A DNA-based and bifunctional nanomedicine for alleviating multi-organ injury in sepsis under diabetic conditions.

Sepsis, defined as a life-threatening organ dysfunction, is associated with increased mortality in individuals with diabetes mellitus. In sepsis under diabetic conditions (SUDC), the superimposed inflammatory response and excessive production of reactive oxygen species (ROS) can cause severe damage to the kidney and liver, making it challenging to effectively repair multi-organ injury. In this study, we report the development of a DNA-based bifunctional nanomedicine, termed IL10-rDON, generated by assembling interleukin 10 (IL10) with rectangular DNA origami nanostructures (rDON) to address multi-organ dysfunction in SUDC. IL10-rDON was shown to predominantly accumulate in the kidney and liver of diabetic mice in vivo and effectively alleviate inflammatory responses through its anti-inflammatory IL10 component. In addition, the consumption of rDON itself significantly reduced excessive ROS in the liver and kidney. Serum and histological examinations further confirmed that IL10-rDON treatment could effectively improve liver and kidney function, as well as the survival of mice with SUDC. This study demonstrates an attractive antioxidant and anti-inflammatory nanomedicine for addressing acute liver and renal failure. The integration of rDON with therapeutic agents using DNA nanotechnology is a promising strategy for generating multifunctional nanomedicine to treat multi-organ dysfunction and other complicated diseases. STATEMENT OF SIGNIFICANCE: Sepsis under diabetic conditions (SUDC) leads to high mortality due to multiple organ failure such as acute liver and kidney injury. The anti-inflammatory cytokine interleukin 10 (IL10) holds great potential to treat SUDC, while disadvantages of IL-10 such as short half-life, non-specific distribution and lack of antioxidant activities limit its wide clinical applications. In this study, we developed a DNA-based, bifunctional nanomedicine (IL10-rDON) by assembling IL10 with rectangular DNA origami nanostructures (rDON). We found that IL10-rDON preferentially accumulated and sufficiently attenuated the increased levels of ROS and inflammation in the kidney and liver injury sites, and eventually improved the survival rate of mice with SUDC. Our finding provides new insights into the application of DNA-based nanomedicine in treating multi-organ failure.

Salvianolic acid B-loaded polydopamine-modified hollow mesoporous organic silica nanoparticles for treatment of breast cancer metastasis via suppressing cancer-associated fibroblasts.

OBJECTIVE: Drug Delivery System was constructed using dopamine-coated organic-inorganic hybrid hollow mesoporous organic silica nanoparticles (HMON-PDA) as drug carriers and salvianolic acid B (SAB) as a model drug. Then, we further investigated whether it can inhibit lung metastasis of breast cancer by inhibiting cancer-associated fibroblasts (CAFs). METHODS: The organic-inorganic hybrid hollow mesoporous organic silica nanoparticles (HMON) were prepared. The particle size, zeta potential, and polydispersion coefficient were characterized. High-performance liquid chromatography was used to determine the effect of different feed ratios of HMON and SAB on drug loading rate. Then, SAB-loaded HMON were modified by polydopamine, which is called SAB@HMON-PDA. Cell viability was detected by MTT assay. The migration of 4T1 cells was investigated by wound healing experiment, and the invasion of 4T1 cells was detected by the transwell method. Finally, the mouse breast cancer lung metastasis models were used to explore whether SAB@HMON-PDA can inhibit lung metastasis of breast cancer by inhibiting CAFs. RESULTS: The obtained nanoparticles have hollow spherical structure. The average particle sizes of HMON, SAB@HMON, and SAB@HMON-PDA were 143.5 ± 0.03, 138.3 ± 0.02, and 172.3 ± 0.18 nm, respectively. The zeta potentials were -44.33±0.15, -41.4 ± 1.30, and -24.13±0.47 mV, respectively. When the ratio of HMON to SAB was 2:1, the drug loading rate reached (18.37±0.04)%. In addition, the prepared SAB@HMON-PDA responded to release SAB under acidic and GSH conditions. The prepared SAB@HMON-PDA could inhibit the migration and invasion of 4T1 cells. The results showed that SAB@HMON-PDA and SAB could inhibit lung metastasis of breast cancer in mice, and SAB@HMON-PDA had a more significant inhibitory effect than SAB. CONCLUSION: We successfully prepared SAB@HMON-PDA with the dual response of pH and GSH. SAB@HMON-PDA can inhibit the migration and invasion of 4T1 cells, and the effect is more significant than free SAB. This inhibitory effect may be related to the inhibition of CAFs. In vivo experiments demonstrated that SAB@HMON-PDA can inhibit lung metastasis of breast cancer by inhibiting CAFs, and its effect was more significant than that of free SAB.

Multifunctional DNA-Based Hydrogel Promotes Diabetic Alveolar Bone Defect Reconstruction.

Diabetic alveolar bone defect (DABD) causes persistent bacterial infection, prolonged inflammation, and delayed bone healing, making it a considerable clinical challenge. In this study, by integrating silver nanoclusters (AgNCs) and M2 macrophage-derived extracellular vesicles (M2EVs), a multifunctional DNA-based hydrogel, called Agevgel, is developed with antibacterial, anti-inflammatory, immunomodulatory, and osteogenic properties to promote DABD rebuilding. AgNCs are tightly embedded into the DNA scaffolds and exhibit effective anti-bacterial activity, while immunomodulatory M2EVs are encapsulated within the shape-variable DNA scaffolds and exhibit potent anti-inflammatory and osteogenic properties. The results reveal that Agevgel effectively prolongs the local retention time and bioactivity of M2EVs in vivo. In particular, the sustained release of M2EVs can last for at least 7 days when applying Agevgel to DABD. Compared to free M2EVs or Aggel (AgNCs encapsulated within the DNA hydrogel) treatments, the Agevgel treatment accelerates the defect healing rate of alveolar bone and dramatically improves the trabecular architecture. Mechanistically, Agevgel plays a key role in regulating macrophage polarization and promoting the expression of proliferative and osteogenic factors. In summary, Agevgel provides a comprehensive treatment strategy for DABD with a great clinical translational value, highlighting the application of DNA hydrogels as an ideal bioscaffolds for periodontal diseases.

Potential mechanism of the AgNCs-hydrogel in promoting the regeneration of diabetic infectious wounds.

Diabetic infectious wound treatment is challenging due to insistent wound infections. To treat such complicated pathological diabetic infectious wounds, multifunctional materials need to be developed, and their mechanisms need to be understood. Here, we developed a material termed AgNCs-hydrogel, which is a multifunctional DNA hydrogel used as dressings by integrating it with antibacterial silver nanoclusters. The AgNCs-hydrogel was applied to promote the regeneration of diabetic infectious wounds in mice because it exhibited superior antibacterial activity and effective ROS-scavenging properties. Based on skin proteomics, we explored the potential mechanism of the AgNCs-hydrogel in treating mouse skin wounds. We found that the AgNCs-hydrogel can regulate some key proteins located primarily in the extracellular exosomes, involved in the negative regulation of the apoptotic process, and perform ATP binding to accelerate diabetic infected wound closure. Therefore, this study provided a multifunctional AgNCs-hydrogel and revealed its potential mechanism in promoting the regeneration of diabetic infectious wounds.

DNA-Based Hydrogels with Multidrug Sequential Release for Promoting Diabetic Wound Regeneration.

Diabetic wound (DW) regeneration is highly challenging due to persistent bacterial infection, excessive production of reactive oxygen species (ROS), prolonged inflammatory response, and insufficient angiogenesis. Ideal management requires the integration and sequential release of bactericidal, antioxidative, anti-inflammatory, and angiogenic agents during DW repair. Here, we develop a DNA-based multidrug hydrogel, termed Agilegel, to promote the efficient healing of DW. Hierarchically structured Agilegel can precisely control the sequential release of vascular endothelial growth factor-alpha (VEGF-α), silver nanoclusters (AgNCs), and interleukin-10 (IL-10) through covalent bonds in its primary structure (phosphate backbone), noncovalent bonds in its secondary structure (base pairs), and physical encapsulation in its advanced structure (pores), respectively. We demonstrate that Agilegel can effectively eliminate bacterial infection through AgNCs and mitigate ROS production through DNA scaffolds. Moreover, during the inflammatory phase, Agilegel promotes the polarization of macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotype using IL-10. Subsequently, Agilegel stimulates cell proliferation, angiogenesis, and extracellular matrix formation through the action of VEGF-α, thereby accelerating the closure of DW. Our results indicate that DNA hydrogels confer the capacity to regulate the sequential release of drugs, enabling them to effectively manage the phased intervention of multiple drugs in the treatment of complex diseases within physiological environments.

Recent research progress on the correlation between metabolic syndrome and Helicobacter pylori infection.

Background: Globally, metabolic syndrome (MS) and Helicobacter pylori (HP) infection, which have gained an epidemic status, are major challenges to human health, society, and medical professionals. Recent studies have demonstrated that MS is closely related to HP infection. Additionally, HP is an important risk factor for gastric cancer. However, systematic reviews on HP are lacking. This review aimed to summarize and analyze the potential correlation of HP infection with MS and its components, as well as the underlying mechanism, to provide reference and strategies for clinical prevention and treatment. Methodology: Previous studies examining the correlation between HP and MS since 1990 were retrieved from the PubMed, Web of Science, and Embase databases. The potential correlation between HP infection and MS and its components was comprehensively analyzed. The keywords "Helicobacter pylori," "HP," "metabolic syndrome," "hypertension," "obesity," "diabetes," or "dyslipidemia" were used in all fields. No language restrictions were imposed. Results: MS was strongly correlated to HP infection. The inflammatory response and inflammatory factors produced during HP infection are important etiological factors for insulin resistance and MS. The co-occurrence of long-term chronic inflammation and immune dysfunction with MS may be the predisposing factor for HP infection. MS components, such as diabetes, hypertension, dyslipidemia, and obesity were also correlated with HP infection in one or both directions. Conclusions: HP infection and MS may promote the pathogenesis of each other. The contribution of HP infection and MS to gastric cancer cannot be ruled out based on co-occurrence. The MS components diabetes and obesity may be bidirectionally correlated with HP infection.

Biodegradable and Antioxidant DNA Hydrogel as a Cytokine Delivery System for Diabetic Wound Healing.

Impaired diabetic wound healing is associated with the persistence of chronic inflammation and excessive oxidative stress, which has become one of the most serious clinical challenges. Wound dressings with anti-inflammatory and reactive oxygen species (ROS)-scavenging properties are desirable for diabetic wound treatment. In this study, a shape-adaptable, biodegradable, biocompatible, antioxidant, and immunomodulatory interleukin-33 (IL-33)-cytogel is developed by encapsulating IL-33 into physically cross-linked DNA hydrogels and used as wound dressings to promote diabetic wound healing. The porous microstructures and biodegradable properties of the IL-33-cytogel ensure the local sustained-release of IL-33 in the wound area, where the sustained-release of IL-33 is maintained for at least 7 days. IL-33-cytogel can induce local accumulation of group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs), as well as M1-to-M2 transition at the wound sites. Additionally, the antioxidant and biocompatible characteristics of DNA hydrogels promote the scavenging of intracellular ROS without affecting cell viability. As a result, local inflammation in the diabetic wound area is resolved upon IL-33-cytogel treatment, which is accompanied by improved granulation tissue regeneration and accelerated wound closure. This study demonstrates a promising strategy in tissue engineering and regenerative medicine by incorporating DNA hydrogels and cytokine immunotherapy for promoting diabetic wound healing.

The relationship between TSH levels and clinical pregnancy outcomes for patients who undergo in vitro fertilization/intracytoplasmic sperm injection: a retrospective study.

Background: Thyroid dysfunction is linked with adverse pregnancy outcomes, an upper limit of a normal thyroid-stimulating hormone (TSH) threshold of 4.12-4.5 mIU/L should be considered for subclinical hypothyroidism in the infertile female population. Whereas, it's controversial whether or not the infertility thresholds for upper limit of TSH threshold of 2.5 mIU/L. In our study examines the correlation of optimal TSH levels and clinical pregnancy outcomes after fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) embryo transfer cycles. Methods: Patients who underwent fresh IVF/ICSI embryo transfer cycles for the first time who presented between January 1, 2015 and December 31, 2017 at the Chongqing Institute of Reproductive and Genetic, Chongqing Health Center for Women and Children were enrolled. We excluded patients with ≥40 years, body mass index (BMI) ≤18 or ≥28 kg/m2, the man with severe oligoasthenospermia, women with poor ovarian reserve, and presence of endocrine disorders, uterine anomaly, sactosalpinx, abnormal thyroid function, preimplantation genetic diagnosis, and chromosomal abnormality or polymorphism. Baseline characteristics and clinical pregnancy outcomes were observed in our study. We detected between TSH levels and clinical pregnancy outcomes in patients undergoing IVF/ICSI by Receiver operating characteristic (ROC) curves and logical regression. Results: A total of 6,088 patients who undergo IVF/ICSI were included. We first detected that the live birth rate had a statistically significant difference when the TSH level was 3 mIU/L. With the TSH ≤3 mIU/L group having a higher live birth rate than the TSH >3 mIU/L group (51.79% vs. 47.89%, P=0.024), meanwhile no significant difference were revealed between the early miscarriage rate (12.54% vs. 14.97%, P=0.091) and early clinical pregnancy rate (59.21% vs. 56.32%, P=0.114). There were no differences in pregnancy outcomes when the TSH threshold was at 3.5 or 4 mIU/L and no association was detected between TSH levels and clinical pregnancy outcomes in patients undergoing IVF/ICSI by ROC curves and logical regression. Conclusions: Patients undergoing IVF/ICSI with a serum TSH level ≤3 mIU/L may have a higher live birth rate rather than ≤2.5 or ≤4 mIU/L.

Physically Cross-Linked DNA Hydrogel-Based Sustained Cytokine Delivery for In Situ Diabetic Alveolar Bone Rebuilding.

The development of a biodegradable and shape-adaptable bioscaffold that can enhance local cytokine retention and bioactivity is essential for the application of immunotherapy in periodontal diseases. Here, we report a biodegradable, anti-inflammatory, and osteogenic ILGel that uses a physically cross-linked DNA hydrogel as a soft bioscaffold for the long-term sustained release of cytokine interleukin-10 (IL-10) to accelerate diabetic alveolar bone rebuilding. Porous microstructures of ILGel favored the encapsulation of IL-10 and maintained IL-10 bioactivity for at least 7 days. ILGel can be gradually degraded or hydrolyzed under physiological conditions, avoiding the potential undesired side effects on dental tissues. Long-term sustained release of bioactive IL-10 from ILGel not only promoted M2 macrophage polarization and attenuated periodontal inflammation but also triggered osteogenesis of mesenchymal stem cells (MSCs), leading to accelerated alveolar bone formation and healing of alveolar bone defects under diabetic conditions in vivo. ILGel treatment significantly accelerated the defect healing rate of diabetic alveolar injury up to 93.42 ± 4.6% on day 21 post treatment compared to that of free IL-10 treatment (63.30 ± 7.39%), with improved trabecular architectures. Our findings imply the potential application of the DNA hydrogel as the bioscaffold for cytokine-based immunotherapy in diabetic alveolar bone injury and other periodontal diseases.

A cooperative collision-avoidance control methodology for virtual coupling trains.

To further improve the line transport capacity, virtual coupling has become a frontier hot topic in the field of rail transit. Specially, the safe and efficient following control strategy based on relative distance braking mode (RDBM) is one of the core technologies. This paper innovatively proposes a cooperative collision-avoidance control methodology, which can enhance the operation efficiency on the premise of ensuring the safety. Firstly, a novel framework for the RDBM based on the predicted trajectory of the preceding train is proposed for the train collision-avoidance control. To reduce the train following distance, a cooperative control model is further proposed and is formulated as a Markov decision process. Then, the Deep-Q-Network (DQN) algorithm is introduced to solve the efficient control problem by learning the safe and efficient control strategy for the following train where the critical elements of the reinforcement learning framework are designed. Finally, experimental simulations are conducted based on the simulated environment to illustrate the effectiveness of the proposed approach. Compared with the absolute distance braking mode (ADBM), the minimum following distance between the adjacent trains can be reduced by 70.23% on average via the proposed approach while the safety can be guaranteed.

Mechanism of the Fibroblast Growth Factor 23/α-Klotho Axis in Peripheral Blood Mononuclear Cell Inflammation in Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent type of dementia and threatens the health of most elderly people and poses a huge burden to families and society. The fibroblast growth factor 23 (FGF23)/α-Klotho axis is associated with multiple aging-related diseases. Hence, this study explored the mechanism of the FGF23/α-Klotho axis in AD. FGF23/α-Klotho protein contents and levels of inflammatory cytokines in AD patients were measured, and the correlation between FGF23/α-Klotho protein contents and inflammatory cytokines was analyzed. FGF23 and α-Klotho expressions were blocked in peripheral blood mononuclear cells (PBMCs) in AD patients (AD-PBMCs) to assess the effects on cell inflammation and the Wnt/ß-catenin pathway activation. The Wnt/ß-catenin pathway was inhibited to evaluate cell inflammation. Combined treatments of the cells were conducted to verify the role of the FGF23/α-Klotho axis and the Wnt/ß-catenin pathway in inflammation in AD-PBMCs. Increased FGF23 protein concentration and reduced α-Klotho protein concentration were observed in AD patients and correlated with inflammatory cytokine levels. FGF23 inhibition or α-Klotho overexpression reduced the production of inflammatory cytokines and activated the Wnt/ß-catenin pathway in AD-PBMCs. Blocking the Wnt/ß-catenin pathway increased inflammatory cytokine production in AD-PBMCs and annulled the effects of the FGF23/α-Klotho axis on AD-induced cell inflammation. We concluded that the FGF23/α-Klotho axis can regulate the AD-induced cell inflammation through the Wnt/ß-catenin pathway.

Liver injury in COVID-19 patients with metabolic syndrome-a narrative review.

OBJECTIVE: To comprehensively analyze that how liver injury in patients with metabolic syndrome is affected by coronavirus disease 2019 (COVID-19) and provide clinical reference to their prevention and treatment. BACKGROUND: The current COVID-19 pandemic poses a major threat to human life and health. Metabolic syndrome is also a major global health problem, and evidence suggests that patients with metabolic syndrome are at an increased risk of COVID-19 complications. Liver injury is one of the main manifestations of extra-pulmonary organ injury in patients with COVID-19. Currently, the effects of metabolic syndrome on liver injury in patients with COVID-19 are unclear. METHODS: In this study, we searched the PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases for articles on the latest developments of liver injury in COVID-19 patients with metabolic syndrome from 2019 to comprehensively analyze the current knowledge of how liver injury in patients with metabolic syndrome is affected by COVID-19. We used the free key words "metabolic syndrome" OR "hypertension" OR "obesity" OR "diabetes" OR "dyslipidemia" OR "liver injury" OR "SARS-CoV-2" OR "COVID-19" in all fields. We imposed no language restrictions. CONCLUSIONS: Both COVID-19 and metabolic syndrome and its components are closely related to liver injury, may induce liver injury through direct or indirect mechanisms. Therefore, when COVID-19 is combined with metabolic syndrome, it may increase the risk of liver injury, and it cannot be ruled out that the two diseases have a superimposed effect on liver injury.

Treatment of α-1 antitrypsin deficiency using hepatic-specified cells derived from human-induced pluripotent stem cells.

OBJECTIVE: α-1 antitrypsin deficiency (AATD) is an inherited liver disease characterized by the "Z" mutations, which can cause pulmonary emphysema and liver fibrosis. Transplantation of the organ (i.e., the lung/liver) is the best treatment method, however, the scarcity of suitable donors limits its application. The cell transplantation technique poses an alternative way of combating liver failure. METHODS: Hepatic specific differentiation of the human induced pluripotent stem cells (iPSCs) was initiated with 100 ng/mL activin A, followed by 20 ng/mL of BMP-4 and 10 ng/mL of FGF-2. The cells were transplanted into the livers of AATD transgenic mice using intra-splenic injections. FK506 was used as an immunosuppressor. At 1, 3, and 6 months post-transplantation, the human serum albumin (HSA) levels and its DNA contents, and the mice serum and liver tissues were measured using enzyme-linked immunosorbent assays (ELISA), polymerase chain reactions (PCR), and immunohistochemistry to estimate the repopulation of the hepatic-specified cells. RESULTS: Post transplantation, the hepatic-specified cells were found to be successfully and progressively repopulated in the transgenic mice livers. Additionally, the hepatic-specified cells did not display any carcinogenicity, as confirmed by the absence of any tumors on the animals. CONCLUSION: We provide a time saving and low cost method of transplanting hepatic-specified cells into the livers of AATD mice without any risk of carcinogenicity, a method that may be a potential option for the treatment of AATD.

A method overview in smart aquaculture.

Aquaculture is an important part of agricultural economy. In the past, major farming accidents often occurred due to subjective experience. There are many factors affecting the water quality of aquaculture. Maintaining an ecological environment with good water quality is the most critical link to ensure the production efficiency and quality of aquaculture. With the continuous development of science and technology, intelligence and informatization in aquaculture has become a new trend. Smart aquaculture cannot only realize real-time monitoring, prediction, warning, and risk control of the physical and chemical factors of the aquaculture environment but can also conduct real-time monitoring of the characteristics and behaviors of the fish, which infers the changes of the aquaculture ecological environment. In this paper, the research achievements over past two decades both are summarized from four aspects: water quality factor acquisition and pre-processing, water quality factor prediction, morphological characteristics, and behavioral characteristic recognition of fish and the mechanism between fish behavior and water quality factors. The advantages and disadvantages of existing research routes, algorithm models, and research methods in smart aquaculture are summarized. The work in this paper can provide a well-organized and summative knowledge reference for further study on the dynamic mechanism between the changes of water quality factors and the fish body characteristics and behavior. Meanwhile, the work can also provide valuable reference for promoting the smart, ecological, and efficient development of aquaculture.

Clinical characteristics of 225 patients with COVID-19 in a tertiary Hospital near Wuhan, China.

BACKGROUND: The 2019 coronavirus disease (COVID-19) was first identified in Wuhan, Hubei, China in December 2019, caused by a novel coronavirus (SARS-CoV-2). There is a need to study the clinical features of patients in a hospital near Wuhan. OBJECTIVE: To identify clinical features of patients with COVID-19 in a tertiary hospital near Wuhan. STUDY DESIGN: General information, clinical manifestations, laboratory data, and computed tomography (CT) data were collected for 225 patients diagnosed of COVID-19 admitted between January 20 and February 14, 2020, to the Hanchuan City People's Hospital. RESULTS: The patients included 120 male and 105 females who had no connection to the Wuhan Huanan Seafood Market. Their average age was 50 ±â€¯14 years. The major clinical symptoms were fever (84.44% of patients), cough (56.44% of patients), and dyspnea (4.00% of patients); 3.56%-22.67% of subjects suffered from expectoration, fatigue, chills, headache, chest pain, and pharyngalgia. Hypertension was present in 20.89% of patients. The counts of white blood cells (WBCs) and lymphocytes were normal or decreased in 86.67% and 99.11% of patients. CRP was increased in 86.22% of patients, PCT in 10.67%, and ESR in 90.22%. CT showed that 86.22% of patients had multiple patchy glassy shadows in both lungs, particularly in the peripheral area. Thirty-seven (16.44%) patients were diagnosed with severe COVID-19. Methylprednisolone was administered in 44.44% of cases. The mortality among the patients was 0.89%. CONCLUSIONS: Clinical characteristics of COVID-19 patients in the tertiary hospital near Wuhan are very similar to those found in Wuhan, but the lower mortality.