ABSTRACT
The signal sequence played a crucial role in the efficacy of mRNA vaccines against virus pandemic by influencing antigen translation. However, limited research had been conducted to compare and analyze the specific mechanisms involved. In this study, a novel approach was introduced by substituting the signal sequence of the mRNA antigen to enhance its immune response. Computational simulations demonstrated that various signal peptides differed in their binding capacities with the signal recognition particle (SRP) 54 M subunit, which positively correlated with antigen translation efficiency. Our data revealed that the signal sequences of tPA and IL-6-modified receptor binding domain (RBD) mRNA vaccines sequentially led to higher antigen expression and elicited more robust humoral and cellular immune protection against the SARS-CoV-2 compared to the original signal sequence. By highlighting the importance of the signal sequence, this research provided a foundational and safe approach for ongoing modifications in signal sequence-antigen design, aiming to optimize the efficacy of mRNA vaccines.
Subject(s)
Protein Sorting Signals , SARS-CoV-2 , mRNA Vaccines , Animals , Mice , SARS-CoV-2/immunology , COVID-19/prevention & control , COVID-19/immunology , Mice, Inbred BALB C , RNA, Messenger/genetics , COVID-19 Vaccines/immunology , Female , Humans , Antigens, Viral/immunology , Antigens, Viral/genetics , Antigens, Viral/chemistry , Antibodies, Viral/immunology , Immunity, Humoral , Vaccines, Synthetic/immunology , Immunity, CellularABSTRACT
BACKGROUND: Psychological distress, especially depression, associated with perianal fistulizing Crohn's disease (PFCD) is widespread and refractory. However, there is a surprising paucity of studies to date that have sought to identify the prevalence and risk factors of depression associated with PFCD. AIM: To estimate the prevalence of depressive symptoms and investigate the depression-related risk factors in patients with PFCD. METHODS: The study was conducted in the form of survey and clinical data collection via questionnaire and specialized medical staff. Depressive symptoms, life quality, and fatigue severity of patients with PFCD were assessed by Patient Health Questionnaire-9, Inflammatory Bowel Disease Patient Quality of Life Questionnaire (IBDQ), and Inflammatory Bowel Disease (IBD) Fatigue Patient Self-assessment Scale. The basic demographic information, overall disease features, perianal clinical information, and laboratory inflammation indicators were also gathered. Multivariate regression analysis was ultimately used to ascertain the risk factors of depression associated with PFCD. RESULTS: A total of 123 patients with PFCD were involved, and 56.91% were suffering from depression. According to multivariate logistic regression analysis, Perianal Disease Activity Index (PDAI) score [odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.50 to 0.95], IBDQ score (OR = 0.93, 95%CI: 0.88 to 0.97), modified Van Assche index (OR = 1.24, 95%CI: 1.01 to 1.53), and IBD Fatigue score (OR = 1.72, 95%CI: 1.23 to 2.42) were independent risk factors of depression-related prevalence among patients with PFCD (P < 0.05). Multiple linear regression analysis revealed that the increasing perianal modified Van Assche index (ß value = 0.166, 95%CI: 0.02 to 0.31) and decreasing IBDQ score (ß value = -0.116, 95%CI: -0.14 to -0.09) were independently associated with the severity of depression (P < 0.05). CONCLUSION: Depressive symptoms in PFCD patients have significantly high prevalence. PDAI score, modified Van Assche index, quality of life, and fatigue severity were the main independent risk factors.
ABSTRACT
The Notch signaling pathway is important in cell cycle regulation and cell proliferation. The transcriptional repressor Suppressor of Hairless [Su(H)] is a molecular switch for downstream target genes of the Notch signaling pathway but the regulatory mechanism of the Su(H) gene in the cell cycle is unclear. We determined the function of the Notch signaling pathway and Bombyx mori Su(H) [BmSu(H)] in the regulation of the silkworm cell cycle. Inhibition of Notch signaling promoted the replication of DNA in silkworm gland cells and expression of the BmSu(H) gene was significantly reduced. Overexpression of the BmSu(H) gene inhibited DNA replication and cell proliferation of silkworm cells, whereas knockout of the BmSu(H) gene promoted DNA replication and cell proliferation. Knockout of the BmSu(H) in silkworms improved the efficiency of silk gland cell endoreplication and increased important economic traits. We demonstrated that BmSu(H) protein can directly bind to the promoters of BmCyclinA, BmCyclinE and BmCDK1 genes, inhibiting or promoting their transcription at the cell and individual level. This study identified molecular targets for genetic improvement of the silkworm and also provided insights into the regulatory mechanism of the cell cycle.
Subject(s)
Bombyx , Cell Cycle , Insect Proteins , Animals , Bombyx/genetics , Bombyx/metabolism , Cell Cycle/genetics , Insect Proteins/genetics , Insect Proteins/metabolism , Receptors, Notch/metabolism , Receptors, Notch/genetics , Signal Transduction , Silk/genetics , Cell Proliferation/genetics , DNA Replication , Promoter Regions, Genetic/genetics , Endoreduplication , Gene Expression Regulation , Repressor Proteins/genetics , Repressor Proteins/metabolismABSTRACT
Multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) is a formidable pathogen responsible for severe intracranial infections post-craniotomy, exhibiting a mortality rate as high as 71%. Tigecycline (TGC), a broad-spectrum antibiotic, emerged as a potential therapeutic agent for MDR A. baumannii infections. Nonetheless, its clinical application was hindered by a short in vivo half-life and limited permeability through the blood-brain barrier (BBB). In this study, we prepared a novel core-shell nanoparticle encapsulating water-soluble tigecycline using a blend of mPEG-PLGA and PLGA materials. This nanoparticle, modified with a dual-targeting peptide Aß11 and Tween 80 (Aß11/T80@CSs), was specifically designed to enhance the delivery of tigecycline to the brain for treating A. baumannii-induced intracranial infections. Our findings demonstrated that Aß11/T80@CSs nanocarriers successfully traversed the BBB and effectively delivered TGC into the cerebrospinal fluid (CSF), leading to a significant therapeutic response in a model of MDR A. baumannii intracranial infection. This study offers initial evidence and a platform for the application of brain-targeted nanocarrier delivery systems, showcasing their potential in administering water-soluble anti-infection drugs for intracranial infection treatments, and suggesting promising avenues for clinical translation.
Subject(s)
Acinetobacter Infections , Acinetobacter baumannii , Humans , Tigecycline/pharmacology , Tigecycline/therapeutic use , Minocycline/pharmacology , Acinetobacter Infections/drug therapy , Drug Resistance, Multiple, Bacterial , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , WaterABSTRACT
BACKGROUND: Autism spectrum disorder (ASD) is heritable neurodevelopmental disorders (NDDs), but environmental risk factors have also been suggested to a play a role in its development. Prenatal, perinatal and parental factors have been associated with an increased risk of ASD in children. The aim of the present study was to explore the prenatal, perinatal, and parenting risk factors in children with autism spectrum disorder (ASD) from Beijing, China by comparing them with typically developing (TD) children. METHODS: A sample of 151 ASD children's parents who from rehabilitation institutions in Beijing were enrolled in this study, and an additional 151 children from kindergartens in Beijing were recruited as a control group (child age: mean = 4.4 years). TD children were matched according to age, sex and maternal education. We explored the maternal AQ (Autism Spectrum Quotient) scores (mean:19.40-19.71, no significant difference between two groups) to referring the genetic baseline. This study evaluated 17 factors with unadjusted and adjusted analyses. RESULTS: Birth asphyxia was associated with a more than a thirteen-fold higher risk of ASD (adjusted odds ratio (AOR) = 13.42). Breastfeeding difficulties were associated with a higher risk of ASD(AOR = 3.46). Parenting influenced the risk of ASD, with low responding (LR) and harsh or neglectful parenting associated with a higher risk of ASD in offspring (AOR = 2.37 for LR, AOR = 3.42 for harsh parenting and AOR = 3.01 for neglectful parenting). Maternal fever during pregnancy was associated with a higher risk of ASD in offspring (AOR = 3.81). CONCLUSIONS: Many factors were associated with ASD in offspring. Further assessment is needed to elucidate the role of modifiable environmental factors to inform prevention strategies.
Subject(s)
Autism Spectrum Disorder , Pregnancy Complications , Pregnancy , Female , Child , Humans , Child, Preschool , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/etiology , Risk Factors , Parents , Family , Case-Control StudiesABSTRACT
Bacterial infection-related diseases continue to pose a significant challenge to global human health. Antibiotic therapy, as a conventional therapeutic strategy, has been extensively employed in clinical settings to treat bacterial infections. However, the effectiveness of these conventional strategies is often impeded by the antimicrobial resistance of bacteria. Consequently, the development of alternative antibacterial agents has emerged as a promising approach to addressing this issue. In recent years, single-atom nanozymes (SAzymes), a novel class of nanocatalytic medicines, have garnered increasing attention due to their numerous advantages, including uniformly dispersed metal active sites, tunable coordination structures, and maximal metal atomic utilization efficiency. To date, a variety of SAzymes have been developed and widely applied in antibacterial therapy. In this minireview, we provide an overview of the latest advances in the synthesis and antibacterial application of different metal-based SAzymes. Furthermore, we discuss the future challenges and opportunities of utilizing SAzymes for bacterial infection treatment. It is our hope that this minireview will contribute to the development of the next generation of SAzyme-based antibacterial agents.
Subject(s)
Bacterial Infections , Humans , Bacterial Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic useABSTRACT
Despite highly effective vaccines, Marek's disease (MD) causes great economic loss to the poultry industry annually, largely due to the continuous emergence of new MD virus (MDV) strains. To explore the pathogenic characteristics of newly emerged MDV strains, we selected two strains (AH/1807 and DH/18) with clinically different pathotypes. We studied each strain's infection process and pathogenicity and observed differences in immunosuppression and vaccine resistance. Specific pathogen-free chickens, unvaccinated or vaccinated with CVI988, were challenged with AH/1807 or DH/18. Both infections induced MD damage; however, differences were observed in terms of mortality (AH/1807: 77.8%, DH/18: 50%) and tumor rates (AH/1807: 50%, DH/18: 33.3%). The immune protection indices of the vaccine also differed (AH/1807: 94.1, DH/18: 61.1). Additionally, while both strains caused interferon-ß and interferon-γ expression to decline, DH/18 infection caused stronger immunosuppression than AH/1807. This inhibition persisted even after vaccination, leading to increased replication of DH/18 that ultimately broke through vaccine immune protection. These results indicate that both strains have different characteristics, and that strains such as DH/18, which cause weaker pathogenic damage but can break through vaccine immune protection, require further attention. Our findings increase the understanding of the differences between epidemic strains and factors underlying MD vaccination failure in China.
Subject(s)
Herpesvirus 2, Gallid , Marek Disease Vaccines , Marek Disease , Poultry Diseases , Vaccines , Animals , Marek Disease/epidemiology , Marek Disease/prevention & control , Chickens , Virulence , China/epidemiology , Poultry Diseases/epidemiology , Poultry Diseases/prevention & controlABSTRACT
Introduction: Maternal immune activation (MIA) is closely related to the onset of autism-like behaviors in offspring, but the mechanism remains unclear. Maternal behaviors can influence offspring's development and behaviors, as indicated in both human and animal studies. We hypothesized that abnormal maternal behaviors in MIA dams might be other factors leading to delayed development and abnormal behaviors in offspring. Methods: To verify our hypothesis, we analyzed poly(I:C)-induced MIA dam's postpartum maternal behavior and serum levels of several hormones related to maternal behavior. Pup's developmental milestones and early social communication were recorded and evaluated in infancy. Other behavioral tests, including three-chamber test, self-grooming test, open field test, novel object recognition test, rotarod test and maximum grip test, were performed in adolescence of pups. Results: Our results showed that MIA dams exhibit abnormal static nursing behavior but normal basic care and dynamic nursing behavior. The serum levels of testosterone and arginine vasopressin in MIA dams were significantly reduced compared with control dams. The developmental milestones, including pinna detachment, incisor eruption and eye opening, were significantly delayed in MIA offspring compared with control offspring, while the weight and early social communication showed no significant differences between the two groups. Behavioral tests performed in adolescence showed that only male MIA offspring display elevated self-grooming behaviors and reduced maximum grip. Discussion: In conclusion, MIA dams display abnormal postpartum static nursing behavior concomitantly with reduced serum levels of testosterone and arginine vasopressin, possibly involving in the pathogenesis of delayed development and elevated self-grooming in male offspring. These findings hint that improving dam's postpartum maternal behavior might be a potential regime to counteract delayed development and elevated self-grooming in male MIA offspring.
ABSTRACT
Background: This study aimed to construct a magnetic resonance imaging (MRI) index for assessing transmural inflammatory activity in the small intestine of patients with Crohn' disease which enables rapid and non-invasive quantitative assessment of Crohn's disease inflammation. Methods: In this prospective study, magnetic resonance enterography (MRE) was performed to examine 29 consecutive patients with Crohn's disease who had undergone ileocolonoscopy in the Jingling hospital of Nanjing. This diagnostic study was not registered on a clinical trial platform. We grade the T2 signal ratio and T1 enhancement ratio with a score of 0 to 3. The ratios were calculated as follow: terminal ileal inflammation of intestinal T2 signal intensity/adjacent normal intestinal T2 signal intensity (T2 ratio 1), terminal ileal inflammation intestinal T2 signal intensity/vertical muscle T2 signal intensity (T2 ratio 2), the fifth phase of the inflamed intestinal T1 signal intensity/noncontrast intestine T1 signal (T1 ratio 3), and the fifth phase of inflamed intestinal T1 signal intensity/adjacent normal intestinal T1 signal (T1 ratio 4). Wall thickness, lymph nodes, perimural T2 signal, comb sign, and ulceration were graded from 0 to 3. the simple endoscopic score for Crohn's disease (SES-CD) from 0 to 12 was used to assess Crohn's disease activity as a reference. The study calculated the correlations between the MRE activity index and endoscopic activity scores and derived the MRE index model to assess Crohn's disease activity. Results: The MRE index model (a T1 ratio 4 score of 1.52 + an ulceration score of 2.03) had a sensitivity of 0.962, a specificity of 0.667, and an area under the curve (AUC) of 0.968 [95% confidence interval (CI): 0.921-1.000]. The intraclass correlation coefficient (ICC) for the interobserver agreement of the MRE index was 0.921 (95% CI: 0.833-0.963). Conclusions: The study derived an MRE index with good sensitivity to inflammatory changes in the small bowel. The index could be used to assess Crohn's disease activity of the small bowel.
ABSTRACT
Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19). We conducted a retrospective study of COVID-19 inpatients in Wuhan Pulmonary Hospital (Wuhan, China) from January 1 to February 29, 2020. The subjects were divided into four groups due to different treatment regimes. We used the Kaplan-Meier method to determine the cumulative rates of in-hospital death and the Cox proportional hazard model to calculate the risk factors and corresponding hazard ratios. A total of 185 patients were included in this study. The median age of the patients was 62 years, including 94 men and 91 women. Kaplan-Meier analysis demonstrated that mortality was higher in older patients, higher in men, and lower in the low-flow oxygen therapy group. Body mass index (BMI) had no influence on mortality, as well as high flow oxygen therapy, Lopinavir-ritonavir (LPV/r) therapy, and the interferon-alpha add LPV/r therapy. Cox proportional hazard regression confirmed that the low flow oxygen therapy was independent protective factor for in-hospital death after adjusting for age, gender, and BMI. In conclusion, the mortality was higher in older patients, higher in men, and lower in the low-flow oxygen therapy group. BMI had no influence on mortality, as well as high flow oxygen therapy, LPV/r therapy, and interferon-alpha add LPV/r therapy.
ABSTRACT
To clarify the mechanisms underlying the improvement of Trichoderma on Chinese wolfberry (Lycium chinense) growth under saline stress, we analyzed the effects of application of organic fertilizer, Trichoderma agent and fertilizer on nitrogen uptake, assimilation, accumulation and use efficiency in Chinese wolfberry, based on a pot experiment with coastal saline soil. The organic fertilizer was the sterilization substance of Trichoderma fertilizer without viable Trichoderma, without any difference in the content of nutrients (such as nitrogen, phosphorus and potassium) between them. The results showed that the application of organic fertilizer, Trichoderma agent and ferti-lizer significantly increased NO3- and NH4+ influx rate in meristematic zone and NO3- influx rate in maturation zone of roots. The magnitude of such enhancement was greater in the application with Trichoderma fertilizer than organic fertilizer. Compared with the control, the application of Trichoderma agent and fertilizer significantly increased root, stem and leaf biomass and nitrogen content as well as plant nitrogen accumulation, strengthened root and leaf nitrate reductase, nitrite reductase and glutamine synthetase activities, and elevated nitrogen uptake efficiency, photosynthetic rate, stable carbon isotope abundance and photosynthetic nitrogen use efficiency. For all those variables, the beneficial effect was obviously stronger in the application with Trichoderma fertilizer than organic fertilizer. Therefore, Trichoderma facilitated nitrogen uptake, assimilation and accumulation in Chinese wolfberry under saline stress, improved photosynthetic carbon fixation ability and nitrogen use efficiency, and ultimately promoted plant growth.
Subject(s)
Lycium , Trichoderma , Carbon Isotopes , Fertilizers/analysis , Glutamate-Ammonia Ligase , Nitrite Reductases , Nitrogen/analysis , Phosphorus , Potassium , SoilABSTRACT
Lithium sulfur batteries (LSBs) have attracted tremendous attention owing to their high theoretical specific capacity and specific energy. However, their practical applications are hindered by poor cyclic life, mainly caused by polysulfide shuttling. The development of advanced materials to mitigate the polysulfide shuttling effect is urgently demanded. Metal-organic frameworks (MOFs) have been exploited as multifunctional materials for the decoration of separators owing to their high surface area, structural diversity, tunable pore size, and easy tailor ability. In this review, we aim to present the state-of-the-art MOF-based separators for LSBs. Particular attention is paid to the rational design (pore aperture, metal node, functionality, and dimension) of MOFs with enhanced ability for anchoring polysulfides and facilitating Li+ transportation. Finally, the challenges and perspectives are provided regarding to the future design MOF-based separators for high-performance LSBs.
ABSTRACT
Spinal cord stimulation (SCS)-induced analgesia was characterized, and its underlying mechanisms were examined in a spared nerve injury model of neuropathic pain in rats. The analgesic effect of SCS with moderate mechanical hypersensitivity was increased with increasing stimulation intensity between the 20% and 80% motor thresholds. Various frequencies (2, 15, 50, 100, 10000 Hz, and 2/100 Hz dense-dispersed) of SCS were similarly effective. SCS-induced analgesia was maintained without tolerance within 24 h of continuous stimulation. SCS at 2 Hz significantly increased methionine enkephalin content in the cerebrospinal fluid. The analgesic effect of 2 Hz was abolished by µ or κ opioid receptor antagonist. The effect of 100 Hz was prevented by a κ antagonist, and that of 10 kHz was blocked by any of the µ, δ, or κ receptor antagonists, suggesting that the analgesic effect of SCS at different frequencies is mediated by different endorphins and opioid receptors.
Subject(s)
Neuralgia , Spinal Cord Stimulation , Analgesics , Animals , Narcotic Antagonists/pharmacology , Neuralgia/therapy , Opioid Peptides , Rats , Receptors, Opioid/physiology , Receptors, Opioid, kappa , Spinal CordABSTRACT
In order to comprehensively explore multitarget mechanism and key active compounds of Artemisia argyi essential oil (AAEO) in the treatment of pressure injuries (PIs), we analyzed the biological functions and pathways involved in the intersection targets of AAEO and PIs based on network pharmacology, and the affinity of AAEO active compounds and core targets was verified by molecular docking finally. In our study, we first screened 54 effective components according to the relative content and biological activity. In total, 103 targets related to active compounds of AAEO and 2760 targets associated with PIs were obtained, respectively, and 50 key targets were overlapped by Venny 2.1.0. The construction of key targets-compounds network was achieved by the STRING database and Cytoscape 3.7.2 software. GO analysis from Matespace shows that GO results are mainly enriched in biological processes, including adrenergic receptor activity, neurotransmitter clearance, and neurotransmitter metabolic process. KEGG analysis by the David and Kobas website shows that the key targets can achieve the treatment on PIs through a pathway in cancer, PI3K-Akt signaling pathway, human immunodeficiency virus 1 infection, MAPK signaling pathway, Wnt signaling pathway, etc. In addition, molecular docking results from the CB-Dock server indicated that active compounds of AAEO had good activity docking with the first 10 key targets. In conclusion, the potential targets and regulatory molecular mechanisms of AAEO in the treatment of PIs were analyzed by network pharmacology and molecular docking. AAEO can cure PIs through the synergistic effect of multicomponent, multitarget, and multipathway, providing a theoretical basis and new direction for further study.
ABSTRACT
Two-dimensional metal-organic nanosheets (2D MONs) are an emerging class of ultrathin, porous, and crystalline materials. The organic/inorganic hybrid nature offers MONs distinct advantages over other inorganic nanosheets in terms of diversity of organic ligands and metal notes. Compared to bulk three-dimensional metal-organic frameworks, 2D MONs possess merits of high density and readily accessible catalytic sites, reduced diffusion pathways for reactants/products, and fast electron transport. These features endow MONs with enhanced physical/chemical properties and are ideal for heterogeneous catalysis. In this Review, state-of-the-art synthetic methods for the fabrication of 2D MONs were summarized. The advances of 2D MONs-based materials for electrocatalysis and photocatalysis, including hydrogen evolution reaction (HER), oxygen evolution reaction (OER), oxygen reduction reaction (ORR), carbon dioxide reduction reaction (CO2 RR), and electro-/photocatalytic organic transformations were systematically discussed. Finally, the challenges and perspectives regarding future design and synthesis of 2D MONs for high-performance electrocatalysis and photocatalysis were provided.
Subject(s)
Metal-Organic Frameworks , Catalysis , Hydrogen , Metal-Organic Frameworks/chemistry , Metals/chemistry , Oxygen/chemistryABSTRACT
Injection of total saponins from Panax notoginseng (ISPN) is a modern preparation derived from traditional Chinese medicine (TCM) and is widely applied in the treatment of cardiovascular, cerebrovascular, ophthalmology, and endocrine system diseases. With the increase in the clinical application of ISPN, its adverse drug reactions (ADRs) and related safety issues have attracted much attention. In the present study, a data-independent acquisition (DIA) strategy was proposed to comprehensively characterize the saponins contained in ISPN based on the ultra-high-performance liquid chromatography/quadrupole-Orbitrap MS (UHPLC/Q-Orbitrap MS) platform. As many as 276 saponins were detected, and 250 compounds were identified or tentatively identified based on the retention times and MS/MS data. Furthermore, a metabolomic strategy was utilized to discover the discriminative saponins between normal and ADR batches. The results showed that six saponins, including ginsenoside Rh4, ginsenoside Rk3, ginsenoside Rg5, ginsenoside Rk1, ginsenoside Rg6, and 20(S)-ginsenoside Rh2, were significantly different between the two groups. According to cytotoxicity analysis and degranulation detection of RBL-2H3 cells, ginsenoside Rg5, ginsenoside Rk1, and 20(S)-ginsenoside Rh2 were considered the potential compounds responsible for clinical ADRs, ultimately. In addition, the quantitative analysis showed that the content of these three compounds in ISPN samples with ADRs was generally higher than that in samples without ADRs. This study demonstrated that it is advisable to screen out potential markers related to ADRs for developing the quality standard of ISPN by the integration of untargeted metabolomic analysis and cell biology study, and thus reduce its ADRs in the clinic.
Subject(s)
Drug Discovery , Metabolomics/methods , Panax notoginseng/chemistry , Saponins/adverse effects , Saponins/chemistry , Chromatography, High Pressure Liquid/methods , Humans , Saponins/administration & dosageABSTRACT
BACKGROUND: Hypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs). RESULTS: In murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α4ß1 and αLß2, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects. CONCLUSION: This synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs.
Subject(s)
Acute Kidney Injury/diagnostic imaging , Acute Kidney Injury/drug therapy , Cell Hypoxia/drug effects , Extracellular Vesicles/chemistry , Macrocyclic Compounds/chemistry , Surface-Active Agents/chemistry , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Animals , Calixarenes/chemistry , Calixarenes/metabolism , Calixarenes/pharmacology , Calixarenes/therapeutic use , Cell Line , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Extracellular Vesicles/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Indoles/therapeutic use , Inflammation , Integrins/metabolism , Macrocyclic Compounds/metabolism , Macrocyclic Compounds/pharmacology , Macrocyclic Compounds/therapeutic use , Macrophages/drug effects , Macrophages/metabolism , Mice , NF-kappa B/metabolism , Organometallic Compounds/chemistry , Organometallic Compounds/metabolism , Organometallic Compounds/pharmacology , Organometallic Compounds/therapeutic use , Signal Transduction/drug effects , Surface-Active Agents/metabolism , Surface-Active Agents/pharmacology , Surface-Active Agents/therapeutic useABSTRACT
OBJECTIVE: To compare the effects of sevoflurane inhalation and intravenous anesthesia on hemodynamics, serum myocardial enzymes, and myocardial markers in elderly patients undergoing hysterectomy. METHODS: Group A and group B were established randomly regarding a total of 126 elderly patients who underwent an elective hysterectomy. Patients in group A were given full anesthesia with sevoflurane, and patients in group B were given anesthesia with intravenous anesthesia. The operation time, anesthesia time, and recovery time in Postanesthesia Care Unit (PACU) were compared; plasma cortisol concentration, hemodynamics, serum myocardial enzymes, and myocardial markers were detected and compared between the two groups of patients before anesthesia (T 0), after anesthesia (T 1), and after surgery (T 2). RESULTS: Group A observed a longer extubation time and recovery time in PACU than group B (P < 0.05). Results show a lower systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and plasma cortisol concentration of T 1 by comparison with those of T 0 (P < 0.05), but no significant difference remains in terms of intergroup SBP, DBP, and HR (P > 0.05), and there was no interaction effect of groups and time (P > 0.05). The two groups showed no great disparity in the levels of lactate dehydrogenase (LDH), aspartate transaminase (AST), creatine kinase (CK), and CK-MB as a subtype of CK before surgery between the two groups of patients (P > 0.05). After surgery, LDH, AST, CK, and CK-MB levels in both groups were witnessed a surge, in which group A obtained higher levels of LDH, AST, CK, and CK-MB (all P < 0.05). CONCLUSION: Total intravenous anesthesia will not increase the hemodynamic fluctuation of elderly patients undergoing hysterectomy and can reduce the damage to the myocardium of patients with surgical trauma, which can protect the myocardium of elderly patients to a certain extent, so it can be adopted as the optimal anesthesia protocol for surgery.
Subject(s)
Anesthesia, Inhalation , Anesthesia, Intravenous/methods , Enzymes/blood , Hemodynamics/drug effects , Hysterectomy/methods , Myocardium/enzymology , Sevoflurane/administration & dosage , Aged , Biomarkers , Electrocardiography , Female , Humans , Hydrocortisone/blood , Middle Aged , Pattern Recognition, Automated , Postanesthesia NursingABSTRACT
Studies have shown that arginine-vasopressin (AVP) is an important neuropeptide regulating social behaviors. The present work aimed to detect changes in the AVP numbers and level in a valproic acid (VPA)-induced rat model of autism and the underlying mechanism of its pathogenesis. Our results indicated that infants exposed to VPA showed obviously impaired communication and repetitive behaviors with reduced number of AVP-ir cells in paraventricular nucleus (PVN) and cerebrospinal fluid (CSF). The postnatal subcutaneous injection of AVP can alleviate social preference deficits and stereotyped behaviors, accompanied with the increase of the AVP concentrations in the CSF. We concluded that AVP system was involved in etiology of VPA-induced autism-like symptoms and postnatal AVP treatment rescued the behavioral deficits,which could be a promising treatment for autism.
Subject(s)
Arginine Vasopressin/genetics , Autistic Disorder/genetics , Neurophysins/genetics , Prenatal Exposure Delayed Effects/drug therapy , Protein Precursors/genetics , Vasopressins/genetics , Adolescent , Animals , Arginine Vasopressin/pharmacology , Autistic Disorder/chemically induced , Autistic Disorder/drug therapy , Autistic Disorder/physiopathology , Behavior, Animal/drug effects , Disease Models, Animal , Female , Humans , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/pathology , Pregnancy , Prenatal Exposure Delayed Effects/genetics , Prenatal Exposure Delayed Effects/pathology , Rats , Social Behavior , Stereotyped Behavior/drug effects , Valproic Acid/toxicityABSTRACT
Background: COVID-19 has been quickly spreading, making it a serious public health threat. It is important to identify phenotypes to predict the severity of disease and design an individualized treatment. Methods: We collected data from 213 COVID-19 patients in Wuhan Pulmonary Hospital from January 1 to March 30, 2020. Principal component analysis (PCA) and cluster analysis were used to classify patients. Results: We identified three distinct subgroups of COVID-19. Cluster 1 was the largest group (52.6%) and characterized by oldest age, lowest cellular immune function, and albumin levels. 38.5% of subjects were grouped into Cluster 2. Most of the lab results in Cluster 2 fell between those of Clusters 1 and 3. Cluster 3 was the smallest cluster (8.9%), characterized by youngest age and highest cellular immune function. The incidence of respiratory failure, acute respiratory distress syndrome (ARDS), heart failure, and usage of non-invasive mechanical ventilation in Cluster 1 was significantly higher than others (P < 0.05). Cluster 1 had the highest death rate of 30.4% (P = 0.005). Although there were significant differences in age between Clusters 2 and 3 (P < 0.001), we found that there was no difference in demand for medical resources. Conclusions: We identified three distinct clusters of the COVID-19 patients. The results show that age alone could not be used to assess a patient's condition. Specifically, management of albumin, and immune function are important in reducing the severity of disease.