Cancer drug delivery remains a formidable challenge due to systemic toxicity and inadequate extravascular transport of nanotherapeutics to cells distal from blood vessels. It is hypothesized that, in absence of an external driving force, the Salmonella enterica serovar Typhimurium could be exploited for autonomous targeted delivery of nanotherapeutics to currently unreachable sites. To test the hypothesis, a nanoscale bacteria‐enabled autonomous drug delivery system (NanoBEADS) is developed in which the functional capabilities of the tumor‐targeting S. Typhimurium VNP20009 are interfaced with poly(lactic‐co‐glycolic acid) nanoparticles. The impact of nanoparticle conjugation is evaluated on NanoBEADS' invasion of cancer cells and intratumoral transport in 3D tumor spheroids in vitro, and biodistribution in a mammary tumor model in vivo. It is found that intercellular (between cells) self‐replication and translocation are the dominant mechanisms of bacteria intratumoral penetration and that nanoparticle conjugation does not impede bacteria's intratumoral transport performance. Through the development of new transport metrics, it is demonstrated that NanoBEADS enhance nanoparticle retention and distribution in solid tumors by up to a remarkable 100‐fold without requiring any externally applied driving force or control input. Such autonomous biohybrid systems could unlock a powerful new paradigm in cancer treatment by improving the therapeutic index of chemotherapeutic drugs and minimizing systemic side effects.

SUMMARYExcessive production of reactive oxygen species (ROS) by an overactive nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system in penile tissue is an important mechanism of erectile dysfunction (ED). S-allyl cysteine (SAC), a bioactive component derived from garlic, was recently reported to exert versatile antioxidant properties. We hypothesized that SAC would be able to resolve diabetes-related ED by reducing ROS generation, and designed this study to investigate this possibility as well as to determine the related underlying mechanisms. A streptozotocin-induced diabetes rat model was established and used for comparative analysis of 4-week treatment regimens with insulin or SAC. The ratio of maximal intracavernous pressure (ICP) to mean arterial blood pressure (MAP) was measured to determine erectile function. Differential levels of ROS, NADPH oxidase subunits, nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signalling pathway, and apoptosis were evaluated in cavernous tissues. Max ICP/MAP was found to be markedly decreased in untreated diabetic rats; SAC, but not insulin, treatment restored the ratio to baseline (in non-diabetic untreated controls). The corpus cavernosum of untreated diabetic rats showed increased p47 phox and p67 phox expression, ROS production and penile apoptotic index, and decreased phospho-endothelial nitric oxide synthase (phospho-eNOS, Ser1177) expression, cGMP concentration, B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio and smooth muscle cell number. SAC treatment normalized all the diabetes-induced effects, whereas insulin treatment partially normalized the alterations, but produced no effects on P47 phox expression, penile ROS level, apoptotic index, Bcl-2/Bax ratio and smooth muscle cell number. Collectively, these data indicate that SAC treatment can restore erectile function in diabetic rats by preventing ROS formation through modulation of NADPH oxidase subunit expression. Furthermore, the poor efficacy of conventional insulin treatment for diabetic ED may be associated with an elevated level of ROS in penile tissue.

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SummarySIRT1 has many important molecular functions in aging, and the estrogen receptors (ERs) have a vasculoprotective effect, although the detailed mechanism for the roles of SIRT1 and ERs in vascular aging remains unclear. We found that ERb expression in the endothelium was reduced in aging mice, and the expression of ERa and SIRT1 did not change, while SIRT1 activity declined. Further investigation showed that the ERb expression was regulated by SIRT1 through complexes of SIRT1-PPARc/RXR-p300 that bind to a PPRE (PPAR response element) site on the ERb promoter, and the declined SIRT1 function in aging mice was due to compromised phosphorylation at S154. A single-mutant SIRT1-C152(D) restored the reduced ERb expression in the endothelium with minimized reactive oxygen species generation and DNA damage and increased mitochondrial function and fatty acid metabolism. In high-fat diet aging mice, the endothelium-specific delivery of ERb or SIRT1-C152(D) on the vascular wall reduced the circulating lipids with ameliorated vascular damage, including the restored vessel tension and blood pressure. We conclude that SIRT1-mediated ERb suppression in the endothelium contributes to vascular aging, and the modulation of SIRT1 phosphorylation through a single-mutant SIRT1-C152(D) restores this effect.

BackgroundA novel reassortant avian-origin influenza A (H7N9) virus was found to infect three Chinese residents, the first H7N9 infection in humans in Asia. Chest computed tomography (CT) for acute respiratory distress syndrome (ARDS) diagnosis is not only expensive but also exposes patients to radiation and might cause patients to be at risk of infection during transportation; in addition, chest radiography cannot be used to monitor the lung repeatedly in real time. Therefore, the routine use of bedside lung ultrasonography for critically ill patients with ARDS is especially valuable.ObjectivesThe aim of this study was to evaluate the application of ultrasound for lung examination in patients with ARDS.MethodsEleven patients infected with H7N9 avian influenza who developed ARDS were diagnosed by lung ultrasonography.ResultsSix patients who had severe ARDS showed a diffuse comet tail sign or a consolidation score ≥ 7 and a lung ultrasound score ≥ 20 points. A diffuse comet tail sign or a consolidation score ≤ 6 and a lung ultrasound score < 25 were observed in four patients. One patient showed a diffuse comet tail sign or consolidation area in four lung areas, with an ultrasound score of 14. Among all 11 patients studied, 6 patients had thoracic puncture and drainage of pleural effusion and 2 patients had pneumothorax puncture drainage.ConclusionsLung ultrasound could be useful for monitoring ARDS caused by the influenza virus A H7N9 strain in clinical applications.

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Background/Aims: The purpose of this study was to investigate the association between MTNR1A and MTNR1B gene polymorphisms and gestational diabetes mellitus (GDM) in Han Chinese women. Methods: Study participants included 350 patients with GDM and 480 control subjects. Three single-nucleotide polymorphisms (SNPs; rs2119882 in MTNR1A and rs10830963 and rs10830962 in MTNR1B) were genotyped using direct sequencing. Genotype and allele distributions of SNPs in cases of GDM and controls were analyzed. Association of the MTNR1A and MTNR1B gene variants with plasma glucose and insulin levels as well as blood lipid levels was further investigated. Results: The frequencies of genotypes and allele types of rs2119882 in MTNR1A and rs10830963 in MTNR1B were significantly different between women with GDM and controls (p < 0.05). Moreover, in the GDM group, these SNPs were associated with increased fasting plasma glucose concentrations (p < 0.001) and increased homeostasis model assessment of insulin resistance (p < 0.001). The rs10830962 polymorphism in MTNR1B was not associated with an increased risk of developing GDM or any of the clinical or metabolic characteristics in patients with GDM (p > 0.05). Conclusion: The genetic polymorphisms rs2119882 in MTNR1A and rs10830963 in MTNR1B are associated with an increased risk of developing GDM and insulin resistance in Han Chinese women.

Aspertetranones A-D (1-4), four new highly oxygenated putative rearranged triketide-sesquiterpenoid meroterpenes, were isolated from the marine algal-associated fungus Aspergillus sp. ZL0-1b14. On the basis of a comprehensive spectroscopic analysis, the planar structures of aspertetranones were determined to possess an unusual skeleton in the terpenoid part. The relative and absolute configurations of the aspertetranones were assigned on the basis of NOESY analysis, X-ray crystallography, and circular dichroism spectroscopy. Compounds 1-4 were evaluated for anti-inflammatory activity in LPS-stimulated RAW264.7 macrophages. Aspertetranone D exhibited an inhibitory effect against IL-6 production with 69% inhibition at 40 μM.