Design,synthesis, and evaluation of curcumin analogues as potential inhibitors of bacterial sialidase

Sialidases are key virulence factors that remove sialic acid from the host cell surface glycan, unmasking receptors that facilitate bacterial adherence and colonisation. In this study, we developed potential agents for treating bacterial infections caused by Streptococcus pneumoniae Nan A that inhibit bacterial sialidase using Turmeric and curcumin analogues. Design, synthesis, and structure analysis relationship (SAR) studies have been also described. Evaluation of the synthesised derivatives demonstrated that compound 5e was the most potent inhibitor of S. pneumoniae sialidase (IC₅₀?=?0.2?±?0.1?µM). This compound exhibited a 3.0-fold improvement in inhibitory activity over that of curcumin and displayed competitive inhibition. These results warrant further studies confirming the antipneumococcal activity 5e and indicated that curcumin derivatives could be potentially used to treat sepsis by bacterial infections.     

Sepsis,complement and the dysregulated inflammatory response

Sepsis in human beings is a major problem involving many individuals and with a high death rate. Except for a single drug (recombinant activated protein C) that has been approved for treatment of septic patients, supportive measures represent the main clinical approach. There are many models of experimental sepsis, mostly in rodents. A commonly used model is cecal ligation and puncture (CLP). In this model, robust activation of complement occurs together with up-regulation of C5a receptors (C5aR, C5L2) in a variety of different organs (lungs, kidneys, liver, heart). In septic human beings there is abundant evidence for complement activation. Interception of C5a or its receptors in the CLP model greatly improves survival in septic rodents. There is compelling evidence that CLP causes an intense pro-inflammatory state and that C5a interaction with its receptors can be linked to apoptosis of the lymphoid system and cells of the adrenal medulla, loss of innate immune functions of blood neutrophils, consumptive coagulopathy and cardiac dysfunction. These findings may have implications for therapeutic interventions in human beings with sepsis.     

孕期营养与早发型子痫前期的关系

目的:探讨早发型子痫前期与孕期营养的关系,为早发型子痫前期的预防提供参考依据。方法:选择2011年10月~2013年10月我院收治的早发型子痫前期患者(发病孕周34周)60例为A组,晚发型子痫前期患者(发病孕周≥34周)58例为B组,以及同时期门诊产检孕周34周的正常孕妇40例为C组,产检孕周≥34周的正常孕妇40例为D组,检测和比较各组孕妇的血清总蛋白、血红蛋白含量、血细胞压积水平。结果:A组血清总蛋白、血红蛋白含量、血细胞压积均显著低于B和C组,差异均有统计学意义(P0.05);而C组血清总蛋白、血红蛋白含量、血细胞压积与D组比较无明显统计学差异(P0.05)。结论:早发型子痫前期的发生可能与孕期低蛋白血症、贫血相关,加强孕妇孕期的营养可能有助于预防早发型子痫前期的发生。     

Characterization of the complex formed between a potent neutralizing ovine-derived polyclonal anti-TNFα Fab fragment and human TNFα

TNFα (tumour necrosis factor α) is an early mediator in the systemic inflammatory response to infection and is therefore a therapeutic target in sepsis. AZD9773 is an ovine-derived, polyclonal anti-TNFα Fab fragment derived from a pool of serum and currently being developed as a treatment for severe sepsis and septic shock. In the present study, we show that although AZD9773 has a modest affinity for TNFα in a binding assay, the K_i in a cell-based assay is approximately four orders of magnitude lower. We show using SEC (size exclusion chromatography) that the maximum size of the complex between AZD9773 and TNFα is consistent with approximately 12 Fabs binding to one TNFα trimer. A number of approaches were taken to map the epitopes recognized by AZD9773. These revealed that a number of different regions on TNFα are involved in binding to the polyclonal Fab. The data suggest that there are probably three epitopes per monomer that are responsible for most of the inhibition by AZD9773 and that all three can be occupied at the same time in the complex. We conclude that AZD9773 is clearly demonstrated to bind to multiple epitopes on TNFα and suggest that the polyclonal nature may account, at least in part, for the very high potency observed in cell-based assays.     

UVC fluencies for preventative treatment of Pseudomonas aeruginosa contaminated polymer tubes

Exposing Pseudomonas aeruginosa biofilm grown on the inner surface of Teflon and silicone tubes to UVC light (265 nm) from light emitting diodes (LED) has previously been shown to substantially reduce biofilm growth. Smaller UVC fluencies were required to disinfect Teflon tubes compared to silicone tubes. Light propagation enhancement in tubes can be obtained if the refractive index of the intra-luminal saline solution is higher than that of the polymer. This condition is achieved by using Teflon tubes with a low refractive index (1.34) instead of the polymers with a high refractive index (1.40–1.50) normally used for tubing in catheter production. Determining whether or not UVC light exposure can disinfect and maintain the intra-luminal number of colony forming units (CFUs) at an exceedingly low level and thus avoid the growth and establishment of biofilm is of interest. The use of UVC diodes is demonstrated to be a preventative disinfection treatment on tubes made of Teflon, which enhances the UVC light propagation, and on tubes made of a softer material, ethylene vinyl acetate (EVA), which is suitable for catheters but much less suitable for UVC light propagation. Simulating an aseptic breach (～10³–10⁴ CFU ml^?1), the UVC disinfection set-up was demonstrated using tubes contaminated with planktonic P. aeruginosa. After the tubes (10–20 cm) were inoculated with the bacterial solution for 3 h, they were emptied and filled with saline solutions (0.9–20%). Next UVC fluencies (0–21 mJ cm^?2) were applied to the tubes 3 h after inoculation. Colony counts were carried out on liquid samples drawn from the tubes the first day after UVC treatment and liquid and surface samples were collected and analyzed 3–4 days later. A fluence of approximately 1.0 mJ cm^?2 was noted as being sufficient for no growth for a period of 3–4 days for the Teflon tubes. Determining the fluence threshold for the EVA tubes was not possible. Almost all of the UVC-treated EVA tubes were disinfected simply by filling the tubes with a saline solution. Direct UVC treatment of the contaminated EVA tubes revealed, however, that a fluence of 21 mJ cm^?2 killed the bacteria present in the tubes and kept them disinfected for a period of 3–4 days.     

Combination of sepsis biomarkers may indicate an invasive fungal infection in haematological patients

Background: Invasive fungal infections are a major threat to a large cohort of immunocompromised patients, including patients with chemotherapy-associated neutropenia. Early differential diagnosis with bacterial infections is often complicated, which leads to a delay in empirical antifungal therapy and increases risk for adverse outcome. Accessibility and performance of specific fungal antigen and PCR-tests are still limited, while sepsis biomarkers are more broadly used in most settings currently.

Methods: Haematological patients hospitalized to receive chemotherapy with proven or probable invasive fungal infection or microbiologically proven bacterial bloodstream infection were included in the study. C-reactive protein was assessed daily during the profound neutropenia period, while procalcitonin or presepsin were measured during the first 48?hours after the onset of febrile episode.

Results: There were totally 64 patients included in the study, 53 with bacterial bloodstream infections and 11 with invasive fungal infections. Combination of CRP >120 with PCT <1.25 or presepsin <170 was shown to be a possible combined biomarker for invasive fungal infections in immunocompromised patients, with areas under the ROC-curves: 0.962 (95% CI 0.868 to 0.995) for PCT-based combination and 0.907 (95% CI 0.692 to 0.990) for presepsin-based combination.     

Ulinastatin attenuates liver injury and inflammation in a cecal ligation and puncture induced sepsis mouse model

Sepsis is a syndrome of life-threatening multiorgan dysfunction caused by host response dysregulation to infection. Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide-induced sepsis. However, little is known about the mechanism underlying its effects on sepsis. In the current study, we investigated the protective effect of UTI on liver injury in a cecal ligation and puncture (CLP)-induced sepsis of C57BL/6 mouse model and explored the possible mechanisms. Mice underwent CLP as sepsis models and were randomized into five groups including the sham group, UTI group, CLP group, UTI-L group, and UTI-H group. UTI was intraperitoneally administered at doses of UTI 1500 U/100 g (UTI-L group) or 3000 U/100 g (UTI-H group), before CLP. The mice were killed, and immunohistochemical changes, cytokine levels, and antioxidant enzyme activities were detected. Our results showed that UTI ameliorated CLP-mediated increases in serum aspartate aminotransferase and alanine aminotransferase activities, histological activity index, degenerative region ratio, and infiltrated inflammatory cell numbers. Moreover, UTI also decreased nitrotyrosine and 4-hydroxynonenal, activated caspase-3, and activated poly (ADP-ribose) polymerase (PARP) levels and inhibited the mitogen-activated protein kinase pathway activation in liver tissues. Our results indicated that UTI could inhibit CLP-induced liver injury by suppressing inflammation and oxidation. Our results indicated that UTI may serve as a potential therapeutic agent for sepsis.     

Photoacoustic microscopy for evaluating a lipopolysaccharide‐induced inflammation model in mice

Photoacoustic microscopy (PAM) is a noninvasive imaging technique and is excellent to study structural and functional changes in the microcirculation. In this work, a lipopolysaccharide (LPS)‐induced inflammation model in mice is noninvasively evaluated by PAM. PAM is used to image the microvascular structural changes in mice for 8 hours after the LPS with different concentrations is applied. Quantitative analysis of five vessel parameters is conducted, which shows that the rate of reduction in microvasculature is highly dependent on the applied LPS concentrations. For low‐concentration LPS, changes in the microvasculature are not obvious over the observation period, whereas for high‐concentration LPS, quick and marked reduction in the microvasculature is observed. In addition, changes in capillaries are more significant than those in relatively large vessels. The results show that PAM is able to evaluate the inflammation mouse model by studying structural (and potentially functional) changes in the microcirculation. Furthermore, PAM may have potential for early intervention and treatment plan optimization of sepsis by monitoring the microcirculation and inflammatory response.      

The NOTCH4-GATA4-IRG1 axis as a novel target in early-onset colorectal cancer

The early onset of colorectal cancer (CRC) in individuals younger than 50 years is an emerging phenomenon, and obesity is a strong risk factor. Inflammatory mechanisms are mediated by immune cells, with macrophages and their phenotypical changes playing a significant role in CRC. Obesity-related hormones, such as leptin and adiponectin, affect macrophage polarization and cytokine expression. Macrophage metabolism, and therefore polarization, directly affects tumor progression and survival in patients with CRC. Altered obesity-related hormone levels induce phosphoinositide kinase-3 (PI3K)/serine-threonine-protein kinase (AKT) activation in colon cancer, causing increased cell survival, hyperplasia, and proliferation. Investigating the effects of obesity-related mechanisms on PI3K/Akt signaling can provide new insights for targeting mechanisms in CRC and obesity among the young. Central molecules for the control of cell proliferation, differentiation, and tumorigenesis within the gastrointestinal tract include downstream targets of the PI3K/AKT pathway, such as Neurogenic locus notch homolog 4 (Notch4) and GATA binding proteins (GATA). Leptin and adiponectin both alter gene expression within this pathway, thereby affecting TAM-mediated CRC progression. Our goal is to introduce the NOTCH4-GATA4-IRG1 axis as a link between inflammation and sporadic CRC and to discuss this pathway as a new potential immunotherapeutic target in individuals affected with obesity and early-onset CRC.