Assessing the impact of occlusal plane rotation on facial aesthetics in orthodontic treatment: a machine learning approach.

BACKGROUND: Adequate occlusal plane (OP) rotation through orthodontic therapy enables satisfying profile improvements for patients who are disturbed by their maxillomandibular imbalance but reluctant to surgery. The study aims to quantify profile improvements that OP rotation could produce in orthodontic treatment and whether the efficacy differs among skeletal types via machine learning. MATERIALS AND METHODS: Cephalometric radiographs of 903 patients were marked and analyzed by trained orthodontists with assistance of Uceph, a commercial software which use artificial intelligence to perform the cephalometrics analysis. Back-propagation artificial neural network (BP-ANN) models were then trained based on collected samples to fit the relationship among maxillomandibular structural indicators, SN-OP and P-A Face Height ratio (FHR), Facial Angle (FA). After corroborating the precision and reliability of the models by T-test and Bland-Altman analysis, simulation strategy and matrix computation were combined to predict the consequent changes of FHR, FA to OP rotation. Linear regression and statistical approaches were then applied for coefficient calculation and differences comparison. RESULTS: The regression scores calculating the similarity between predicted and true values reached 0.916 and 0.908 in FHR, FA models respectively, and almost all pairs were in 95% CI of Bland-Altman analysis, confirming the effectiveness of our models. Matrix simulation was used to ascertain the efficacy of OP control in aesthetic improvements. Intriguingly, though FHR change rate appeared to be constant across groups, in FA models, hypodivergent group displayed more sensitive changes to SN-OP than normodivergent, hypodivergent group, and Class III group significantly showed larger changes than Class I and II. CONCLUSIONS: Rotation of OP could yield differently to facial aesthetic improvements as more efficient in hypodivergent groups vertically and Class III groups sagittally.

The role and mechanism of citrus flavonoids in cardiovascular diseases prevention and treatment.

Cardiovascular diseases (CVDs) have been ranked as the leading cause of death in the world, whose global incidence is increasing year by year. Citrus, one of the most popular fruits in the world, is rich in flavonoids. Citrus flavonoids attract special attention due to a variety of biological activities, especially in the prevention and treatment of CVDs. The research progress of citrus flavonoids on CVDs have been constantly updated, but relatively fragmented, which needed to be systematically summarized. Hence, the recent research about citrus flavonoids and CVDs were reviewed, including the types and in vivo processes of citrus flavonoids, epidemiology study and mechanism on prevention and treatment of CVDs by citrus flavonoids. This review would provide a theoretical basis for the citrus flavonoids research and a new idea in the citrus industry development and application.

Cadmium induces renal inflammation by activating the NLRP3 inflammasome through ROS/MAPK/NF-κB pathway in vitro and in vivo.

Cadmium (Cd) has been reported to induce kidney damage by triggering oxidative stress and inflammation. The NLR family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated a role in the pathogenesis of inflammation. However, the connection between Cd and NLRP3 inflammasome in the development of renal inflammation remains unknown. In this study, in vitro experiments based on the telomerase-immortalized human renal proximal-tubule epithelial cell line (RPTEC/TERT1) were carried out. Results revealed that CdCl2 (2-8 µM) increased ROS production and activated NLRP3, thereby enhancing secretion of IL-1ß and IL-18 (P < 0.05). Knock-down of NLRP3 rescued the RPTEC/TERT1 cells from Cd-induced inflammatory damage. Cd activated the MAPK/NF-κB signaling pathway in RPTEC/TERT1 cells (P < 0.05). In addition, treatment with N-acetylcysteine (NAC) improved inflammation and blocked the upregulation of the MAPK/NF-κB signaling pathway. Pre-treatment with MAPK and NF-κB inhibitors also suppressed NLRP3 inflammasome activation (P < 0.05). Moreover, CdCl2 (25-00 mg/L) stimulated the MAPK/NF-κB signaling pathway, activated the NLRP3 inflammasome, and increased inflammatory response (P < 0.05) leading to renal injury in rats. Exposure to cadmium elevated serum levels of NLRP3 and IL-1ß in populations (P < 0.05). Further analysis found that serum NLRP3 and IL-1ß levels were positively correlated with urine cadmium (UCd) and urine N-acetyl-ß-D-glucosaminidase (UNAG). Overall, Cd induced renal inflammation through the ROS/MAPK/NF-κB signaling pathway by activating the NLRP3 inflammasome. Our research thus provides new insights into the molecular mechanism that NLRP3 contributes to Cd-induced kidney damage.

A novel polysaccharide isolated from Flammulina velutipes, characterization, macrophage immunomodulatory activities and its impact on gut microbiota in rats.

The structural characteristics of a novel Flammulina velutipes polysaccharide (FVP2) were explored in this study. Besides, immunomodulatory activities of FVP2 on RAW 264.7 cell and its impact on gut microbiota in rats were investigated. FVP2 has a molecular weight of 18.3 kD, and its main components include galactose (19.96%), glucose (60.66%) and mannose (19.38%). By NMR analysis, the main-chain structure consisted of (1 â†’ 3)-linked-ß-D-Gal, (1 â†’ 6) -linked-ß-D-Gal, (1 â†’ 6)-linked-α-D-Glc and (1 â†’ 3,6)-linked-α-D-Man was identified. Results of the in vitro assays on RAW 264.7 murine macrophage cells showed FVP2 could significantly up-regulate the expression of NO, TNF-α and IL-6. FVP2 was intragastrically administered to rats for 2 weeks. Compared with the control group, two caecal short-chain fatty acids (SCFAs) concentration (isobutyric acid and butyric acid) and the abundance of beneficial microbiota of the FVP2-treated group were significantly increased (p < .05) respectively. The results demonstrated that FVP2 could effectively enhance the level of butyric acid and increase beneficial gut microbiota, which could improve the intestinal barrier function and maintain the intestinal mucosal integrity, suggesting that FVP2 could potentially be an immunomodulators or a functional food to promote intestinal health.

A Two-Pronged Delivery Strategy Disrupting Positive Feedback Loop of Neutrophil Extracellular Traps for Metastasis Suppression.

Neutrophil extracellular traps (NETs) severely affect tumor metastasis through a self-perpetuating feedback loop involving two key steps: (1) mitochondrial aerobic respiration-induced hypoxia promotes NET formation and (2) NETs enhance mitochondrial metabolism to exacerbate hypoxia. Herein, we propose a two-pronged approach with the activity of NET-degrading and mitochondrion-damaging by simultaneously targeting drugs to NETs and tumor mitochondria of this loop. In addition to specifically recognizing and eliminating extant NETs, the NET-targeting nanoparticle also reduces NET-induced mitochondrial biogenesis, thus inhibiting the initial step of the feedback loop and mitigating extant NETs' impact on tumor metastasis. Simultaneously, the mitochondrion-targeting system intercepts mitochondrial metabolism and alleviates tumor hypoxia, inhibiting neutrophil infiltration and subsequent NET formation, which reduces the source of NETs and disrupts another step of the self-amplifying feedback loop. Together, the combination significantly reduces the formation of NET-tumor cell clusters by disrupting the interaction between NETs and tumor mitochondria, thereby impeding the metastatic cascade including tumor invasion, hematogenous spread, and distant colonization. This work represents an innovative attempt to disrupt the feedback loop in tumor metastasis, offering a promising therapeutic approach restraining NET-assisted metastasis.

Novel biomimetic peptide-loaded chitosan nanoparticles improve dentin bonding via promoting dentin remineralization and inhibiting endogenous matrix metalloproteinases.

OBJECTIVE: This study aims to synthesize novel chitosan nanoparticles loaded with an amelogenin-derived peptide QP5 (TMC-QP5/NPs), investigate their remineralization capability and inhibitory effects on endogenous matrix metalloproteinases (MMPs), and evaluate the dentin bonding properties of remineralized dentin regulated by TMC-QP5/NPs. METHODS: TMC-QP5/NPs were prepared by ionic crosslinking method and characterized by dynamic light scattering method, scanning electron microscopy, transmission electron microscope, atomic force microscope, Fourier transform infrared spectroscopy, and differential scanning calorimetry. The encapsulation and loading efficiency of TMC-QP5/NPs and the release of QP5 were examined. To evaluate the remineralization capability of TMC-QP5/NPs, the mechanical properties, and the changes in structure and composition of differently conditioned dentin were characterized. The MMPs inhibitory effects of TMC-QP5/NPs were explored by MMP Activity Assay and in-situ zymography. The dentin bonding performance was detected by interfacial microleakage and microshear bond strength (µSBS). RESULTS: TMC-QP5/NPs were successfully synthesized, with uniform size, good stability and biosafety. The encapsulation and loading efficiency of TMC-QP5/NPs was respectively 69.63 ± 2.22% and 13.21 ± 0.73%, with a sustained release of QP5. TMC-QP5/NPs could induce mineral deposits on demineralized collagen fibers and partial occlusion of dentin tubules, and recover the surface microhardness of dentin, showing better remineralization effects than QP5. Besides, TMC-QP5/NPs significantly inhibited the endogenous MMPs activity. The remineralized dentin induced by TMC-QP5/NPs exhibited less interfacial microleakage and higher µSBS, greatly improved dentin bonding. SIGNIFICANCE: This novel peptide-loaded chitosan nanoparticles improved resin-dentin bonding by promoting dentin remineralization and inactivating MMPs, suggesting a promising strategy for optimizing dentin adhesive restorations.

Revealing the representative facial traits of different sagittal skeletal types: decipher what artificial intelligence can see by Grad-CAM.

OBJECTIVES: Aesthetic improvement is a significant concern in dental therapy. While orthodontic treatment primarily targets hard tissue, the impact on soft tissue and the extent of these changes remains empirical. This study aims to unveil the intricate relationship between facial soft tissue and skeletal types using artificial intelligence (AI) analysis. METHODS: First, we collected a dataset of 1044 3-side-photographs and categorized them based on cephalometric measurements. After pre-processing and data augmentation, samples were fed to two independent models (Sfa, Res model) for training and testing. After validating that the Sfa model could accurately recognize the skeletal types based merely on photographs, Grad-CAM algorithm was utilized for model decipherment. Verification of the vital traits were carried out by facial adjustment simulation. RESULTS: The Sfa model demonstrated superior accuracy (0.9293) in identifying skeletal types based solely on soft tissue, compared to the Res model (0.8395) and even trained orthodontists (0.764), testifying our hypothesis that AI could be more capable of processing imperceptible cues compared to mankind. Intriguingly, Grad-CAM revealed that cheek volume, forehead, chin and nasolabial traits could be representative features of each type, exceeding the traditional knowledge which merely concerns mandible and chin. CONCLUSION: By constructing a deep learning model as a classifier and then decipher it with Grad-CAM, we revealed the subtle and unnoticed cues associating skeletal and soft tissue, as well as provided a novel approach that could aid practitioners in devising tailored treatment plans for enhanced esthetic outcomes. CLINICAL SIGNIFICANCE: The proposed AI methods offer valuable assistance to practitioners in identifying uncoordinated facial traits that may detract from a patient's attractiveness. By incorporating these insights into customized treatment plans, dental therapy can maximize esthetic benefits for individual patient.

A lipidomic study: Nobiletin ameliorates hepatic steatosis through regulation of lipid alternation.

Hepatic lipidome has been given emphasis for years since hepatic steatosis is the most remarkable character of nonalcoholic fatty liver diseases, an increasingly serious health issue worldwide. Nobiletin (NOB), one of the citrus flavonoids, exerted outstanding effect on lipid metabolism disorder. However, the underlying mechanism of NOB exerting effect on hepatic lipid alternation remains unclear. In this study, the animal model was built by feeding APOE-/- mice with high fat diet (HFD). The results of Oil Red O-stained liver section and the biochemical assay of lipid parameters confirmed the protective effect of NOB on hepatic steatosis and global lipid metabolism disorder in APOE-/- mice. The hepatic lipidomic study revealed a total of 958 lipids significantly altered by HFD and a total of 86, 116, 212 lipid metabolites changed by L-NOB (50 mg/kg/d NOB), M-NOB (100 mg/kg/d NOB) and H-NOB (200 mg/kg/d NOB) respectively. In the further screening analysis, an amount of 60 lipids were identified as the potential lipid markers of NOB treatment, most of which belonged to glycerophospholipids lipid categories and exhibited obvious correlation with each other and the lipid parameters related to hepatic steatosis. Taken together, our data demonstrated that glycerophospholipids metabolism played an indispensable role in the progression of hepatic steatosis and the protective effect of NOB. Besides, the modulation towards genes involved in lipid synthesis was observed after NOB administration in this study. These finding illustrated the antihepatic steatosis effect of NOB based on altering hepatic lipidome, particularly the glycerophospholipids metabolism, and provided a new insight in the pathogenesis of hepatic steatosis.

Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic-Reticulum-Targeted Therapy: Left or Right?

Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER-targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER-related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER-targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial-mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER-targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca2+ release from the ER and functions as a cascade amplifier of ER dysfunction, which accelerates Ca2+ release, resulting in immunogenic cell death (ICD) induction and eventually triggering immune responses. Together, ER-targeting therapy benefits from the autophagy-enhancing strategy more than the autophagy-inhibiting strategy for antitumor and antimetastasis treatment.

Biomimetic nanoparticle synchronizing pyroptosis induction and mitophagy inhibition for anti-tumor therapy.

Inducing pyroptosis in cancer cells can result in a strong anti-tumor immune response. Our preliminary study indicates that pyroptosis can be temporarily strengthened by disrupting mitochondria, but ultimately diminished by defensive mitophagy. Here, this study reports a nano-system camouflaged with hybrid membranes consisting of homologous cell membrane and corresponding mitochondrial membrane, which is used to deliver a drug complex Ca@GOx consisting of calcium phosphate and glucose oxidase. By taking advantage of the homing effects of cell membrane and the orientated fusion mechanism of subcellular membrane, the nano-system is able to deliver Ca@GOx to mitochondria, induce mitochondrial Ca2+ overload and generate significant levels of ROS, thus leading to pyroptosis. However, it's found that this system exhibits limited anti-tumor effects in vivo due to the compensatory activation of mitophagy serving as negative feedback to pyroptosis. To address this issue, mitophagy-inhibiting chloroquine is loaded into nanoparticles to intensify pyroptosis. As a result, the combination significantly promotes tumor infiltration of CD8+T cells and improves anti-tumor effects. Together, this study establishes a rational combination of targeted mitochondria disruption and mitophagy blockage for effective pyroptosis-based therapy.

Hypoglycemic Effect of Nobiletin via Gut Microbiota-Metabolism Axis on Hyperglycemic Mice.

SCOPE: Prediabetes and diabetes are major public health problems worldwide without specific cure currently. Gut microbes have been recognized as one of the vital therapeutic targets for diabetes. The exploration that nobiletin (NOB) whether affects gut microbes provides a scientific basis for its application. METHODS AND RESULTS: A hyperglycemia animal model is established using high-fat-fed ApoE-/- mice. After 24 weeks of NOB intervention, the level of fasting blood glucose (FBG), glucose tolerance, insulin resistance, and glycosylated serum protein (GSP) are measured. Pancreas integrity is observed by hematoxylin-eosin (HE) staining and transmission electron microscopy. 16s RNA sequencing and untargeted metabolomics are to determine the changes of intestinal microbial composition and metabolic pathways. The levels of FBG and GSP in hyperglycemic mice are effectively reduced. The secretory function of pancreas is improved. Meanwhile, NOB treatment restored the gut microbial composition and affected metabolic function. Furthermore, NOB treatment regulates the metabolic disorder mainly through lipid metabolism, amino acid metabolism, and Secondary bile acid metabolism, etc. In addition, it is possibly existed mutual promotion between microbe and metabolites. CONCLUSION: NOB probably plays a vital role in the hypoglycemic effect and pancreatic islets protection by improving microbiota composition and gut metabolism.

Nobiletin mitigates NAFLD via lipophagy and inflammation.

Nonalcoholic fatty liver disease (NAFLD), an increasingly serious health issue around the world, is characterized as a lipid metabolic disorder without any satisfactory treatment. Nobiletin (NOB), a citrus flavonoid, is considered a promising candidate for NAFLD prevention although there is limited research towards its exact mechanism. In this study, the preventative effect of NOB on NAFLD was investigated using high fat diet-fed ApoE-/- mice and free fatty acid-treated HepG2 cells. The results of hematoxylin and eosin staining of liver sections revealed that L-NOB (50 mg kg-1 d-1 NOB), M-NOB (100 mg kg-1 d-1 NOB) and H-NOB (200 mg kg-1 d-1 NOB) could significantly ameliorate NAFLD. Further exploration illustrated that NOB alleviated hepatic steatosis mainly via TFEB-mediated lysosomal biogenesis and lipophagy. Besides, NOB could mitigate NLRP3 inflammasome assembly and modulate M1/M2 macrophage polarization in vivo and in vitro. The mechanisms above allowed NOB to attenuate NAFLD, but their close association needed further investigation. Our research not only illustrated NOB as a potential candidate for NAFLD prevention, but also provided new insight into the pathogenic mechanisms of NAFLD development.

Reinforcing vascular normalization therapy with a bi-directional nano-system to achieve therapeutic-friendly tumor microenvironment.

Detrimental tumor microenvironment (TME) relies on distorted tumor vasculature for further tumor expansion. Vascular normalization therapy partly improves TME through vessel repairing, while these therapies enter an unbreakable Möbius ring due to each attempt hindered by pro-angiogenic factors from TME, leading to limited duration and extent of vascular normalization. Here, we developed a nanosystem including FLG and MAR/MPA nanodrugs to regulate both tumor vasculature and TME. FLG nanodrugs were constructed by connecting VEGF/VEGFR2 inhibitory low molecular weight heparin and gambogic acid with F3 peptide decoration for directly regulating on vascular endothelial cells and inducing vascular normalization. Meanwhile, MAR/MPA nanodrugs encapsulating CCL5/CCR5 blocker maraviroc were designed to restrict cytokine functions of angiogenesis and TME deterioration, contributing to vasculature repairing and TME reconstruction. Our results demonstrated this combined nanosystem synergistically induced vascular normalization window lasting 9 days and restored vascular permeability and oxygen supply in Panc-1 tumor. Furthermore, in melanoma, our nanosystem achieved immune improvements with increased infiltration of CD4+ and CD8+T cells in a remodeled TME. The two nanodrugs assisting each other in terms of both vascular repairing and TME improvements successfully reversed the vicious crosstalk to a positive one, achieving overall TME remodeling and promoting therapeutic efficiency.

PINK1/Parkin-mediated mitophagy inhibits warangalone-induced mitochondrial apoptosis in breast cancer cells.

Breast cancer is the most common malignancy in women all around the world, especially in many countries in Asia. However, antitumor drugs with unique curative effects and low toxic side-effects have not been found yet. Warangalone is an isoflavone extracted from the Cudrania tricuspidata fruit, and is reported to possess anti-inflammatory and anti-cancer activity. The purpose of this study was to determine the effects of warangalone on breast cancer cells. In this study, we found that warangalone decreased the viability of breast cancer cells by increasing the generation of reactive oxygen species (ROS) resulting in mitochondrial damage and decreased mitochondrial membrane potential (MMP). Warangalone induced mitochondrial apoptosis by increasing the BAX/BCL-2 ratio. Warangalone activated mitophagy via upregulation of PINK1 and Parkin expression and co-localization. The combination of warangalone and autophagy inhibitors or PINK1 siRNA increased the degree of cell apoptosis compared to treatment with warangalone alone. Warangalone damages mitochondria via ROS, thereby triggering PINK1/Parkin-mediated mitophagy and inducing mitochondrial apoptosis. However, autophagy/mitophagy protects against warangalone-induced mitochondrial apoptosis. A combination of warangalone and autophagy/mitophagy inhibitors may be a potential treatment for breast cancer.

Subacute toxicity of mesoporous silica nanoparticles to the intestinal tract and the underlying mechanism.

The biological safety of mesoporous silica nanoparticles (MSNs) has gradually attracted attention. However, few studies of their toxicity to the intestine and mechanism are available. In this study, their primary structures were characterized, and their subacute toxicity to mice was investigated. After 2 weeks of intragastric administration of MSNs, they significantly enhanced serum ALP, ALT, AST and TNF-α levels and caused infiltration of inflammatory cells in the spleen and intestines. MSNs induced intestinal oxidative stress and colonic epithelial cell apoptosis in mice. Intestinal epithelial cells exhibited mitochondrial ridge rupture and membrane potential decrease after MSN treatment. Additionally, MSNs increased ROS and NLRP3 levels and inhibited expression of the autophagy proteins LC3-II and Beclin1. MSNs significantly changed the intestinal flora diversity in mice, especially for harmful bacteria, leading to intestinal microecology imbalance. Meanwhile, MSNs influenced the expression of metabolites, which were involved in a range of metabolic pathways, including pyrimidine metabolism, central carbon metabolism in cancer, protein digestion and absorption, mineral absorption, ABC transport and purine metabolism. These results indicated that the subacute toxicity of mesoporous silicon was mainly caused by intestinal damage. Thus, our research provides additional evidence about the safe dosage of MSNs in the clinical and food industries.

Novel fenugreek gum-cellulose composite hydrogel with wound healing synergism: Facile preparation, characterization and wound healing activity evaluation.

Hydrogels can be used as bioactive dressings, which outperform traditional dressings and are widely used in wound hemostasis and healing. However, it is still a challenge to develop a hydrogel with good stability and strong mechanical properties for wound hemostasis and healing. Herein, we developed a novel composite polysaccharide hydrogel from fenugreek gum and cellulose. Fenugreek gum was combined with cellulose through hydrogen bonding to form a hydrogel to improve the mechanical properties of the composite hydrogel. The composite hydrogel had a porous structure, thermal stability, good water absorption and a sustained release effect. Furthermore, the composite hydrogel demonstrated good biocompatibility in vitro and in vivo. Notably, the superior performance of wound hemostasis and healing has been confirmed. Our results indicated that the composite hydrogel was a promising medical dressing and had the potential to promote wound healing.

[Mental health status and its influencing factors among general population and medical personnel in Guangdong Province during COVID-19 pandemic].

OBJECTIVE: To investigate the mental health status and its influencing factors among general population and healthcare professionals in Guangdong Province during COVID-19 pandemic. METHODS: A online questionnaire-based survey was conducted from March 11st to March 15th, 2020.The questionnaire consisted of 4 parts to survey the participants'basic information, understanding of COVID-19 outbreak-associated information, cognition of COVID-19 pandemic and status of anxiety and depression.A total of 1433 valid responses were collected, including 706 from the general population and 727 from healthcare professionals.Cronbach's α coefficient and exploratory factor analysis were used for reliability and validity assessment.Chi-square, Wilcoxon and Kruskal-Wallis test were used for univariate analysis and ordinal or nominal logistic regression was used for multivariate analysis of the data. RESULTS: There was no significant difference between the general population and the healthcare professionals in terms of anxiety, depression and cognition of COVID-19 outbreak after adjustment for demographic variables, but the levels of anxiety and depression of these participants were both higher than those before the pandemic.In the participants from the general population, multivariate logistic regressions showed an OR for anxiety of 1.93(1.18, 3.17) among those who spent 1-2 h a day in reading COVID-19-related news, while those who spent over 3 h had an OR value for anxiety of 1.88(1.14, 3.11);the unmarried individuals had a depression OR of 2.19(1.51, 3.18). Inaccurate cognition of COVID-19 outbreak was positive correlated with the occurrence of anxiety and depression.Unmarried individuals and those with higher educational levels had better cognition of COVID-19 outbreak.Among the healthcare professionals, multivariate logistic regressions suggested that insufficient rest time and worries about contracting the virus contributed to the occurrence of anxiety and depression.Among the nursing staff, the OR of obvious depression was 2.99(1.45, 6.18).Compared to healthcare professionals not working in designated hospital for COVID-19, those who work in the designated hospitals had ORs for obvious and severe depression of 0.48(0.25, 0.93) and 0.39(0.17, 0.89), respectively.Concerns over contracting the virus increased the possibility of incorrect cognition of COVID-19. CONCLUSIONS: Psychological interventions are essential for both the general population and healthcare professionals, especially for unmarried individuals in the general population and the nursing staff.An excessive exposure to COVID-19-related information may have detrimental effects on the mental health.For healthcare professionals, sufficient rest needs to be ensured, and education programs on COVID-19 should be implemented among both residents and healthcare professionals to improve their mental health.

Jet-Lagged Nanoparticles Enhanced Immunotherapy Efficiency through Synergistic Reconstruction of Tumor Microenvironment and Normalized Tumor Vasculature.

Lactic acid (LA), an anaerobic glycolysis metabolite normally oversecreted by tumor cells, can inhibit the activity of T cells and stimulate the rapid proliferation and migration of tumor endothelial cells (TECs), thereby limiting the synergistic treatment efficiency of tumor immunotherapy and vascular normalization. Herein, Jet-lagged nanoparticles, apatinib (APA)-loaded TEC-targeting nanodrug (APA/MCP) and lonidamine (LND)-loaded tumor cell-targeting nanodrug (LND/MCA), are constructed to combine vascular normalization therapy and tumor cell metabolic treatment. APA/MCP can block VEGF/VEGFR2 to inhibit TEC proliferation and LND/MCA can inhibit LA efflux to remodel tumor acid metabolism. After treatment, Jet-lagged nanoparticles remarkably reduce the level of LA in tumor microenvironment (TME) through limiting LA efflux. Besides, the pericyte cell coverage ratio of tumor vasculature increased to 69%, which is significantly improved compared to the APA/MCP group (47%). Moreover, the results of in vivo pharmacodynamic studies show that after the above synergistic reconstruction of TME and normalized tumor vasculature, the therapeutic effect of programmed death 1 (PD-1) drug is improved 3-folds to that of the PD-1 group. Above all, the strategy in this paper may propose an innovative vision to facilitate the tumor immunotherapy through high-precision spatiotemporal delivery strategy of nanodrugs.

Bio-orthogonal click-targeting nanocomposites for chemo-photothermal synergistic therapy in breast cancer.

Chemo-photothermal synergistic treatment has a high potential to complement traditional cancer therapy and amplify its outcome. Precision in the delivery of these therapeutic agents to tumor cells has been indicated as being key to maximizing their therapeutic effects. Method: We developed a bio-orthogonal copper-free click-targeting nanocomposite system (DLQ/DZ) that markedly improved specific co-delivery of the chemotherapeutic agent doxorubicin and the photosensitizer zinc phthalocyanine to breast cancer cells via a two-step mechanism. In the first step, an azide-modified sugar (tetraacetylated N-azidoacetyl-D-mannosamine, Ac4ManNAz) was injected intratumorally for glycoengineering of the tumor cell surface. Subsequently, DLQ/DZ was administered to achieve tumor enrichment via bio-orthogonal copper-free click-targeting. Results: During the first step in our experiments, high density azide groups (3.23×107/cell) were successfully glycoengineered on the surface of tumor cells following Ac4ManNAz administration in vitro. Subsequently, the highly efficient bio-orthogonal click chemical reaction between receptor-like azide groups on tumor cells and DBCO on nanocomposites significantly enhanced the cellular uptake and tumor-specific distribution (4.6x increase) of the nanocomposites in vivo. Importantly, Ac4ManNAz+DLQ/DZ treatment augmented the anti-cancer effect of combined chemotherapy and PTT (96.1% inhibition rate), nearly ablating the tumor. Conclusions: This bio-orthogonal click-targeting combination strategy may provide a promising treatment approach for surficial breast cancers.

Nobiletin Triggers Reactive Oxygen Species-Mediated Pyroptosis through Regulating Autophagy in Ovarian Cancer Cells.

Ovarian cancer is one of the most serious female malignancies worldwide. Despite intensive efforts being made to overcome ovarian cancer, there still remain limited optional treatments for this disease. Nobiletin, a prospective food-derived phytochemical extracted from citrus fruits, has recently been reported to suppress ovarian cancer cells, but the role of pyroptosis in ovarian carcinoma with nobiletin still remains unknown. In this study, we aim to explore the effect of nobiletin on ovarian carcinoma and further expound the underlying mechanisms of nobiletin-induced ovarian cancer cell death. Our results showed that nobiletin could significantly inhibit cell proliferation, induce DNA damage, and also lead to apoptosis by increasing the cleaved poly (ADP-ribose) polymerase (PARP) level of human ovarian cancer cells (HOCCs) in a dose-dependent manner. Moreover, we revealed that nobiletin decreased mitochondrial membrane potential and induced reactive oxygen species (ROS) generation and autophagy of HOCCs, contributing to gasdermin D-/gasdermin E-mediated pyroptosis. Taken together, nobiletin as a functional food ingredient represents a promising new anti-ovarian cancer candidate that could induce apoptosis and trigger ROS-mediated pyroptosis through regulating autophagy in ovarian cancer cells.