Hydrogel-forming viscous liquid in response to ROS restores the gut mucosal barrier of colitis mice via regulating oxidative redox homeostasis.

The disrupted oxidative redox homeostasis plays a critical role in the progress of ulcerative colitis (UC). Herein, hydrogel-forming viscous liquid (HSD) composed of cysteamine-grafted hyaluronic acid (HS) and superoxide dismutase (SOD) has been designed for UC. When the viscous HSD liquid was infused into colitis colon, SOD would convert the pathological superoxide (O2·-) to hydrogen peroxides (H2O2), which was subsequently scavenged by HS. Accordingly, the sol-gel transition of HSD was initiated by scavenging H2O2, enhancing its adhesion toward colitis colon. H2O2-treated HSD presented the higher storage modulus and stronger adhesion force toward porcine colon than the untreated HSD. Besides, H2O2-treated HSD presented the slower erosion profile in the colitis-mimicking medium (pH 3-5), while its rapid degradation was displayed in physiologic condition (pH7.4). The combination of pH-resistant erosion and ROS-responsive adhesion for HSD rendered it with the specifical retention on the inflamed colonic mucosa of DSS-induced colitis mice. Rectally administrating HSD could effectively hinder the body weight loss, reduce the disease activity index and improve the colonic shorting of DSS-induced colitis mice. Moreover, the pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) were substantially decreased, the colonic epitheliums were well rearranged and the tight junction proteins were greatly recovered after HSD treatment. Besides, HSD also modulated the gut flora, markedly augmenting the abundance of Firmicutes, Barnesiella and Lachnospiraceae. Moreover, HSD treatment could regulate oxidative redox homeostasis via activating Nrf2-HO-1 pathway to reduce ROS and malondialdehyde and upregulate antioxidant enzymes (SOD, GPx and GSH). Collectively, HSD might be a promising therapy for UC treatments. STATEMENT OF SIGNIFICANCE: Herein, a hydrogel-forming viscous liquid (HSD) was designed by cysteamine-grafted hyaluronic acid (HS) and superoxide dismutase (SOD) for UC treatments. When the viscous HSD liquid was infused into a colitis colon, SOD would convert the pathological superoxide to hydrogen peroxides (H2O2), which was subsequently scavenged by HS. Accordingly, the sol-gel transition of HSD was initiated by scavenging H2O2, enhancing its adhesion to the colitis colon. The colonic epitheliums of DSS-induced colitis mice were well rearranged and the tight junction proteins (Zonula-1 and Claudin-5) were greatly recovered after the HSD treatment. Moreover, the HSD treatment could regulate oxidative redox homeostasis via activating the Nrf2-HO-1 pathway to reduce ROS and malondialdehyde and upregulate antioxidant enzymes (SOD, GPx and GSH).

Design, synthesis and bioactivity evaluation of fisetin derivatives as potential anti-inflammatory agents against LPS-induced acute lung injury.

Acute lung injury (ALI) refers to a common and life-threatening disease attributed to inflammation. However, effective drug treatments have been rare for ALI. Natural products have been considered as a vital source of drug discovery which indicates that it's a workable method to find new anti-inflammatory drugs in natural products. Inspired by the various biological activities of fisetin, we reported the design and synthesis of a series of fisetin derivatives which were also evaluated for their anti-inflammatory activities in J774A.1 macrophages. Most of the obtain derivatives could effectively inhibit the release of IL-6 and TNF-α in vitro experiments without cytotoxicity. The most promising compound 5b exhibited significant in vivo anti-inflammatory activity in the model of LPS-induced ALI in mice. On the whole, this study could provide novel candidates for the treatment of ALI.

Mitogen-stimulated cell proliferation and cytokine production in major depressive disorder patients.

BACKGROUND: Major depressive disorder (MDD) is related to human's immune status, and immunological indicators such as mitogen stimulated cell proliferation and cytokines may become candidate biomarkers for disease diagnosis. METHODS: One hundred diagnosed major depressive disorder subjects and 100 health controls were enrolled in this study. Phytohaemagglutinin and lipopolysaccharide stimulated cell proliferations and cytokine concentrations were detected in peripheral blood mononuclear cells from both groups. The corresponding stimulated responses were conducted and confirmed in chronic unpredictable mild stress (CUMS) mice. RESULTS: Compared to the people in control group, there were lower cell proliferations and lower TNF-α produced in lipopolysaccharide stimulated peripheral blood mononuclear cells in depression patients, lower IL-2 and IL-10 produced in phytohaemagglutinin stimulated peripheral blood mononuclear cells in depression patients, higher IL-6, IL-10 and lower IL-2 secretions were detected in peripheral plasma in depression patients. In CUMS mice we found lower splenocyte proliferations, lower IL-1α productions and higher IL-6 secretions in lipopolysaccharide stimulated splenocytes. It seems lipopolysaccharide stimulated cell proliferation activities were inhibited in depressive states. CONCLUSIONS: Lower lipopolysaccharide stimulated cell proliferation and phytohaemagglutinin stimulated or plasma cytokine IL-2 decreases should be potential monitoring indices in the depressive state assessment for major depressive disorder patients.

Prevention of Dermal Abscess Formation Caused by Staphylococcus aureus Using Phage JD007 in Nude Mice.

Aim: In this study, Staphylococcus phage JD007 bactericidal activity and induced immune responses during treatment were assessed in a dermal abscess model. Materials and Methods: Dermal abscesses in nude mice were established by injecting a clinical isolate of S. aureus SA325 isolated from the back under-dermal abscess of an in-patient. Results: Phage JD007 was able to inhibit the growth of S. aureus SA325 at MOI = 1 or 10, significantly preventing the formation of dermal abscesses. Moderate immune responses were observed in the prevention group through detection of cytokines. Conclusion: Phage JD007 inhibits the formation of dermal abscesses caused by a clinical S. aureus strain in nude mice without robust immune responses.

Prevotella and Klebsiella proportions in fecal microbial communities are potential characteristic parameters for patients with major depressive disorder.

BACKGROUND: The diagnosis of major depression disorder (MDD) and other mental disorders were depended on some subjective survey scales. There are confirmed relationship between the gut flora and the mental states of MDD patients. METHODS: The V3-V4 region of the 16S rRNA gene was extracted from the fecal microbial communities in MDD patients, PCR amplified and sequenced on the Illumina Miseq platform. RESULTS: More phylum Firmicutes, less Bacteroidetes, and more genus Prevotella, Klebsiella, Streptococcus and Clostridium XI were found in MDD patients. The changes of the proportion of Prevotella and Klebsiella were consistent with Hamilton depression rating scale. LIMITATIONS: The conclusion was limited by small sample sizes and potential uncontrollable influence factors on fecal microbiota. DISCUSSION: Prevotella and Klebsiella proportion in fecal microbial communities should be concerned in the diagnosis and therapeutic monitoring of MDD in future.

First report of two rapid-onset fatal infections caused by a newly emerging hypervirulent K. Pneumonia ST86 strain of serotype K2 in China.

Here, we present the first report of one suspected dead case and two confirmed rapid-onset fatal infections caused by a newly emerging hypervirulent Klebsiella pneumoniae ST86 strain of serotype K2. The three cases occurred in a surgery ward during 2013 in Shanghai, China. A combination of multilocus sequence typing, pulsed-field gel electrophoresis, phenotypic and PCR tests for detecting virulence factors (VFs) was used to identify the isolates as K2 ST86 strains with common VFs, including Aerobactin and rmpA. Furthermore, the two K2 ST86 strains additionally harbored a distinct VF kfu (responsible for iron uptake system), which commonly existed in invasive K1 strains only. Thus, the unusual presence of both K1 and K2 VFs in the lethal ST86 strain might further enhance its hypervirulence and cause rapid onset of a life-threatening infection. Nevertheless, despite the administration of a combined antibiotic treatment, these three patients all died within 24 h of acute onset, thereby highlighting that the importance of early diagnosis to determine whether the ST86 strains harbor key K2 VF and unusual K1 kfu and whether patients should receive a timely and targeted antibiotic therapy to prevent ST86 induced fatal pneumonia. Finally, even though these patients are clinically improved, keeping on with oral antibiotic treatment for additional 2-3 weeks will be also vital for successfully preventing hvKP reinfection or relapse.