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Summary Bacterial vectors can be engineered to generate microscopic living therapeutics to produce and deliver anticancer agents. Escherichia coli Nissle 1917 (Nissle 1917) is a promising candidate with probiotic properties. Here, we used Nissle 1917 to develop a metabolic strategy to produce 5‐aminolevulinic acid (5‐ALA) from glucose as 5‐ALA plays an important role in the photodynamic therapy of cancers. The coexpression of hemAM and hemL using a low copy‐number plasmid led to remarkable accumulation of 5‐ALA. The downstream pathway of 5‐ALA biosynthesis was inhibited by levulinic acid (LA). Small‐scale cultures of engineered Nissle 1917 produced 300 mg l−1 of 5‐ALA. Recombinant Nissle 1917 was applied to deliver 5‐ALA to colorectal cancer cells, in which it induced the accumulation of antineoplastic protoporphyrin X (PpIX) and specific cytotoxicity towards colorectal cancer cells irradiated with a 630 nm laser. Moreover, this novel combination therapy proved effective in a mouse xenograft model and was not cytotoxic to normal tissues. These findings suggest that Nissle 1917 will serve as a potential carrier to effectively deliver 5‐ALA for cancer therapy.

Background Human rhinovirus (HRV) is one of the major viruses of acute respiratory tract disease among infants and young children. This work aimed to understand the epidemiological and phylogenetic features of HRV in Guangzhou, China. In addition, the clinical characteristics of hospitalized children infected with different subtype of HRV was investigated. Methods Hospitalized children aged Results HRV was detected in 6.41% of the 655 specimens. HRV infection was frequently observed in children under 2 years old (57.13%). HRV-A and HRV-C were detected in 18 (45%) and 22 (55%) specimens. All 40 HRV strains detected were classified into 29 genotypes. The molecular evolutionary rate of HRV-C was estimated to be 3.34 × 10–3 substitutions/site/year and was faster than HRV-A (7.79 × 10–4 substitutions/site/year). Children who experienced rhinorrhoea were more common in the HRV-C infection patients than HRV-A. The viral load was higher in HRV-C detection group than HRV-A detection group (p = 0.0148). The median peak symptom score was higher in patients with HRV-C infection as compared to HRV-A (p = 0.0543), even though the difference did not significance. Conclusion This study revealed the molecular epidemiological characteristics of HRV in patients with respiratory infections in southern China. Children infected with HRV-C caused more severe disease characteristics than HRV-A, which might be connected with higher viral load in patients infected with HRV-C. These findings will provide valuable information for the pathogenic mechanism and treatment of HRV infection.

Human cytomegalovirus (HCMV), the human beta-herpesvirus, can cause severe syndromes among both immunocompromised adult patients and newborns. Type I interferon (IFN-I) exerts an important effect to resist infections caused by viruses such as HCMV, while IFN evasion may serve as a key determining factor for viral dissemination and disease occurrence within hosts. In this study, UL23, a tegument protein of HCMV, was confirmed to be a key factor for negatively regulating the type I IFN immune response. A detailed analysis indicated that the viral UL23 protein increases the IFN-I antiviral resistance during HCMV infections. Furthermore, UL23 was shown to significantly reduce the levels of IFN-stimulated genes (ISGs) and promoter activity of IFN-I-stimulated response element. Mechanically, UL23 was discovered to impair the signal transducer and activator of transcription 1 (STAT1) phosphorylation, although it was not found to affect phosphorylation and expression of STAT2, Janus activated kinase 1, or tyrosine kinase 2, which are associated with IFN-I signal transduction pathway. Additionally, a significantly reduced nuclear expression of STAT1 but not of IFN regulatory factor 9 or STAT2 was observed. Findings of this study indicate that HCMV UL23 is a viral antagonist that acts against the cellular innate immunity and reveal a possible novel effect of UL23 on IFN-I signaling.

Cerebral small vessel disease (CSVD) is composed of several diseases affecting the small arteries, arterioles, venules, and capillaries of the brain, and refers to several pathological processes and etiologies. Neuroimaging features of CSVD include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. The main clinical manifestations of CSVD include stroke, cognitive decline, dementia, psychiatric disorders, abnormal gait, and urinary incontinence. Currently, there are no specific preventive or therapeutic measures to improve this condition. In this review, we will discuss the pathophysiology, clinical aspects, neuroimaging, progress of research to treat and prevent CSVD and current treatment of this disease.

The hexavalent form of chromium, Cr (VI), has been associated with various diseases in humans. In this study, we examined the mechanisms underlying the effect of Cr (VI) on glucose and lipid metabolism in vivo and in vitro. We found that Cr (VI) induced abnormal liver function, increased fasting blood glucose (FBG), as well as glucose and insulin intolerance in mice. Furthermore, Cr (VI) decreased glucose-6-phosphate (G6P) level and glucose transporter-2 (GLUT2) expression, increased the levels of triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), reduced high-density lipoprotein-cholesterol (HDL-C), and increased sterol regulatory element-binding proteins 1 (SREBP1) and fat synthase (FAS) in vitro and in vivo. Moreover, Cr (VI) promoted intracellular ROS production in vitro, and induced reduction of antioxidant enzyme level and Nrf2/HO-1 expression in vitro and in vivo. Also, N-acetyl cysteine (NAC, effective antioxidant and free radical scavenger) pretreatment inhibited the production of intracellular ROS, significantly suppressed Cr (VI)-induced oxidative stress, lipid accumulation, decreased G6P and GLUT2, and improved impaired glucose tolerance and glucose and insulin intolerance caused by Cr (VI) in mice. Dh404 activated expression of Nrf2 decreased ROS level, increased HO-1 expression, ameliorated activity of the antioxidant enzyme, inhibited Cr (VI) increase of SREBP1, FAS level, and reduction of G6P and GLUT2. To sum up, these data suggest that dysregulation of ROS/Nrf2/HO-1 has an important role in Cr (VI)-induced glucose/lipid metabolic disorder.

To evaluate the health risk of radon and its progeny, a large amount of accurate monitoring data is needed according to the theory and practice of health risk assessment. However, the indoor radon levels in different regions in China and worldwide reveal temporal and spatial variations. In addition, the residents living in different areas follow distinct living modes. Therefore, it is recommended and accepted by many researchers to detect the radon level in local areas and subsequently conduct health risk assessments based on local detection data. In this study, 21 bedrooms of households in Weifang city were selected, and the indoor 222Rn and 220Rn levels were detected with RAD7 radon detector in winter, while the annual effective radiation dose was calculated for ordinary residents in Weifang city. Our investigation showed that the 24- and 12-hour average levels of 222Rn were 35.7±15.2 Bq/m3 and 36.2±15.8 Bq/m3, respectively. The 24- and 12-hour average levels of 220Rn were 30.4±12.3 Bq/m3 and 22.4±11.6 Bq/m3, respectively. There were significant differences in the average levels of 222Rn and 220Rn between floors. The estimated annual effective radiation dose received by ordinary residents in Weifang city was 1.7193 mSv, of which 0.9479 mSv originated from 222Rn and its progeny and 0.7714 mSv originated from 220Rn and its progeny, accounting for 55.1% and 44.9%, respectively, of the total dose. Our findings suggest that 220Rn should not be ignored by local residents in Weifang city, and more attention should be paid to 220Rn in future research.

Alzheimer’s disease (AD) is a type of neurodegenerative disorder and the most common form of dementia. MicroRNA (miRNA) has been shown to play a role in various diseases, including AD. It also has been reported to regulate autophagy. We extracted miRNA from blood samples and constructed an miRNA-101a lentivirus vector. In this study we found the level of miRNA-101a was significantly reduced in the plasma of patients with AD and APPswe/PS1ΔE9 transgenic mice. The relative expression of miRNA-101a exhibited a relatively high diagnostic performance (area under receiver operating characteristic curve: 0.8725) in the prediction of AD with a sensitivity of 0.913 and a specificity of 0.733 at the threshold of 0.6463. Under electron microscopy, autophagic vacuoles in AD-related cells numbered more than the cells up-regulating miRNA-101a in the in vitro experiments. Dual-luciferase reporter assay and Western blot results proved that the MAPK1 pathway plays a role in the formation of autophagic vacuoles in AD. This study found that the autophagy phenomenon regulated by miRNA-101a via the MAPK pathway might be a new mechanism in AD. This could provide new insights into AD formation and treatment.

Human respiratory syncytial virus (RSV) is one of the major viruses of acute respiratory tract disease among infants and young children. We performed molecular epidemiology analysis of RSV among inpatient children in Guangzhou, China. Phylogenetic and Bayesian analysis showed that genotype ON1 was the only subgroup A virus in this study. Interestingly, the majority of Guangzhou ON1 strains formed a well-supported cluster, and these strains shared a novel set of five amino acid substitutions that never illustrated before. Furthermore, the degree of disease severity was assessed using a severity scoring system. The patients carrying the novel RSV A strain were associated with milder respiratory symptoms compared to other RSV A positives. In conclusion, a specific set of five amino acid substitutions was found in China and further analysis showed that disease severity was associated with these alterations. These findings will provide valuable information for the pathogenic mechanism and vaccine development of RSV.

Gestational exposure to PM2.5 is a worldwide environmental issue associated with long-lasting behavior abnormalities and neurodevelopmental impairments in the hippocampus of offspring. PM2.5 may induce hippocampus injury and lead to autism-like behavior such as social communication deficits and stereotyped repetitive behavior in children through neuroinflammation and neurodegeneration. Here, we investigated the preventive effect of B-vitamin on PM2.5-induced deleterious effects by focusing on anti-inflammation, antioxidant, synaptic remodeling and neurodevelopment. Pregnant mice were randomly divided into three groups including control group (mice subject to PBS only), model group (mice subject to both 30 μL PM2.5 of 3.456 μg/μL and 10 mL/(kg·d) PBS), and intervention group (mice subject to both 30 μL PM2.5 of 3.456 μg/μL and 10 mL/(kg·d) B-vitamin supplementation (folic acid, vitamin B6 and vitamin B12 with concentrations at 0.06, 1.14 and 0.02 mg/mL, respectively)). In the current study B-vitamin significantly alleviated neurobehavioral impairment reflected in reduced social communication disorders, stereotyped repetitive behavior, along with learning and spatial memory impairment in PM2.5-stimulated mice offspring. Next, B-vitamin corrected synaptic loss and reduced mitochondrial damage in hippocampus of mice offspring, demonstrated by normalized synapse quantity, synaptic cleft, postsynaptic density (PSD) thickness and length of synaptic active area. Furthermore, significantly down-regulated expression of pro-inflammatory cytokines including NF-κB, TNF-α and IL-1β, and lipid peroxidation were found. We observed elevated levels of oxidant-related genes (SOD, GSH and GSH-Px). Moreover, decreased cleaved caspase-3 and TUNEL-positive cells suggested inhibited PM2.5-induced apoptosis by B-vitamin. Furthermore, B-vitamin increased neurogenesis by increasing EdU-positive cells in the subgranular zone (SGZ) of offspring. Collectively, our results suggest that B-vitamin supplementation exerts preventive effect on autism-like behavior and neurodevelopmental impairment in hippocampus of mice offspring gestationally exposed to PM2.5, to which alleviated mitochondrial damage, increased anti-inflammatory and antioxidant capacity and synaptic efficiency, reduced neuronal apoptosis and improved hippocampal neurogenesis may contribute.

The objective of this study was to observe the effects of moderate-intensity training on the activity of heme oxygenase (HO) and expression of HO-1 mRNA in the aorta and the cardiac muscle of spontaneously hypertensive rats (SHRs). After 9 weeks of swimming exercise, the activity of HO and expression of HO-1 mRNA in the SHRs were measured. The resting blood pressure in the exercise group was increased by 1.7% (P > 0.05), whereas it was significantly elevated by 10.3% (P < 0.01) in the SHR rats. Compared with animals in the control and sedentary groups, the expression level of HO-1 mRNA of aorta and cardiac muscle in the exercise group was significantly enhanced (P < 0.01). The HO activity and the content of plasma carbon monoxide (CO) in the sedentary group were dramatically decreased (P < 0.05 and P < 0.01, respectively) compared with the control group. HO activity and content of plasma CO in the exercise group were significantly higher compared with those in the sedentary group (P < 0.05 and P < 0.01, respectively). The HO/CO metabolic pathway might be involved in the regulation of blood pressure of the SHR models.

Air pollution is a serious environmental health problem closely related to the occurrence of central nervous system diseases. Exposure to particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5) during pregnancy may affect the growth and development of infants. The present study was to investigate the effects of maternal exposure to PM2.5 during pregnancy on brain development in mice offspring. Pregnant mice were randomly divided into experimental groups of low-, medium-, or high-dosages of PM2.5, a mock-treated group which was treated with the same amount of phosphate buffer solution (PBS), and acontrol group which was untreated. The ethology of offspring mice on postnatal days 1, 7, 14, 21, and 30, along with neuronal development and apoptosis in the cerebral cortex were investigated. Compared with the control, neuronal mitochondrial cristae fracture, changed autophagy characteristics, significantly increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cell rate, and mRNA levels of apoptosis-related caspase-8 and caspase-9 were found in cerebral cortex of mice offspring from the treatment groups, with mRNA levels of Bcl-2 and ratio of Bcl-2 to Bax decreased. Treatment groups also demonstrated enhanced protein expressions of apoptosis-related cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9, along with declined proliferating cell nuclear antigen (PCNA), Bcl-2, and ratio of Bcl-2 to Bax. Open field experiments and tail suspension experiments showed that exposure to high dosage of PM2.5 resulted in decreased spontaneous activities but increased static accumulation time in mice offspring, indicating anxiety, depression, and social behavioral changes. Our results suggested that maternal exposure to PM2.5 during pregnancy might interfere with cerebral cortex development in mice offspring by affecting cell apoptosis.