Comprehending the inhibition mechanism of indole-based bis-acylhydrazone compounds on α-glucosidase: Spectral and theoretical approaches.

Indole-based bis-acylhydrazone compounds can inhibit the activity of α-glucosidase and control the concentration of blood glucose. In this paper, the characteristics of three indole-based bis-acylhydrazone compounds with different inhibitory activities of α-glucosidase as well as the interaction with α-glucosidase were studied by experiments and computational simulation techniques. Enzyme kinetic and spectral experiments showed that the indole-based bis-acylhydrazone compounds were able to inhibit enzyme activity through mixed inhibition dominated by competitive inhibition, and during the binding reaction, indole-based bis-acylhydrazone compounds can quench the intrinsic fluorescence of α-glucosidase through static quenching and an aggregation of the indole-based bis-acylhydrazone with α-glucosidase produces a stable complex with a molar ratio of 1:1, and the combination of indole-based bis-acylhydrazone compounds could lead to slight change in the conformation of α-glucosidase. The theoretical simulation demonstrated that the stability of the complex systems was positively correlated with the inhibitory activity of indole-based bis-acylhydrazone compounds, and the indole-based bis-acylhydrazone compounds occupied the active site in the multi-ligand system, resulting in a significant decrease in the binding ability of starch to active amino acids. These results suggested that indole-based bis-acylhydrazone compound was expected to be a new type of α-glucosidase inhibitor.

The impact of medium-chain triglycerides on weight loss and metabolic health in individuals with overweight or obesity: A systematic review and meta-analysis.

BACKGROUNDS: The efficacy of medium-chain triglycerides (MCTs) for weight management and mitigating metabolic disorders among individuals with overweight and obesity remains a topic of ongoing discussion. Notably, there is a gap in the distinction between pure MCTs and medium-long-chain triglycerides (MLCTs). METHODS: This meta-analysis investigates the efficacy of MCTs on weight loss and glucolipid metabolism in these populations, explicitly evaluating the differential effects of pure MCTs and MLCTs. We performed a random-effects meta-analysis on relevant studies examining weight loss and glucolipid parameters, incorporating a subgroup analysis conducted based on intervention types, pure MCTs versus MLCTs. RESULTS: Our findings revealed diets enriched with MCTs are more effective in achieving weight reduction (WMD: -1.53%; 95% CI: -2.44, -0.63; p < 0.01), particularly those containing pure MCTs (WMD: -1.62%; 95% CI: -2.78, -0.46; p < 0.01), compared to long-chain fatty acids (LCTs) enriched diets. However, our subgroup analysis indicates that an MLCTs-enriched diet did not significantly reduce weight loss. Additionally, MCTs-enriched diets were associated with significant reductions in blood triglyceride levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scores, compared to LCTs-enriched diets. CONCLUSIONS: Hence, the authors recommend incorporating pure MCTs in dietary interventions for individuals with overweight and obesity, particularly those with comorbidities such as dyslipidemia and impaired glucose metabolism.

Massive Hepatocellular Carcinoma Combined With Giant Uterine Fibroid on 18F-FDG PET/CT.

ABSTRACT: A 50-year-old woman was admitted due to a liver mass discovered by ultrasound in routine physical examination. MRI demonstrated a large hepatocellular carcinoma. It also discovered an abdominal mass simultaneously. 18F-FDG PET/CT was performed for staging. PET/CT showed mixed and mild metabolism of the hepatic lesion and giant abdominopelvic mass, respectively. Hepatocellular carcinoma combined with a benign mass in abdominopelvic cavity from uterine was considered and finally proved pathologically. We present a rare case of woman with large liver cancer accompanied by giant uterine fibroid where 18F-FDG PET/CT helped in making the right diagnosis.

Effects of intensive psychological intervention on treatment compliance, psychological status, and quality of life of patients with epilepsy.

BACKGROUND: Epilepsy is a nervous system disease characterized by recurrent attacks, a long disease course, and an unfavorable prognosis. It is associated with an enduring therapeutic process, and finding a cure has been difficult. Patients with epilepsy are predisposed to adverse moods, such as resistance, anxiety, nervousness, and anxiety, which compromise treatment compliance and overall efficacy. AIM: To explored the influence of intensive psychological intervention on treatment compliance, psychological status, and quality of life (QOL) of patients with epilepsy. METHODS: The clinical data of 105 patients with epilepsy admitted between December 2019 and July 2023 were retrospectively analyzed, including those of 50 patients who underwent routine intervention (control group) and 55 who underwent intensive psychological intervention (research group). Treatment compliance, psychological status based on the Self-Rating Anxiety Scale (SAS) and Depression Scale Self-Rating Depression Scale (SDS) scores, hope level assessed using the Herth Hope Scale (HHS), psychological resilience evaluated using the Psychological Resilience Scale, and QOL determined using the QOL in Epilepsy-31 Inventory (QOLIE-31) were comparatively analyzed. RESULTS: Treatment compliance in the research group was 85.5%, which is significantly better than the 68.0% of the control group. No notable intergroup differences in preinterventional SAS and SDS scores were identified (P > 0.05); however, after the intervention, the SAS and SDS scores decreased significantly in the two groups, especially in the research group (P < 0.05). The two groups also exhibited no significant differences in preinterventional HHS, Connor-Davidson Resilience Scale (CD-RISC), and QOLIE-31 scores (P > 0.05). After 6 months of intervention, the research group showed evidently higher HHS, CD-RISC, tenacity, optimism, strength, and QOLIE-31 scores (P < 0.05). CONCLUSION: Intensive psychological intervention enhances treatment compliance, psychological status, and QOL of patients with epilepsy.

Targeted inhibition of autophagy in hepatic stellate cells by hydroxychloroquine: An effective therapeutic approach for the treatment of liver fibrosis.

BACKGROUND AND PURPOSE: Liver fibrosis is a wound-healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. METHODS: The delivery system of HCQ@retinol-liposome nanoparticles (HCQ@ROL-LNPs) targeting aHSC was constructed by the film dispersion and pH-gradient method. TGF-ß-induced HSC activation and thioacetamide (TAA)-induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL-LNPs in liver fibrosis were studied subsequently in vitro and in vivo. RESULTS: HCQ@ROL-LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL-LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. CONCLUSION: Construction of HCQ@ROL-LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases.

Effect of Cinnamaldehyde on Systemic Candida albicans Infection in Mice.

OBJECTIVE: To investigate the therapeutic efficacy of cinnamaldehyde (CA) on systemic Candida albicans infection in mice and to provide supportive data for the development of novel antifungal drugs. METHODS: Ninety BALB/c mice were randomly divided into 3 groups according to a random number table: CA treatment group, fluconazole (positive control) group, and Tween saline (negative control) group, with 30 mice in each group. Initially, all groups of mice received consecutive intraperitoneal injections of cyclophosphamide at 200 mg/kg for 2 days, followed by intraperitoneal injection of 0.25 mL C. albicans fungal suspension (concentration of 1.0 × 107 CFU/mL) on the 4th day, to establish an immunosuppressed systemic Candida albicans infection animal model. Subsequently, the mice were orally administered CA, fluconazole and Tween saline, at 240, 240 mg/kg and 0.25 mL/kg respectively for 14 days. After a 48-h discontinuation of treatment, the liver, small intestine, and kidney tissues of mice were collected for fungal direct microscopic examination, culture, and histopathological examination. Additionally, renal tissues from each group of mice were collected for (1,3)- ß -D-glucan detection. The survival status of mice in all groups was monitored for 14 days of drug administration. RESULTS: The CA group exhibited a fungal clearance rate of C. albicans above 86.7% (26/30), significantly higher than the fluconazole group (60.0%, 18/30, P<0.01) and the Tween saline group (30.0%, 9/30, P<0.01). Furthermore, histopathological examination in the CA group revealed the disappearance of inflammatory cells and near-normal restoration of tissue structure. The (1,3)-ß-D-glucan detection value in the CA group (860.55 ± 126.73 pg/mL) was significantly lower than that in the fluconazole group (1985.13 ± 203.56 pg/mL, P<0.01) and the Tween saline group (5910.20 ± 320.56 pg/mL, P<0.01). The mouse survival rate reached 90.0% (27/30), higher than the fluconazole group (60.0%, 18/30) and the Tween saline group (30.0%, 9/30), with a significant difference between the two groups (both P<0.01). CONCLUSIONS: CA treatment exhibited significant therapeutic efficacy in mice with systemic C. albicans infection. Therefore, CA holds potential as a novel antifungal agent for targeted treatment of C. albicans infection.

In vitro investigation of the binding characteristics of dacomitinib to human α 1-acid glycoprotein: Multispectral and computational modeling.

Dacomitinib is a highly selective second-generation tyrosine kinase inhibitor that can irreversibly bind to tyrosine kinase and is mainly used in the treatment of lung cancer. The binding characteristics of dacomitinib with human α 1-acid glycoprotein (HAG) were analyzed by multispectral and computational simulation techniques. The fluorescence spectra showed that dacomitinib can quench the fluorescence of HAG by forming the HAG-dacomitinib complex with a molar ratio of 1:1 (static quenching). At the temperature similar to that of the human body, the affinity of dacomitinib to HAG (8.95 × 106 M-1) was much greater than that to BSA (3.39 × 104 M-1), indicating that dacomitinib will give priority to binding onto HAG. Thermodynamics parameters analysis and driving force competition experiments showed that hydrogen bonding and hydrophobic forces were the major sources for keeping the complex of HAG-dacomitinib stable. The experimental outcomes also showed that the binding of dacomitinib can lead to the loosening of the skeleton structure of HAG, which led to a slight change in the secondary structure, and also reduces the hydrophobicity of the microenvironment of Trp and Tyr residues. The binding sites of dacomitinib on HAG and the contribution of key amino acid residues to the binding reaction were determined by molecular docking and molecular dynamics (MD) simulation. In addition, it was found that there was a synergistic effect between dacomitinib and Mg2+ and Co2+ ions. Mg2+ and Co2+ could increase the Kb of dacomitinib to HAG and prolong the half-life of dacomitinib.

Potential neuroprotective benefits of plant-based fermented foods in Alzheimer's disease: an update on preclinical evidence.

Alzheimer's disease (AD) currently lacks effective treatments, making its prevention a critical focus. While accumulating evidence supports that plant-based fermented foods may contribute to AD prevention, the neuroprotective effect of plant-based fermented foods on AD has not been comprehensively reviewed. In this study, we conducted a systematic review of preclinical studies on the efficacy of plant-based fermented foods in AD. The literature search was based on databases including PubMed, Embase, Web of Science, and Scopus. The PICO approach was employed for report inclusion, and each report was assessed for risk of bias using the SYRCLE's RoB tool. From the analysis of 25 retrieved reports, we extracted essential details, including bibliographic information, animal models and characteristics, sources of plant-based fermented foods, dosages, administration routes, durations, and outcome measures. Our findings indicate that plant-based fermented foods may positively impact acute and long-term cognitive function, as well as beta-amyloid-mediated neurodegeneration. This review sheds light on the potential neuroprotective benefits of plant-based fermented foods for various AD-related aspects, including oxidative stress, synaptotoxicity, neuroinflammation, tau hyperphosphorylation, dysfunctional amyloidogenic pathways, and cognitive deficits, as observed in rodent models of AD. However, the small number of studies obtained from our literature search and the finding that many of them were of moderate methodological quality suggest the need for further investigation to substantiate the beneficial potential of this class of functional food for the management of AD.

Association between MTHFR C677T Gene Polymorphisms and the Efficacy of Vitamin Therapy in lowering Homocysteine Levels among Stroke Patients with Hyperhomocysteinemia.

BACKGROUND: The impact of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation on the relationship between plasma homocysteine (Hcy) levels and stroke has been extensively studied and documented in previous study. However, it remains unclear whether the MTHFR C677T mutation can affect the response to Hcy lowering treatment in stroke patients with hyperhomocysteinemia (HHcy). Understanding the impact of genetic factors on treatment response can help optimize personalized treatment strategies for stroke patients with HHcy. We aimed to investigate the potential association between the MTHFR C677T gene polymorphisms and the effectiveness of Hcy lowering treatment using vitamin therapy in stroke patients with HHcy. METHODS: The MTHFR C677T genotype polymorphisms were identified using polymerase chain reaction-restriction fragment length polymorphism, and the distribution of three genotypes in the MTHFR C677T gene locus was compared. The treatment effects of Hcy lowering agents were compared among patients with different genotypes. RESULTS: Among the 320 stroke patients enrolled in the study, 258 (80.6%) were diagnosed with HHcy. Of these, 162 patients (Effective Group) responded well to the clinical Hcy lowering treatment, while 96 patients (Invalid Group) failed to achieve sufficient response even after taking combination supplements of folic acid, Vitamin B6, and methylcobalamin for one month. Significant differences were observed in terms of age (p < 0.001), hypertension (p = 0.034), dyslipidemia (p = 0.022), hyperuricemia (p = 0.013) and genotype distribution of MTHFR C677T gene polymorphism (p < 0.001) between the Invalid group and the Effective group. The multivariate regression analysis revealed that the T allele (odd rations [OR], 1.327; 95% confidence interval [CI], 1.114-1.580; p = 0.0015) was independently associated with an insufficient Hcy lowering treatment effect. Additionally, the TT genotype was independently associated with insufficient response in both the codominant model (OR, 1.645; 95% CI, 1.093-2.476; p = 0.017) and the recessive model (TT versus CC + CT; OR, 1.529; 95% CI, 1.145-2.042; p = 0.004). However, no relationship was observed between CT + TT genotypes and poor treatment effect in the dominate model. CONCLUSIONS: Our findings suggested that the TT genotype and T allele of MTHFR C677T polymorphism were independently associated with an insufficient Hcy lowering treatment effect in stroke patients with HHcy.

High Contrast Bioimaging of Tumor and Inflammation with a Bicyclic Dioxetane Chemiluminescent Probe.

The link between inflammation and the evolution of cancer is well established. Visualizing and tracking both tumor proliferation and the associated inflammatory response within a living organism are vital for dissecting the nexus between these two processes and for crafting precise treatment modalities. We report the creation and synthesis of an advanced NIR chemiluminescence probe that stands out for its exceptional selectivity, extraordinary sensitivity at nanomolar concentrations, swift detection capabilities, and broad application prospects. Crucially, this probe has been successfully utilized to image endogenous ONOO- across different inflammation models, including abdominal inflammation triggered by LPS, subcutaneous inflammatory conditions, and tumors grafted onto mice. These findings highlight the significant promise of chemiluminescence imaging in enhancing our grasp of the intricate interplay between cancer and inflammation and in steering the development of potent, targeted therapeutic strategies.

Comprehending the intermolecular interaction of dacomitinib with bovine serum albumin: experimental and theoretical approaches.

Dacomitinib (DAC), as a member of tyrosine kinase inhibitors is primarily used to treat non-small cell lung cancer. The intermolecular interaction between DAC and bovine serum albumin (BSA) was comprehended with the help of experiments and theoretical simulations. The outcomes indicated that DAC quenched the endogenous fluorescence of BSA through static quenching mode. In the binding process, DAC was preferentially inserted into the hydrophobic cavity of BSA subdomain IA (site III), and a fluorescence-free DAC-BSA complex with molar ratio of 1:1 was generated. The outcomes confirmed that DAC had a stronger affinity on BSA and the non-radiative energy transfer occurred in the combination process of two. And, it can be inferred from the outcomes of thermodynamic parameters and competition experiments with 8-aniline-1-naphthalenesulfonic acid (ANS) and D-(+)- sucrose that hydrogen bonds (H-bonds), van der Waals forces (vdW) and hydrophobic forces had a significant impact in inserting DAC into the hydrophobic cavity of BSA. The outcomes from multi-spectroscopic measurements that DAC could affect the secondary structure of BSA, that was, α-helix content decreased slightly from 51.0% to 49.7%. Moreover, the combination of DAC and BSA led to a reduction in the hydrophobicity of the microenvironment around tyrosine (Tyr) residues in BSA while had little influence on the microenvironment of around tryptophan (Trp) residues. The outcomes from molecular docking and molecular dynamics (MD) simulation further demonstrated the insertion of DAC into site III of BSA and hydrogen energy and van der Waals energy were the dominant energy of DAC-BSA stability. In addition, the influence of metal ions (Fe3+, Cu2+, Co2+, etc.) on the affinity of the system was explored.Communicated by Ramaswamy H. Sarma.

Insight into intermolecular binding mechanism of apatinib mesylate and human alpha-1-acid glycoprotein: combined multi-spectroscopic approaches with in silico.

Apatinib mesylate (APM), an oral tyrosine kinase inhibitor, has a good anti-tumor activity in the treatment of various cancers, particularly in advanced non-small cell lung cancer. In this study, the intermolecular binding mechanism between APM and human alpha-1-acid glycoprotein (HAG) was investigated by combining multi-spectroscopic approaches with in silico techniques. The findings revealed that APM gave rise to the fluorescence quenching of HAG by forming a ground-state complex between APM and HAG with a stoichiometric ratio of 1:1, and APM has a moderate affinity for HAG as the binding constant of APM and HAG of approximately 105 M-1, which was larger than the APM-HAG complex. The findings from thermodynamic parameter analysis indicated that the dominant driving forces for the formation of the APM-HAG complex were van der Waals forces, hydrogen bonding and hydrophobic interactions, which were also verified with site-probe studies and molecular docking. The findings from in silico study indicated that APM inserted into the opening of the hydrophobic cavity of HAG, leads to a slight conformational change in the HAG, which was verified by circular dichroism (CD) measurements, that was, the beta sheet level of HAG decreased. Additionally, the results of synchronous and 3D fluorescence spectroscopies confirmed the decline in hydrophobicity of the microenvironment around Trp and Tyr residues. Moreover, some common metal ions such as Cu2+, Mg2+, Fe3+, Ca2+, and Zn2+ could cause the alteration in the binding constant of APM with HAG, leading to the change in the efficacy of APM. It will be expected that these study findings are to provide useful information for further understanding pharmacokinetic and structural modifications of APM.Communicated by Ramaswamy H. Sarma.

MED12 variants associated with X-linked recessive partial epilepsy without intellectual disability.

OBJECTIVES: The MED12 gene encodes mediator complex subunit 12, which is a component of the mediator complex involved in the transcriptional regulation of nearly all RNA polymerase II-dependent genes. MED12 variants have previously been associated with developmental disorders with or without nonspecific intellectual disability. This study aims to explore the association between MED12 variants and epilepsy. MATERIALS AND METHODS: Trios-based whole-exome sequencing was performed in a cohort of 349 unrelated cases with partial (focal) epilepsy without acquired causes. The genotype-phenotype correlations of MED12 variants were analyzed. RESULTS: Five hemizygous missense MED12 variants, including c.958A>G/p.Ile320Val, c.1757G>A/p.Ser586Asn, c.2138C>T/p.Pro713Leu, c.3379T>C/p.Ser1127Pro, and c.4219A>C/p.Met1407Leu were identified in five unrelated males with partial epilepsy. All patients showed infrequent focal seizures and achieved seizure free without developmental abnormalities or intellectual disability. All the hemizygous variants were inherited from asymptomatic mothers (consistent with the X-linked recessive inheritance pattern) and were absent in the general population. The two variants with damaging hydrogen bonds were associated with early-onset seizures. Further genotype-phenotype analysis revealed that congenital anomaly disorder (Hardikar syndrome) was associated with (de novo) destructive variants in an X-linked dominant inheritance pattern, whereas epilepsy was associated with missense variants in an X-linked recessive inheritance pattern. Phenotypic features of intellectual disability appeared as the intermediate phenotype in terms of both genotype and inheritance. Epilepsy-related variants were located at the MED12-LCEWAV domain and the regions between MED12-LCEWAV and MED12-POL. CONCLUSION: MED12 is a potentially causative gene for X-linked recessive partial epilepsy without developmental or intellectual abnormalities. The genotype-phenotype correlation of MED12 variants explains the phenotypic variations and can help the genetic diagnosis.

Kaempferol is a novel antiviral agent against channel catfish virus infection through blocking viral attachment and penetration in vitro.

Channel catfish virus (CCV, Ictalurid herpesvirus 1) is the causative pathogen of channel catfish virus disease, which has caused high mortality and substantial economic losses in the catfish aquaculture industry. Due to the lack of licensed prophylactic vaccines and therapeutic drugs, the prevention and control of CCV infection seem to remain stagnant. Active compounds from medicinal plants offer eligible sources of pharmaceuticals and lead drugs to fight against endemic and pandemic diseases and exhibit excellent effect against viral infection. In this study, we evaluated the antiviral ability of 12 natural compounds against CCV with cell models in vitro and found kaempferol exhibited the strongest inhibitory compound against CCV infection among all the tested compounds. Correspondingly, kaempferol decreased transcription levels of viral genes and the synthesis of viral proteins, as well as reduced proliferation and release of viral progeny, the severity of the CPE induced by CCV in a dose-dependent manner, based on quantitative real-time PCR (RT-qPCR), western blotting, viral cytopathic effects (CPE) and viral titer assessment. Moreover, time-of-drug-addition assays, virus attachment, and penetration assays revealed that kaempferol exerted anti-CCV activity probably by blocking attachment and internalization of the viral entry process. Altogether, the present results indicated that kaempferol may be a promising candidate antiviral agent against CCV infection, which shed light on the development of a novel and potent treatment for fish herpesvirus infection.

The epidemiology of traumatic brain injuries in the fastest-paced city in China: a retrospective study.

Introduction: Traumatic brain injury (TBI) seriously affects the quality of human health and the prognosis of the patient, but the epidemiological characteristics of TBI can vary among populations. Numerous changes have occurred in the epidemiological characteristics of individuals with TBI in the fast-paced city of Shenzhen, China. However, little is known about these characteristics. This study aimed to investigate the changes in TBI epidemiology, help clinicians improve medical treatment. Methods: In this retrospective cross-sectional analysis, we collected the data of 4,229 patients with TBI admitted to 20 hospitals in Shenzhen in 2017. We collected data on age, gender, cause and severity of the injury, eventual diagnosis, time from injury to admission in a neurosurgery department, and patient outcomes. Two neurosurgeons simultaneously collected the data. We compared these results with a similar study conducted in Shenzhen during the period from 1994 to 2003 to clarify and explain the changes in the epidemiological characteristics of TBI. Results: The majority of respondents were men [2,830 (66.9%)]. The mean age was 32.5 ± 21.4 years. The youngest patient was less than 1 year old, and the oldest patient was 101 years old. A total of 3,947 (93.3%) patients had a favorable outcome, 219 (5.2%) had an unfavorable outcome, and 63 (1.5%) died. The predominant external cause was falls (1,779 [42.1%]); this was the most common cause of TBI in children and older adults. Riders of electric bicycles (423 [29.0%]) were the most vulnerable to traffic accident-related injuries. Time greater than 50 h from injury to admission to a neurosurgical department had a significant effect on prognosis (p < 0.001). Conclusion: The epidemiological characteristics of TBI have changed significantly over the past 20 years. Falls, rather than traffic accidents, were the most common cause of TBI. Further research is needed to devise solutions to decrease the incidence of falls and improve the outcomes of TBI.

Two-Membrane Hybrid Nanobiomimetic Delivery System for Targeted Autophagy Inhibition of Activated Hepatic Stellate Cells To Synergistically Treat Liver Fibrosis.

Liver fibrosis is one of the most common and highly prevalent chronic liver diseases caused by multiple pathogenic factors, and there is still no effective therapeutic drugs up to now. The activated hepatic stellate cells (aHSCs) are the main executor in liver fibrosis, and the autophagy plays a key role in the proliferation and differentiation of aHSCs, which promotes the development of liver fibrosis. However, autophagy has the opposite effect on the different kinds of liver cells in the development of liver fibrosis, and the clinical treatment has been limited by the poor selectivity and inefficient drug delivery to aHSCs. Therefore, in this study, a liposome (Lip) and exosome (Exo) two-membrane hybrid nanobiomimetic delivery system HCQ@VA-Lip-Exo was designed, which was modified by vitamin A (VA) to target the aHSCs and carried the autophagy inhibitor hydroxychloroquine (HCQ). The experimental results in vitro and in vivo revealed that the constructed aHSC-targeted hybrid delivery system HCQ@VA-Lip-Exo combined with the benefits of HCQ and exosomes derived from bone marrow mesenchymal stem cells. HCQ@VA-Lip-Exo had good aHSC-targeted delivery ability, effective autophagy inhibition, and synergistical anti-liver fibrosis performance, thus reducing the production and deposition of the extracellular matrix to inhibit the liver fibrosis. This combined strategy provided a potential idea for the construction and clinical application of a two-membrane hybrid delivery system as an effective targeted therapy of liver fibrosis.

Plastic bronchitis associated with respiratory syncytial virus infection: a case report.

BACKGROUND: The etiology of Plastic bronchitis (PB) is unknown. The incidence of pulmonary infection associated with PB has increased year by year, but respiratory syncytial virus (RSV) as a pathogen causes PB has rarely been reported. CASE PRESENTATION: A 2-year-old immunocompromised girl was admitted to the hospital with cough, fever for 5 days, and aggravated with shortness of breath for 1 day. With mechanical ventilation, her respiratory failure was not relieved, and subcutaneous emphysema and mediastinal pneumatosis appeared. Extracorporeal membrane oxygenation (ECMO) was administrated, but the tidal volume was low. Therefore, a bronchoscopy was performed, by which plastic secretions were found and removed. Pathology of the plastic secretions confirmed the diagnosis of type I PB. RSV was the only positive pathogen in the alveolar lavage fluid by the next-generation sequencing test. After the bronchoscopic procedure, her dyspnea improved. The patient was discharged with a high-flow nasal cannula, with a pulse oxygen saturation above 95%. Half a year after discharge, she developed sequelae of bronchitis obliterans. CONCLUSION: RSV could be an etiology of PB, especially in an immunocompromised child. In a patient with pulmonary infection, if hypoxemia is presented and unresponded to mechanical ventilation, even ECMO, PB should be considered, and bronchoscopy should be performed as soon as possible to confirm the diagnosis and to treat.

A comprehensive review of the applications of bacteriophage-derived endolysins for foodborne bacterial pathogens and food safety: recent advances, challenges, and future perspective.

Foodborne diseases are caused by food contaminated by pathogenic bacteria such as Escherichia coli, Salmonella, Staphylococcus aureus, Listeria monocytogenes, Campylobacter, and Clostridium, a critical threat to human health. As a novel antibacterial agent against foodborne pathogens, endolysins are peptidoglycan hydrolases encoded by bacteriophages that lyse bacterial cells by targeting their cell wall, notably in Gram-positive bacteria due to their naturally exposed peptidoglycan layer. These lytic enzymes have gained scientists' interest in recent years due to their selectivity, mode of action, engineering potential, and lack of resistance mechanisms. The use of endolysins for food safety has undergone significant improvements, which are summarized and discussed in this review. Endolysins can remove bacterial biofilms of foodborne pathogens and their cell wall-binding domain can be employed as a tool for quick detection of foodborne pathogens. We explained the applications of endolysin for eliminating pathogenic bacteria in livestock and various food matrices, as well as the limitations and challenges in use as a dietary supplement. We also highlight the novel techniques of the development of engineering endolysin for targeting Gram-negative bacterial pathogens. In conclusion, endolysin is safe and effective against foodborne pathogens and has no adverse effect on human cells and beneficial microbiota. As a result, endolysin could be employed as a functional bio-preservative agent to improve food stability and safety and maintain the natural taste of food quality.

Exploring the binding behaviors between nisoldipine and bovine serum albumin as a model protein by the aid of multi-spectroscopic approaches and in silico.

Bovine serum albumin (BSA), a model protein was used to evaluate the binding behavior of nisoldipine and human serum albumin by a series of experiments and in silico in this article. The outcomes suggested that nisoldipine and BSA formed the nisoldipine-BSA complex with a molar ratio of 1:1, caused the fluorescence quenching of BSA, which quenching mechanism was attributable to static quenching. The binding constant of the nisoldipine-BSA complex was (1.3-3.0) × 104 M-1 at 298-310 K, indicating that nisoldipine on BSA protein had a moderate affinity. During the complexation of nisoldipine with BSA, nisoldipine can spontaneously insert into the site II (subdomain III A) of BSA and the distance of energy transfer from donor group in protein to acceptor group in nisoldipine was 3.21 nm, which led to the change in the hydrophobicity of the microenvironment surrounding Trp residues and in the secondary structure of BSA. Additionally, the findings also confirmed that the hydrogen bond and van der Waals force were responsible for forming the nisoldipine-BSA complex and the complexation process was a spontaneous exothermic process.Communicated by Ramaswamy H. Sarma.

Investigation on the binding behavior of human α1-acid glycoprotein with Janus Kinase inhibitor baricitinib: Multi-spectroscopic and molecular simulation methodologies.

Baricitinib is a Janus Kinase (JAK) inhibitor that is primarily used to treat moderately to severely active rheumatoid arthritis in adults and has recently been reported for the treatment of patients with severe COVID-19. This paper describes the investigation of the binding behavior of baricitinib to human α1-acid glycoprotein (HAG) employing a variety of spectroscopic techniques, molecular docking and dynamics simulations. Baricitinib can quench the fluorescence from amino acids in HAG through a mix of dynamic and static quenching, according to steady-state fluorescence and UV spectra observations, but it is mainly static quenching at low concentration. The binding constant (Kb) of baricitinib to HAG at 298 K was at the level of 104 M-1, indicating a moderate affinity of baricitinib to HAG. Hydrogen bonding and hydrophobic interactions conducted the main effect, according to thermodynamic characteristics, competition studies between ANS and sucrose, and molecular dynamics simulations. For the change in HAG conformation, the results of multiple spectra showed that baricitinib was able to alter the secondary structure of HAG as well as increase the polarity of the microenvironment around the Trp amino acid. Furthermore, the binding behavior of baricitinib to HAG was investigated by molecular docking and molecular dynamics simulations, which validated experimental results. Also explored is the influence of K+, Co2+, Ni2+, Ca2+, Fe3+, Zn2+, Mg2+ and Cu2+plasma on binding affinity.