Tat-dependent conditionally replicating adenoviruses expressing diphtheria toxin A for specifically killing HIV-1-infected cells.

HIV-1 infection remains a public health problem with no cure. Although antiretroviral therapy (ART) is effective for suppressing HIV-1 replication, it requires lifelong drug administration due to a stable reservoir of latent proviruses and may cause serious side effects and drive the emergence of drug-resistant HIV-1 variants. Gene therapy represents an alternative approach to overcome the limitations of conventional treatments against HIV-1 infection. In this study, we constructed and investigated the antiviral effects of an HIV-1 Tat-dependent conditionally replicating adenovirus, which selectively replicates and expresses the diphtheria toxin A chain (Tat-CRAds-DTA) in HIV-1-infected cells both in vitro and in vivo. We found that Tat-CRAds-DTA could specifically induce cell death and inhibit virus replication in HIV-1-infected cells mediated by adenovirus proliferation and DTA expression. A low titer of progeny Tat-CRAds-DTA was also detected in HIV-1-infected cells. In addition, Tat-CRAds-DTA showed no apparent cytotoxicity to HIV-1-negative cells and demonstrated significant therapeutic efficacy against HIV-1 infection in a humanized mouse model. The findings in this study highlight the potential of Tat-CRAds-DTA as a new gene therapy for the treatment of HIV-1 infection.

Exosomes derived from induced cardiopulmonary progenitor cells alleviate acute lung injury in mice.

Cardiopulmonary progenitor cells (CPPs) constitute a minor subpopulation of cells that are commonly associated with heart and lung morphogenesis during embryonic development but completely subside after birth. This fact offers the possibility for the treatment of pulmonary heart disease (PHD), in which the lung and heart are both damaged. A reliable source of CPPs is urgently needed. In this study, we reprogrammed human cardiac fibroblasts (HCFs) into CPP-like cells (or induced CPPs, iCPPs) and evaluated the therapeutic potential of iCPP-derived exosomes for acute lung injury (ALI). iCPPs were created in passage 3 primary HCFs by overexpressing GLI1, WNT2, ISL1 and TBX5 (GWIT). Exosomes were isolated from the culture medium of passage 6-8 GWIT-iCPPs. A mouse ALI model was established by intratracheal instillation of LPS. Four hours after LPS instillation, ALI mice were treated with GWIT-iCPP-derived exosomes (5 × 109, 5 × 1010 particles/mL) via intratracheal instillation. We showed that GWIT-iCPPs could differentiate into cell lineages, such as cardiomyocyte-like cells, endothelial cells, smooth muscle cells and alveolar epithelial cells, in vitro. Transcription analysis revealed that GWIT-iCPPs have potential for heart and lung development. Intratracheal instillation of iCPP-derived exosomes dose-dependently alleviated LPS-induced ALI in mice by attenuating lung inflammation, promoting endothelial function and restoring capillary endothelial cells and the epithelial cells barrier. This study provides a potential new method for the prevention and treatment of cardiopulmonary injury, especially lung injury, and provides a new cell model for drug screening.

Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms.

Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.

Impaired cell-cell communication and axon guidance because of pulmonary hypoperfusion during postnatal alveolar development.

BACKGROUND: Pulmonary hypoperfusion is common in children with congenital heart diseases (CHDs) or pulmonary hypertension (PH) and causes adult pulmonary dysplasia. Systematic reviews have shown that some children with CHDs or PH have mitigated clinical outcomes with COVID-19. Understanding the effects of pulmonary hypoperfusion on postnatal alveolar development may aid in the development of methods to improve the pulmonary function of children with CHDs or PH and improve their care during the COVID-19 pandemic, which is characterized by cytokine storm and persistent inflammation. METHODS AND RESULTS: We created a neonatal pulmonary hypoperfusion model through pulmonary artery banding (PAB) surgery at postnatal day 1 (P1). Alveolar dysplasia was confirmed by gross and histological examination at P21. Transcriptomic analysis of pulmonary tissues at P7(alveolar stage 2) and P14(alveolar stage 4) revealed that the postnatal alveolar development track had been changed due to pulmonary hypoperfusion. Under the condition of pulmonary hypoperfusion, the cell-cell communication and axon guidance, which both determine the final number of alveoli, were lost; instead, there was hyperactive cell cycle activity. The transcriptomic results were further confirmed by the examination of axon guidance and cell cycle markers. Because axon guidance controls inflammation and immune cell activation, the loss of axon guidance may explain the lack of severe COVID-19 cases among children with CHDs or PH accompanied by pulmonary hypoperfusion. CONCLUSIONS: This study suggested that promoting cell-cell communication or supplementation with guidance molecules may treat pulmonary hypoperfusion-induced alveolar dysplasia, and that COVID-19 is less likely to cause a cytokine storm in children with CHD or PH accompanied by pulmonary hypoperfusion.

Highly Sensitive Flexible Sensors for Human Activity Monitoring and Personal Healthcare.

Flexible sensors are capable of converting multiple human physiological signals into electrical signals for various applications in clinical diagnostics, athletics, and human-machine interaction. High-performance flexible strain sensors are particularly desirable for sensitive, reliable, and long-term monitoring, but current applications are still constrained due to high response threshold, low recoverability properties, and complex preparation methods. In this study, we present a stable and flexible strain sensor by a cost-effective self-assemble approach that demonstrates remarkable sensitivity (2169), ultrafast response and recovery time (112 ms), and wide dynamic response range (0-50%), as confirmed in human pulse and human-computer interaction. These excellent performances can be attributed to the design of a Polydimethylsiloxane (PDMS) substrate integrated with multiwalled carbon nanotubes (MWCNT) and graphene nanosheets (GNFs), which results in high electrical conductivity. The MWCNT serves as a bridge, connecting the GNFs to create an efficient conductive path even under a strain of 50%. We also demonstrate the strain sensor's capability in weak physiological signal pulse measurement and excellent resistance to mechanical fatigue. Moreover, the sensor shows diverse sensitivities in various tensile states with different signal patterns, making it highly suitable for full-range human monitoring and flexible wearable systems.

Equivalence theorem for the spectral density of light waves scattered from different types of anisotropic media.

The spectral density equivalence theorem of light waves on scattering from different types of anisotropic media is discussed. The possibility of producing identical spectral density distribution as light waves are scattered by different anisotropic media is also discussed. Moreover, the conditions under which a determinate anisotropic medium and random anisotropic medium may produce identical spectral densities are obtained. It is shown that the complete equivalence theorem in whole space or the partial equivalence theorem in some special planes can be realized under particular conditions.

Combination regimens containing daratumumab for initial diagnosed acquired thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia associated with disseminated microvascular platelet-rich thrombus. Before the introduction of plasma therapy, acute TTP was almost universally fatal, which improved survival from < 10 to 80-90%. However, patients who survived an acute attack were at high risk for recurrence and long-term morbidity. It was reported that daratumumab can eradicate persistent ADAMTS13-inhibiting autoantibodies and restore ADAMTS13 activity in two patients with relapsed immune-mediated TTP without associated adverse drug reactions. Here we report a case series of patients with initial diagnosed acquired TTP treated with combination regimens containing daratumumab. All the patients achieved clinical response after the initial treatment. Three patients achieved clinical remission, one patient relapsed and one patient suffered an exacerbation during follow-up. The two patients were retreated with glucocorticoids, plasma exchange combined with daratumumab, and clinical remission was achieved again. Combination of daratumumab in the treatment of initial diagnosed acquired thrombotic thrombocytopenic purpura can rapidly restore ADAMST13 activity and turn negative for ADAMST13 inhibitors, resulting in long-term remission in patients.

Application of Glutamine-enriched nutrition therapy in childhood acute lymphoblastic leukemia.

BACKGROUND: We investigated the effects of glutamine (Gln)-enriched nutritional therapy during chemotherapy on the nutritional status and immune function of children with acute lymphoblastic leukemia (ALL). METHODS: We enrolled 48 children who were newly diagnosed with ALL in our department during the period of 2013.1-2014.12. The patients (follow random number table) were randomly divided into the control group (peptamen) and the treatment group (peptamen + glutamine), 24 cases in each group. The remission induction regimens were all based on VDLP (D) chemotherapy (VCR (Vincrisstine), DNR (Daunomycin), L-ASP (L-Asparagiase), Prednisolone and Dexamethasone). The treatment group received Gln-enriched nutritional therapy every day during the full course of chemotherapy,and the control group is as same as the treatment group except without glutamine. The indicators of general nutritional status, such as weight, height, and triceps skinfold thickness, and the indicators of biochemical tests, such as serum albumin, prealbumin, creatinine-height index, retinol binding protein, and urinary hydroxyproline index, were compared between the two groups at the end of the first, second, third and the fourth week when the chemotherapy was completed. And in the fourth week, flow cytometry was applied to detect the levels of T cell subsets and the activities of natural killer (NK) cells in peripheral blood of the two groups. RESULTS: 1. after 4 weeks nutritional therapy, there is no significant difference (p > 0.05) between the two groups of children in weight, height and other indicators. 2. At the end of 2 weeks treatment, the level of prealbumin (PA) and retinol-binding protein (RBP) is higher in treatment group than that in the control group (P <0.05), at the end of 3 weeks treatment, the thickness of triceps skinfold is higher (P <0.05) than that in the control group; 3. At the end of 3 and 4 weeks, the concentrations serum ALB, PA, RBP and UHI were higher than in the control group (P <0.05); 4. There is statistically significant (p < 0.05) between the two groups in edema incidence; 5. At the end of treatment (4 weeks), the percentages of CD3 +, CD4 +, CD4 +/CD8 +, NK cell are significantly decreased in the two groups (P <0.05). CONCLUSION: Gln-enriched nutritional therapy can effectively improve the systemic nutritional status of children with leukemia, improve immune function.

Thirty-day rat toxicity study reveals reversible liver toxicity of mifepristone (RU486) and metapristone.

OBJECTIVE: Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs. METHODS: The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses. RESULTS: Oral mifepristone (3000 mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200 mg/kg/day) caused reversible hepatotoxicity that only occurred at 200 mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight. CONCLUSION: The present study, for the first time, reveals reversible hepatotoxicity in rats caused by the 30-d consecutive administration at the high dose, and warns the potential hepatotoxicity caused by long-term administrations of high doses of mifepristone or metapristone in clinical trials but not by the acute single abortion doses.

Epigenetic regulation of miR-129-2 and its effects on the proliferation and invasion in lung cancer cells.

MicroRNAs (miRNAs) play a pivotal role in carcinogenesis. Dysregulation of miRNAs, both oncogenic miRNAs and tumour-suppressive miRNAs, is closely associated with cancer development and progression. The levels of miRNAs could be changed epigenetically by DNA methylation in the 5' untranslated region (UTR) of pre-mature miRNAs. To investigate whether DNA methylation alters the expression of miR-129 in lung cancer, we did DNA methylation assays and found that 5' UTR region of miR-129-2 gene was absolutely methylated in both A549 and SPCA-1 lung cancer cells, but totally un-methylated in 95-D cells. The expression of miR-129 was restored by 5-Aza-2'-deoxycytidine (DAC), a de-methylation agent, in both A549 and SPCA-1 cells, resulting in attenuated cell migration and invasion ability, and decreased protein level of NF-κB, which indicates the involvement of NF-κB pathway. To further illustrate the roles of miR-129 in lung tumourigenesis, we overexpressed miR-129 in lung cancer cells by transfection of miR-129 mimics, and found arrested cell proliferation at G2/M phase of cell cycle and inhibited cell invasion. These findings strongly suggest that miR-129 is a tumour suppressive miRNA, playing important roles in the development and progression of human lung cancer.

Analysis of noisy multi-angle dynamic light scattering data.

In multi-angle dynamic light scattering measurements, due to the inevitable presence of baseline measurement noise, the normalized intensity autocorrelation function (ACF) data deviates from the true value. This leads to incorrect angular weighting estimates, which affect the accuracy of inversion results and determination of particle size distributions (PSDs). We outline a method to calculate better angular weighting coefficients from the noisy intensity ACF data. The method involves first compensating for the baseline error in the ACF data and then determining the weighting coefficients. We demonstrate the method using simulated ACF data containing baseline error for unimodal and bimodal PSDs and also for experimental data for unimodal and bimodal samples. For the unimodal PSDs ACF data were simulated for 100-900 nm and 100-650 nm particle size ranges, and for bimodal PSDs 360-900 nm and 100-900 nm particle size ranges were used. The performance of our method was shown by comparing the results of weighting coefficient and PSD determination with and without baseline compensation to the known coefficient values and PSDs. With baseline compensation the relative error of the weighting coefficients decreased significantly. Furthermore, with baseline compensation, the PSD results for the four groups of simulated data were improved. The deviations between the known and recovered PSDs were decreased, the relative error of peak position obviously decreased, and the occurrence of false peaks was reduced. The PSD results from the experimental data further validates the conclusion that the method proposed apparently reduces the relative error of peak position, effectively eliminates the false peak, and improves the accuracy of the recovered PSD.

Hepatic polypeptide nutrient solution improves high-cholesterol diet-induced rats with nonalcoholic fatty liver disease by activating AMP-activated protein kinase signaling pathway.

Hepatic polypeptide nutrient solution (HP) is a mixture of hepatoprotective peptides derived from fresh porcine liver with various effects. However, the role and mechanisms of HP in nonalcoholic fatty liver disease (NAFLD) are still not well understood. We investigated the effects of HP NAFLD rats induced by high-cholesterol diet (HCD) and its underlying mechanisms. Rats were provided with HCD for 4 weeks and then received HP or metformin after 2 weeks of HCD feeding. The study found that HP reduced cholesterol and triglyceride levels in rats with NAFLD (all p < .05). Histopathological examination also showed that HP improved the liver lesions induced by the HCD diet. Furthermore, the oxidative stress and inflammatory responses of NAFLD rats treated with HP were also improved. In addition, it was discovered that HP triggered the activation of AMPK and decreased the expression of SREBP-1c and FAS while enhancing the expression of PPAR α and CPT-1 in liver. These findings indicated that HP might have therapeutic potential for NAFLD, possibly via activating AMPK signaling pathway.

Catalytic NIR chemiluminescence sensor with enhanced persistence and intensity for in vivo imaging.

Chemiluminescence (CL) is a self-illumination phenomenon that involves the emission of light from chemical reactions, and it provides favorable spatial and temporal information on biological processes. However, it is still a great challenge to construct effective CL sensors that equip strong CL intensity, long emission wavelength, and persistent luminescence for deep tissue imaging. Here, we report a liposome encapsulated polymer dots (Pdots)-based system using catalytic CL substrates (L-012) as energy donor and fluorescent polymers and dyes (NIR 695) as energy acceptors for efficient Near-infrared (NIR) CL in vivo imaging. Thanks to the modulation of paired donor and acceptor distance and the slow diffusion of biomarker by liposome, the Pdots show a NIR emission wavelength (λ em, max = 720 nm), long CL duration (>24 h), and a high chemiluminescence resonance energy transfer efficiency (46.5 %). Furthermore, the liposome encapsulated Pdots possess excellent biocompatibility, sensitive response to H2O2, and persistent whole-body NIR CL imaging in the drug-induced inflammation and the peritoneal metastatic tumor mouse model. In a word, this NIR-II CL nanoplatform with long-lasting emission and high spatial-temporal resolution will be a concise strategy in deep tissue imaging and clinical diagnostics.

Noninvasive glucose monitoring using portable GOx-Based biosensing system.

Wearable biosensors have gained huge interest due to their potential for real-time physiological information. The development of a non-invasive blood glucose device is of great interests for health monitoring in reducing the diabetes incidence. Here, we report a sandwich-structured biosensor that is designed for glucose levels detection by using sweat as the means of monitoring. The Prussian blue nanoparticles (PBNPs) and carboxylated carbon nanotubes (MWCNT-COOH) were self-assembled on the electrode to improve the electrochemical performance and as the sensor unit, glucose oxidase (GOx) was immobilized by chitosan (CS) as the reaction catalysis unit, and finally encapsulated with Nafion to ensure a stable performance. As a result, the GOx/PBNPs/MWCNT-COOH sensor displays a low detection limit (7.0 µM), high sensitivity (11.87 µA mM-1 cm-2), and excellent interference resistance for a full sweat glucose application range (0.0-1.0 mM) for both healthy individuals and diabetic patients. Additionally, the glucose sensor exhibits stable stability for two weeks and can be successfully applied to screen-printed carbon electrodes (SPCE), demonstrating its great potential for personalized medical detection and chronic disease management.

A surgical mouse model of neonatal right ventricular outflow tract obstruction by pulmonary artery banding.

BACKGROUD: Diseased animal models play an extremely important role in preclinical research. Lacking the corresponding animal models, many basic research studies cannot be carried out, and the conclusions obtained are incomplete or even incorrect. Right ventricular (RV) outflow tract (RVOT) obstruction leads to RV pressure overload (PO) and reduced pulmonary blood flow (RPF), which are 2 of the most important pathophysiological characteristics in pediatric cardiovascular diseases and seriously affect the survival rate and long-term quality of life of many children. Due to the lack of a neonatal mouse model for RVOT obstruction, it is largely unknown how RV PO and RPF regulate postnatal RV and pulmonary development. The aim of this study was to construct a neonatal RVOT obstruction mouse model. METHODS AND RESULTS: Here, we first introduced a neonatal mouse model of RVOT obstruction by pulmonary artery banding (PAB) on postnatal day 1. PAB induced neonatal RVOT obstruction, RV PO, and RPF. Neonatal RV PO induced cardiomyocyte proliferation, and neonatal RPF induced pulmonary dysplasia, the 2 features that are not observed in adult RVOT obstruction. As a result, PAB neonates exhibited overall developmental dysplasia, a sign similar to that of children with RVOT obstruction. CONCLUSIONS: Because many pediatric cardiovascular diseases are associated with RV PO and RPF, the introduction of a neonatal mouse model of RVOT obstruction may greatly enhance our understanding of these diseases and eventually improve or save the lives of many children.

Cardiopulmonary progenitors facilitate cardiac repair via exosomal transfer of miR-27b-3p targeting the SIK1-CREB1 axis.

Ischemic heart disease, especially myocardial infarction (MI), is one of the leading causes of death worldwide, and desperately needs effective treatments, such as cell therapy. Cardiopulmonary progenitors (CPPs) are stem cells for both heart and lung, but their repairing role in damaged heart is still unknown. Here, we obtained CPPs from E9.5 mouse embryos, maintained their stemness while expanding, and identified their characteristics by scRNA-seq, flow cytometry, quantitative reverse transcription-polymerase chain reaction, and differentiation assays. Moreover, we employed mouse MI model to investigate whether CPPs could repair the injured heart. Our data identified that CPPs exhibit hybrid fibroblastic, endothelial, and mesenchymal state, and they could differentiate into cell lineages within the cardiopulmonary system. Moreover, intramyocardial injection of CPPs improves cardiac function through CPPs exosomes (CPPs-Exo) by promotion of cardiomyocytic proliferation and vascularization. To uncover the underlying mechanism, we used miRNA-seq, bulk RNA-seq, and bioinformatic approaches, and found the highly expressed miR-27b-3p in CPPs-Exo and its target gene Sik1, which can influence the transcriptional activity of CREB1. Therefore, we postulate that CPPs facilitate cardiac repair partially through the SIK1-CREB1 axis via exosomal miR-27b-3p. Our study offers a novel insight into the role of CPPs-Exo in heart repair and highlights the potential of CPPs-Exo as a promising therapeutic strategy for MI.

Growth performance and cecal microbiota of broiler chicks as affected by drinking water disinfection and/or herbal extract blend supplementation.

Environmental exposures during early life are important for animals' intestinal microbiota composition and their production performance. This experiment investigated the growth performance, hematology parameters, jejunal morphology, and cecal microbiota of broiler chicks as affected by exogenous factors from the aspects of drinking water quality and dietary manipulation. A total of 480-day-old broiler chicks (Arbor acre; 41.59 ± 0.88 g) were randomly assigned into 4 groups (CON, HWGM, CA, CAHWGM). Each group had 6 replicates with 20 birds per replicate. Broiler chicks in CON group were fed with basal diet and drank normal drinking water; in HWGM group were fed with basal diet supplemented with 1.5g/kg herbal extract blend (hops, grape seed, and wheat germ) and drank normal drinking water; in CA group were fed with basal diet and drank sodium dichlorocyanurate (50 mg/L) treated-drinking water; in CAHWGM group were fed with basal diet supplemented with 1.5 g/kg herbal extract blend and drank chlorinated drinking water. The experimental period was 42 d. We found that broiler chicks drank chlorinated drinking water led to an increase in body weight gain and feed efficiency during d 22 to 42 and 1 to 42, as well as a decrease in cecal Dysgonomonas and Providencia abundance. Dietary supplementation of herbal extract blend increased cecal Lactobacillus and Enterococcus abundance, whereas decreased Dysgonomonas abundance. Moreover, we observed that cecal Dysgonomonas abundance synergistically decreased by treating drinking water with sodium dichlorocyanurate and supplementing herbal extract blend to the diet. Therefore, results obtained in this study indicated that providing chlorinated drinking water is an effective strategy to improve the growth performance of broiler chicks by regulating intestinal microbiota. Additionally, dietary supplementation of herbal extract blend alone or combined with chlorinated drinking water is able to regulate cecal microbiota.

Si-Ni-San Reduces Hepatic Lipid Deposition in Rats with Metabolic Associated Fatty Liver Disease by AMPK/SIRT1 Pathway.

Background: Metabolic associated fatty liver disease (MAFLD) is a chronic disease characterized by excessive lipid deposition in the liver without alcohol or other clear liver-damaging factors. AMP-activated protein kinase (AMPK)/silencing information regulator (SIRT)1 signaling pathway plays an important role in MAFLD development. Si-Ni-San (SNS), a traditional Chinese medicine, has shown reducing hepatic lipid deposition in MAFLD rats, however, the underlying mechanisms of SNS are barely understood. Purpose: The aim of this research was to investigate the mechanisms of SNS in reducing hepatic lipid deposition in MAFLD rats by regulating AMPK/SIRT1 signaling pathways. Methods: The components of SNS were determined by high performance liquid chromatography with mass spectrometry (HPLC-MS) analysis. MAFLD rats were induced by high-fat and high-cholesterol diet (HFHCD), and treated by SNS. SNS-containing serum and Compound C (AMPK inhibitor) were used to treat palmitic acid (PA)-induced HepG2 cells. To elucidate the potential mechanism, lipid synthesis-related proteins (SREBP-1c and FAS), fatty acid oxidation (PPARα and CPT-1), and AMPK/SIRT1 signaling pathway (p-AMPK and SIRT1) were assessed by Western blot. Results: SNS improved serum lipid levels, liver function and reduced hepatic lipid deposition in MAFLD rats. SNS-containing serum reduced lipid deposition in PA-induced HepG2 cells. SNS could up-regulate protein expressions of PPARα, CPT-1, p-AMPK and SIRT1, and down-regulate protein expressions of SREBP-1c and FAS. Similar effects of SNS-containing serum were observed in PA-induced HepG2 cells. Meanwhile, Compound C weakened the therapeutic effects of SNS-containing serum on lipid deposition. Conclusion: SNS could reduce hepatic lipid deposition by inhibiting lipid synthesis and promoting fatty acid oxidation, which might be related with activating the AMPK/SIRT1 signaling pathway. This study could provide a theoretical basis for the clinical use of SNS to treat MAFLD.

Volume overload impedes the maturation of sarcomeres and T-tubules in the right atria: a potential cause of atrial arrhythmia following delayed atrial septal defect closure.

Introduction: Adult patients with atrial septal defects (ASD), the most common form of adult congenital heart disease, often die of arrhythmias, and the immaturity of cardiomyocytes contributes significantly to arrhythmias. ASD typically induces a left-to-right shunt, which then leads to the right atrium (RA) volume overload (VO). Whether or not VO contributes to RA cardiomyocyte immaturity and thereby causes arrhythmias in adult patients with ASD remains unclear. Methods: Here, we developed the first neonatal RA VO mouse model by creating a fistula between the inferior vena cava and abdominal aorta on postnatal day 7. RA VO was confirmed by increases in the mean flow velocity, mean pressure gradient, and velocity time integral across the tricuspid valve, and an increase in the RA diameter and RA area middle section. Results: We found that VO decreased the regularity and length of sarcomeres, and decreased the T-element density, regularity, and index of integrity of T-tubules in RA cardiomyocytes, suggesting that the two most important maturation hallmarks (sarcomere and T-tubules) of RA cardiomyocytes were impaired by VO. Accordingly, the calcium handling capacity of cardiomyocytes from postnatal day 21 (P21) RA was decreased by VO. VO caused a significant elongation of the PR interval. The expression of connexin 43 (Cx43) was decreased in RA VO. Moreover, gene ontology (GO) analysis of the downregulated genes in RA demonstrated that there was an abundance of enriched terms associated with sarcomeres and T-tubules exposed to VO. The results were further verified by qRT-PCR. Conclusions: In conclusion, the first neonatal RA VO mouse model was developed; furthermore, using this neonatal RA VO mouse model, we revealed that VO impeded RA sarcomere and T-tubule maturation, which may be the underlying causes of atrial arrhythmias in adult patients with ASD.

Regulating effects of chlorinated drinking water on cecal microbiota of broiler chicks.

In this study, 2 types of drinking water were provided to broiler chicks to evaluate the relationship between the bacterial load of drinking water and cecal microbiota. One type of drinking water was untreated, while the other type was daily treated with sodium dichlorocyanurate (50 mg/L). A total of 240 broiler chicks were divided into 2 groups based on their initial body weight. There were 6 replicates in each group, and each replicate cage contained 20 birds. Each cage was assigned to a different floor of the battery cage. On the final day, water samples were collected from each replicate cage at the opening of the drinking cup height, and one bird was selected from each replicate cage to obtain cecal content samples for measuring microbiota composition using the 16S rRNA technique. We found that drinking water treated with sodium dichlorocyanurate significantly reduced the richness and diversity of microbiota and diminished/disappeared most gram-negative bacteria. Broiler chicks that consumed chlorinated drinking water exhibited changes in the composition of cecal microbiota, with Alistipes serving as the marker species in the cecal content of broiler chicks that consumed untreated water, whereas AF12 served as the marker species in the cecal content of broiler chicks that consumed chlorinated drinking water. Functional prediction using the MetaCyc database and species composition analysis of metabolic pathways showed that changes in 7 metabolic pathways were related to the abundance of Providencia. Therefore, we concluded that chlorinated drinking water reduced the bacterial load in drinking water, thereby altering the cecal microbiota composition and regulating the metabolic activity of broiler chicks.