Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid‐rich necrotic cores in hypercholesterolemic mice

Atherosclerosis is an inflammatory disease associated with the activation of innate immune TLRs and nucleotide‐binding oligomerization domain‐containing protein (NOD)‐like receptor pathways. However, the function of most innate immune receptors in atherosclerosis remains unclear. Here, we show that NOD2 is a crucial innate immune receptor influencing vascular inflammation and atherosclerosis severity. 10‐week stimulation with muramyl dipeptide (MDP), the NOD2 cognate ligand, aggravated atherosclerosis, as indicated by the augmented lesion burden, increased vascular inflammation and enlarged lipid‐rich necrotic cores in Ldlr^?/? mice. Myeloid‐specific ablation of NOD2, but not its downstream kinase, receptor‐interacting serine/threonine‐protein kinase 2, restrained the expansion of the lipid‐rich necrotic core in Ldlr^?/? chimeric mice. In vitro stimulation of macrophages with MDP enhanced the uptake of oxidized low‐density lipoprotein and impaired cholesterol efflux in concordance with upregulation of scavenger receptor A1/2 and downregulation of ATP‐binding cassette transporter A1. Ex vivo stimulation of human carotid plaques with MDP led to increased activation of inflammatory signaling pathways p38 MAPK and NF‐κB‐mediated release of proinflammatory cytokines. Altogether, this study suggests that NOD2 contributes to the expansion of the lipid‐rich necrotic core and promotes vascular inflammation in atherosclerosis.     

Then and now: The progress in hepatitis B treatment over the past 20 years

The ultimate goals of treating chronic hepatitis B(CHB)is prevention of hepatocellular carcinoma(HCC)and hepatic decompensation.Since the advent of effective antiviral drugs that appeared during the past two decades,considerable advances have been made not only in controlling hepatitis B virus(HBV)infection,but also in preventing and reducing the incidence of liver cirrhosis and HCC.Furthermore,several recent studies have suggested the possibility of reducing the incidence of recurrent or new HCC in patients even after they have developed HCC.Currently,six medications are available for HBV treatment including,interferon and five nucleoside/nucleotide analogues.In this review,we will examine the antiviral drugs and the progresses that have been made with antiviral treatments in the field of CHB.     

Reliability and Validity of the King's Health Questionnaire for Male Lower Urinary Tract Symptoms in Taiwan

Objectives: To investigate the reliability and validity of the King's Health Questionnaire (KHQ), and understand the impacts of lower urinary tract symptom (LUTS) on health‐related quality of life (HR‐QoL). Methods: A cross‐sectional design was used and a convenience of 393 men participated in the study. The reliability was measured by testing the Cronbach's α coefficients. Factor analysis was used to explore the underlying factor structure of the KHQ. The discriminant validity was assessed using the one‐way analysis of variance (ANOVA) tests with post hoc analysis (Games‐Howell method) by comparing the differences scores in KHQ domains between men with three LUTS severity groups (mild, moderate, and severe). Results: Men with severe, moderate, mild LUTS accounted for 7.9, 25.4, and 66.7%, respectively. Internal consistency of KHQ was excellent with Cronbach's α coefficients of 0.750–0.943. Factor analysis showed three underlying components to explain constructive validity. The KHQ subscores in both the severe and moderate LUTS groups were significantly higher than those in mild LUTS group (all P < 0.05), implying that the discriminant validity was adequate. Excepting for two single‐item questions, the first three greater disparities in KHQ domains between the severe and mild LUTS groups were “Emotion”, “Sleeping/Energy”, and “Physical limitation”, while the least disparities was found in “Personal relationships” domain. Conclusion: LUTS could produce a substantial impact on different domains of HR‐QoL. The traditional Chinese KHQ has suitable reliability and validity for men with general LUTS, and might be a useful tool for HR‐QoL measure in future.     

Changes in facial appearance after maxillomandibular advancement for severe obstructive sleep apnoea hypopnoea syndrome in Chinese patients: a subjective and objective evaluation

This study evaluates the outcome and change in facial appearance after maxillomandibular advancement (MMA) in Chinese adults with severe obstructive sleep apnoea hypopnoea syndrome (OSAHS). Twelve patients underwent MMA with adjunctive procedures for severe OSAHS. All underwent physical examination, Epworth Sleepiness Scale evaluation, cephalometry, polysomnography, and facial photographic assessment before and 6 months after MMA. The aesthetic plane (relationship of nose, lips, and chin) was used to judge soft tissue facial profile change after MMA. Postoperative cephalometric data were compared with normal occlusive standards and aesthetic norms. Pre- and postoperative aesthetic appearance was evaluated by 100 lay people using a 10-point visual analogue scale. The maxillomandibular complex (MMC) was advanced 5-10mm (mean 7.4mm). The success rate was 83%. All patients were satisfied with the functional and aesthetic results. Postoperative SNA, SNB, and posterior airway space increased and mandibular plane-to-hyoid distance decreased significantly in all patients. The lower lip was closer to EP than the preoperative and normal occlusive standard. In 11 of 12 patients, the lay aesthetic scores were significantly higher postoperatively. MMA is effective for Chinese adults with severe OSAHS. In most patients, facial appearance was more attractive after MMC advancement of 5-10mm.     

Stabilization of protein-protein interactions in drug discovery

Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery.

Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach.

Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.     

The effects of toxoplasma infection on rodent behavior are dependent on dose of the stimulus

Parasite Toxoplasma gondii blocks the innate aversion of rats for cat urine, putatively increasing the likelihood of a cat predating a rat. This is thought to reflect an adaptive behavioral manipulation, because toxoplasma can reproduce only in cat intestines. While it will be adaptive for the parasite to cause an absolute behavioral change, fitness costs associated with the manipulation itself suggest that the change is optimized and not maximized. We investigate these conflicting suggestions in the present report. Furthermore, exposure to cat odor causes long-lasting acquisition of learnt fear in the rodents. If toxoplasma manipulates emotional valence of cat odor rather than just sensory response, infection should affect learning driven by the aversive properties of the odor. As a second aim of the present study, we investigate this assertion. We demonstrate that behavioral changes in rodents induced by toxoplasma infection do not represent absolute all-or-none effects. Rather, these effects follow a non-monotonous function dependent on strength of stimulus, roughly resembling an inverted-U curve. Furthermore, infection affects conditioning to cat odor in a manner dependent upon strength of unconditioned stimulus employed. Non-monotonous relationship between behavioral manipulation and strength of cat odor agrees with the suggestion that a dynamic balance exists between benefit obtained and costs incurred by the parasite during the manipulation. This report also demonstrates that toxoplasma affects emotional valence of the cat odor as indicated by altered learned fear induced by cat odor.     

Substance P regulates macrophage inflammatory protein 3alpha/chemokine C-C ligand 20 (CCL20) with heme oxygenase-1 in human periodontal ligament cells

Although substance P (SP), a potent proinflammatory peptide, is involved in inflammation and immune responses, the effect of SP on the expression of macrophage inflammatory protein 3alpha[MIP-3alpha, chemokine C-C ligand 20 (CCL20)] in periodontal ligament (PDL) cells is unknown. Equally enigmatic is the link between SP, the stress protein heme oxygenase-1 (HO-1), and CCL20 production. We investigated whether SP induces the release of chemokine CCL20 from immortalized PDL (IPDL) cells, and further clarify SP-mediated pathways. We also examined the relationship between HO-1 and CCL20 by treating PDL cells with SP. Incubating IPDL cells with SP increased expression of CCL20 mRNA and CCL20 protein in a dose-time-dependent manner. Highly selective p38 and extracellular-regulated kinase 1/2 (ERK1/2) inhibitors abrogated SP-induced expression of CCL20 in IPDL cells. SP is also responsible for initiating phosphorylation of IkappaB, degradation of IkappaB and activation of nuclear factor (NF)-kappaB. SP induced expression of HO-1 in both a concentration- and time-dependent manner, and CCL20 reflected similar patterns. The inductive effects of SP on HO-1 and CCL20 were enhanced by HO-1 inducer hemin and the membrane-permeable guanosine 3',5'-monophosphate (cGMP) analogue 8-bromo-cGMP. Conversely, this pathway was inhibited by the HO-1 inhibitor zinc protoporphyrin IX (ZnPP IX) and the selective inhibitor of guanylate cyclase, 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one (ODQ). We report herein the pathway that connects SP along with other modulators of neuroimmunoregulation to the induction of HO-1 and the inflammatory mediator macrophage inflammatory protein (MIP)-3alpha/CCL20 in IPDL cells, which play an important role in the development of periodontitis or inflammation during orthodontic tooth movement.     

Nitric oxide promotes the progression of periapical lesion via inducing macrophage and osteoblast apoptosis

This study aimed to elucidate the modulation by nitric oxide (NO) of the apoptosis of macrophages and osteoblasts, the essential cellular components in the development of periapical lesions. Lipopolysaccharide (LPS) induced prominent nitrite synthesis in J774 mouse macrophage cell lines. Exposure to LPS induced obvious apoptosis in J774 cells, whereas transient transfection with murine inducible nitric oxide synthase (iNOS), small interfering RNA (siRNA) diminished this effect. Tumor necrosis factor-alpha (TNF-alpha) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) (a NO donor) triggered apoptosis in UMR-106 rat osteoblastic cell lines and a synergistic effect was noted when TNF-alpha and SNAP were added to the medium together. Administration of siRNAs for c-Fos and c-Jun: components of activator protein-1 (AP-1) and transforming growth factor-beta1 attenuated the combined effect markedly. Terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) stain in a rat model of induced periapical lesion showed positive apoptotic signals in macrophages and osteoblasts. Administration of N(G)-monomethyl-l-arginine markedly diminished the extent of bone loss and the amounts of apoptotic macrophages and osteoblasts. In conclusion, NO mediates LPS-stimulated apoptosis of macrophages. It also induces osteoblast apoptosis and augments the pro-apoptotic effect of cytokines. Inhibition of NO synthesis in vivo attenuates apoptosis and the size of periapical lesions. Taken together, these results suggest that NO may promote the progression of periapical lesion by inducing the apoptosis of macrophages and osteoblasts.