONO photolysis was dominant, with contributions of 82.6, 49.3, and 63.2% in winter, summer, and autumn, respectively. Our findings may aid in understanding HONO formation in different seasons in rural areas and may highlight the impact of HONO on atmospheric oxidation capacity.

Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Deliver miR-21 to Promote Corneal Epithelial Wound Healing through PTEN/PI3K/Akt Pathway.

Objective: Rapid restoration of corneal epithelium integrity after injury is particularly important for preserving corneal transparency and vision. Mesenchymal stem cells (MSCs) can be taken into account as the promising regenerative therapeutics for improvement of wound healing processes based on the variety of the effective components. The extracellular vesicles form MSCs, especially exosomes, have been considered as important paracrine mediators though transferring microRNAs into recipient cell. This study investigated the mechanism of human umbilical cord MSC-derived small extracellular vesicles (HUMSC-sEVs) on corneal epithelial wound healing. Methods: HUMSC-sEVs were identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Corneal fluorescein staining and histological staining were evaluated in a corneal mechanical wound model. Changes in HCEC proliferation after HUMSC-sEVs or miR-21 mimic treatment were evaluated by CCK-8 and EdU assays, while migration was assessed by in vitro scratch wound assay. Full-length transcriptome sequencing was performed to identify the differentially expressed genes associated with HUMSC-sEVs treatment, followed by validation via real-time PCR and Western blot. Results: The sEVs derived from HUMSCs can significantly promote corneal epithelial cell proliferation, migration in vitro, and corneal epithelial wound healing in vivo. Similar effects were obtained after miR-21 transfection, while the beneficial effects of HUMSC-sEVs were partially negated by miR-21 knockdown. Results also show that the benefits are associated with decreased PTEN level and activated the PI3K/Akt signaling pathway in HCECs. Conclusion: HUMSC-sEVs could enhance the recovery of corneal epithelial wounds though restraining PTEN by transferring miR-21 and may represent a promising novel therapeutic agent for corneal wound repair.

Dexamethasone attenuates dry eye-induced pyroptosis by regulating the KCNQ1OT1/miR-214 cascade.

Dry eye disease (DED) is an inflammatory disorder of the ocular surface seriously affecting the quality of life of patients. Topical dexamethasone (Dex) administration protects the cornea from the hyperosmotic stress (HS) induced by tears. Pyroptosis participates in the activation of epithelial inflammation during DED. However, it remains unclear whether Dex attenuates the progression of DED through pyroptosis. In this study, we aimed to investigate the effect of Dex on DED using both cell and animal models and its underlying mechanism. The inflammatory factors contained in tears were detected using a cytokine assay. The pyroptosis in DED mice and human corneal epithelial cells (HCECs) treated with hyperosmotic medium under various treatments was evaluated by immunohistochemical assays (IHC) or western blotting (WB). RNA expression was manipulated with siRNA or agomir microRNAs and measured using a polymerase chain reaction. The scratch assay was used to assess the migration rate of HCECs. Remaining corneal defects were evaluated using fluorescein staining and photographed using a digital camera. Dex could suppress the release of inflammatory factors and notably attenuate pyroptosis, KCNQ1OT1 expression, and NF-κB activation induced by HS injury in vivo and in vitro. KCNQ1OT1 upregulation could activate pyroptosis by sponging miR-214. Furthermore, KCNQ1OT1 knockdown and miR-214 overexpression reversed the effect of HS, promoted the migration of HCECs, and accelerated corneal wound healing. Dex effectively suppressed HS-induced pyroptosis through the KCNQ1OT1/miR-214/caspase-1 signaling axis by inhibiting the NF-κB activation. Our results provide a novel understanding of the mechanism of Dex as an anti-inflammatory drug in DED.

Significant emission reductions of carbonaceous aerosols from residential coal burning by a novel stove.

Carbonaceous aerosols (CA) are crucial components in the atmospheric PM2.5 and derived from diverse sources. One of the major sources for CA is from the incomplete combustion of bituminous coal that has been prevailingly used by household stoves in rural areas for heating during winter. To efficiently eliminate the CA emission, a new household stove (NHS) was developed based on a novel combustion technology and CA emissions from the NHS and a traditional household stove (THS) were comparably investigated under the actual stove operation conditions in a farmer's house. Compared with the THS, the emission factors of organic carbon (OC), elemental carbon (EC), and water-soluble organic carbon (WSOC) from the NHS were reduced by 96%±1%, 98%±1%, and 91%±1% under the flaming process and 95%±1%, 96%±2%, and 83%±4% under the smoldering process, respectively. Additionally, the mass absorption efficiency of WSOC from the NHS reduced by 3 folds and the radiative forcing by WSOC relative to EC shrank remarkably by a factor of 3-8. Based on the reduction of emissions and light absorption of WSOC, the promotion of the NHS offers a possible solution to achieve the clean combustion of residential solid fuel.

Optimization of Ultrasonic-Assisted Extraction of Active Components and Antioxidant Activity from Polygala tenuifolia: A Comparative Study of the Response Surface Methodology and Least Squares Support Vector Machine.

Dried roots of Polygala tenuifolia (YuanZhi in Chinese) are widely used in Chinese herbal medicine. These components in YuanZhi have significant anti-oxidation properties owing to high levels of 3,6'-disinapoylsucrose (DISS) and Polygalaxanthone III (PolyIII). In order to efficiently extract natural medicines, response surface methodology (RSM) and least squares support vector machine (LSSVM) were used for the modeling and optimization of ultrasound-assisted extraction of DISS and PolyIII together to determine the antioxidant activity of the extracts obtained from YuanZhi. For the optimal combination of the comprehensive yield of DISS and PolyIII (Y), the Box-Behnken design (BBD) was used to improve extraction time (X1), extraction temperature (X2), liquid-solid ratio (X3), and ethanol concentration (X4). The optimal process parameters were determined to be as follows: extraction time, 93 min; liquid-solid ratio, 40 mL/g; extraction temperature, 48 °C; and ethanol concentration, 67%. With these conditions, the predictive optimal combination comprehensive evaluation value is 13.0217. It was clear that the LS-SVM model had higher accuracy in predictive and optimization capabilities, with higher antioxidant activity and lower relative deviations values, than did RSM. Hence, the LS-SVM model proved to be more effective for the analysis and improvement of the extraction process.

Polymeric coating on ß-TCP scaffolds provides immobilization of small extracellular vesicles with surface-functionalization and ZEB1-Loading for bone defect repair in diabetes mellitus.

Repair of critical-size bone defects in patients with diabetes mellitus (DM) has always been a challenge in clinical treatment. The process of bone defect regeneration can be impaired by underlying diseases including DM, but the mechanism remains unclear. In bone tissue engineering, the integration of bionic coatings and bioactive components into basic scaffolds are common function-enhancing strategies. Small extracellular vesicles (sEVs) have been applied for cell-free tissue regeneration in the last few years. We previously reported that sEVs have flexible and easily-extensible potential, through modular design and engineering modification. The impairment of CD31hiendomucinhi endothelial cells (ECs) whose function is coupling of osteogenesis and angiogenesis, is considered an important contributor to diabetic bone osteopathy, and ZEB1, which is highly expressed in CD31hiendomucinhi ECs, promotes angiogenesis-dependent bone formation. Thus we believe these ECs hold much promise for use in bone regeneration. In addition, c(RGDfC) has been reported to be a highly-effective peptide targeting αvß3, which is highly expressed in the bone microenvironment. In this study, we developed a hyaluronic acid (HA)/poly-L-lysine (PLL) layer-by-layer (LbL) self-assembly coating on ß-TCP (ß-tricalcium phosphate) scaffolds providing immobilization of modularized engineered sEVs (with c(RGDfC) surface functionalization and ZEB1 loading) to facilitate bone defect regeneration under DM conditions. RNA-seq was used to explore possible molecular mechanisms, and the therapeutic effects of bone regeneration were systematically evaluated in vitro and in vivo. Our data demonstrated that this strategy could be very effective in promoting the repair of diabetic bone defects, by enhancing angiogenesis, promoting osteogenesis and inhibiting osteoclast formation.