Poly(ADP-ribose) polymerase-1 (PARP-1) plays an essential role in DNA repair by catalyzing the polymerization of ADP-ribose unit to target proteins. Several studies have shown that PARP-1 can ...regulate inflammatory responses in various disease models. The intracellular Nod-like receptor NLRP3 has emerged as the most crucial innate immune receptor because of its broad specificity in mediating immune response to pathogen invasion and danger signals associated with cellular damage. In our study, we found NLRP3 stimuli-induced caspase-1 maturation and IL-1β production were impaired by PARP-1 knockout or PARP-1 inhibition in bone marrow-derived macrophages (BMDM). The step 1 signal of NLRP3 inflammasome activation was not affected by PARP-1 deficiency. Moreover, ATP-induced cytosolic ROS production was lower in
Parp-1
−/−
BMDM, resulting in the decreased inflammasome complex assembly. PARP-1 can translocate to cytosol upon ATP stimulation and trigger the PARylation modification on NLRP3, leading to NLRP3 inflammasome assembly. PARP-1 was also a bridge between NLRP3 and thioredoxin-interacting protein (TXNIP) and participated in NLRP3/TXNIP complex formation for inflammasome activation. Overall, PARP-1 positively regulates NLRP3 inflammasome activation via increasing ROS production and interaction with TXNIP and NLRP3, leading to PARylation of NLRP3. Our data demonstrate a novel regulatory mechanism for NLRP3 inflammasome activation by PARP-1. Therefore, PARP-1 can serve as a potential target in the treatment of IL-1β associated inflammatory diseases.
UV irradiation can injure the epidermis, resulting in sunburn, inflammation, and cutaneous tissue disorders. Previous studies demonstrate that EGFR in keratinocytes can be activated by UVB and ...contributes to inflammation. Poly (ADP‐ribose) polymerase‐1 (PARP‐1) is a nuclear enzyme and plays an essential role in DNA repair under moderate stress. In this study, we set out to understand how PARP‐1 regulates UVB irradiation‐induced skin injury and interplays with EGFR to mediate the inflammation response. We found that PARP‐1 deficiency exacerbated the UVB‐induced inflammation, water loss, and back skin damage in mice. In human primary keratinocytes, UVB can activate PARP‐1 and enhance DNA damage upon PARP‐1 gene silencing. Moreover, PARP‐1 silencing and PARP inhibitor olaparib can suppress UVB‐induced COX‐2 and MMP‐1 expression, but enhance TNF‐α and IL‐8 expression. In addition, EGFR silencing or EGFR inhibition by gefitinib can decrease UVB‐induced COX‐2, TNF‐α, and IL‐8 expression, suggesting EGFR activation via paracrine action can mediate UVB‐induced inflammation responses. Immunoblotting data revealed that PARP‐1 inhibition decreases UVB‐induced EGFR and p38 activation. Pharmacological inhibition of p38 also dramatically led to the attenuation of UVB‐induced inflammatory gene expression. Of note, genetic ablation of PARP‐1 or EGFR can attenuate UVB‐induced ROS production, and antioxidant NAC can attenuate UVB‐induced EGFR‐p38 signaling axis and PARP‐1 activation. These data suggest the regulatory loops among EGFR, PARP‐1, and ROS upon UVB stress. PARP‐1 not only serves DNA repair function but also orchestrates interactions to EGFR transactivation and ROS production, leading to p38 signaling for inflammatory gene expression in keratinocytes.
Background and Purpose
The interleukin (IL)‐36 pathway is a critical player in the pathogenesis of pustular psoriasis. However, therapies targeting this pathway are limited or unaffordable (e.g. the ...anti‐IL‐36 receptor antibody). AMP‐activated protein kinase (AMPK), a regulator of cellular energy and metabolism, is known to participate in inflammatory diseases. However, its role in IL‐36‐induced skin inflammation remains unclear. Therefore, we sought to investigate the role of AMPK signals in regulating IL‐36‐induced responses in the skin.
Experimental Approach
IL‐36‐stimulated primary normal human epidermal keratinocytes (NHEKs) and IL‐36‐injected (intradermally) BALB/c mice served as the cell and animal models, respectively. Additionally, 5‐aminoimidazole‐4‐carboxamide riboside (AICAR) and A769662 served as AMPK activators.
Key Results
AICAR and A769662 significantly suppressed the IL‐36‐induced IL‐8 (CXCL8) and CCL20 production from NHEKs. IL‐36‐induced IκBζ protein expression was prominently reduced and IKK/IκBα phosphorylation was attenuated by AICAR and A769662. Conversely, AMPKα knockdown increased IκBζ protein expression and IKK/IκBα phosphorylation in IL‐36‐treated NHEKs. Furthermore, AICAR and A769662 enhanced IL‐36‐induced‐IκBζ protein degradation via the proteasome‐dependent but not the lysosome‐dependent pathway. Pretreatment of NHEKs with IL‐36 slightly suppressed the AICAR‐ and A769662‐triggered phosphorylation of AMPK and acetyl‐CoA carboxylase. In the mouse model, topical application of AICAR significantly reduced ear swelling, redness, epidermal thickening, neutrophil infiltration and inflammatory and antimicrobial peptide gene expression.
Conclusion and Implications
AMPK activation suppresses IL‐36‐induced IL‐8 and CCL20 release by regulating IκBζ expression in keratinocytes and reduces IL‐36‐induced skin inflammation in mice, suggesting that AMPK activation is a potential strategy for treating patients with IL‐36‐mediated inflammatory skin disorders.
Purpose
Electronic word-of-mouth (eWOM) is very important for consumer decision making; previous international product diffusion studies have investigated eWOM and cultural factors that influence ...consumers’ acceptance of new products, but they have not adequately compared the differences in these factors between the USA and China. Therefore, the purpose of this paper is to compare the impact of eWOM on consumer choices in China and the USA. The authors addressed the following questions: What are the cross-cultural differences in consumers’ eWOM behavior between the USA and China: Which genres of Hollywood movies have better cross-culture predictability in terms of box office performance; and What factors affect the success of Hollywood movies in entering the Chinese market?
Design/methodology/approach
Real eWOM data were collected from two online movie review websites, IMDb.com (the USA) and Douban.com (China), from January 2010 to December 2015. In addition, box office revenue information was collected from BoxOfficeMojo.com. The authors used an independent sample
t
-test to check whether the differences in consumers’ eWOM behavior between China and the USA and different types of movie lead to cultural discount differences. Furthermore, a log-linear regression model is used to examine which factors influence the commercial success of new movies.
Findings
There are specific similarities and differences between the American and Chinese movie markets. First, the results show that American consumers are more engaged in online review systems and tend to submit extreme reviews, but Chinese consumers tend to submit moderate reviews on movies, and the eWOM variance there is smaller than in the USA. Second, genres are useful variables as indicators of movie content; the genres of comedy and drama are not popular in the Chinese market. Finally, eWOM variance has a positive impact on box office in China, but eWOM variance has no impact on the US box office. In addition, the interactive effect of the average rating and eWOM variance on sales is positively significant in China. Importantly, the one-star reviews have a negative impact on the Chinese box office, but it has no impact on US box office.
Practical implications
Understanding how cultural factors influence consumer eWOM communication will help managers to better apply this new marketing communication tool to create more aggressive and targeted promotional plans. Marketers may use eWOM behavior to better respond to and target consumers to overcome barriers to the selection of their products by consumers. Therefore, more effective management of eWOM can improve the acceptance of and preference for products in different cultural consumer groups.
Originality/value
This study expands the existing body of knowledge on eWOM and international marketing literature. Clearly, culture is an important determinant of eWOM’s impact on sales. In addition, it provides strategic direction and practical implications for eWOM communication management in cross-cultural settings.
An OHC online health community (OHC) is an interactive platform for virtual communication between patients and physicians. Patients can typically search, seek, and share their experience and rate ...physicians, who may be involved in giving advice. Some OHC providers provide incentives in form of honorary titles to encourage the web-based involvement of physicians, but it is unclear whether the award of honorary titles has an impact on their consultation volume in an OHC.
This study is designed to identify the differential treatment effect of the incentive policy on the service volumes for the subgroups of treatment and control in an OHC. This study aims to answer the following questions: Does an honorary title for physicians impact their service volumes in an OHC? During the period of discontinuity, can we identify the sharp effect of the incentive award on the outcomes of physicians' service volumes?
We acquired the targeted samples based on treatment, namely, physicians with an honorary title or not and outcomes measured before and after the award of the 2 subgroups. A regression discontinuity design was applied to investigate the impact of the honorary titles incentive as a treatment in an OHC. There was a sharply discontinuous effect of treatment on physicians' online health service performance. The experimental data set consisted of 346 physicians in the treatment group (with honorary titles). Applying the propensity score matching method, the same size of physicians (n=346) was matched and selected as the control group.
A sharp discontinuity was found at the time of the physician receiving the honorary title. The results showed that the parametric estimates of the coefficient were significantly positively (P<.001) associated with monthly home page views. The jump in the monthly volumes of home page views was much sharper than that of the monthly consultations.
The changes in the volumes of monthly consultations and home page views reflect the differential treatment effect of honorary titles on physicians' service volumes. The effect of the incentive policy with honorary titles is objectively estimated from both the perspective of online and offline medical services in an OHC. Being named with honorary titles significantly multiplied monthly home page views, yet it did not significantly impact monthly consultations. This may be because consultation capacity is limited by the physician's schedule for consultations.
Background
Online health care services are a possible solution to alleviate the lack of medical resources in rural areas, and further understanding of the related medical service pricing system would ...contribute to improvement of the online health care community (OHC). Although many studies have investigated the OHC, the impact of physicians’ reputations and wage levels on consulting prices in the OHC has rarely been discussed in the literature.
Objective
This study was designed to explore the determinants of consulting prices in the OHC. We addressed the following questions: (1) Are the prices of online health consultation services affected by wage levels at the doctor’s location? (2) How does a physician’s online and offline reputation affect their consulting prices?
Methods
Employing a large-scale sample of 16,008 doctors in China, we first used descriptive statistics to investigate the determinants of consulting prices in their entirety. Hierarchical linear modeling was then used to investigate the determinants of consulting prices in the OHC.
Results
The empirical results led to the conclusion that if doctors have more elevated clinic titles, work in higher-level hospitals, have better online reputations, and/or have made more past sales, their consulting prices will be higher. Additionally, the wage level in the city in which the doctor is working determines their opportunity cost and therefore also affects consulting prices.
Conclusions
The findings indicate that the characteristics of the doctor, the doctor’s online reputation, and past sales affect the consulting price. In particular, the wage level in the city affects the price of the consultation. These findings highlight that the OHC is important because it can indeed break through geographical restrictions and give rural residents the opportunity to obtain medical service from doctors in big cities. However, doctors from cities often charge higher fees because of their higher opportunity cost. The results reveal that one of the most important functions of the OHC is to reduce the medical disparity between urban and rural areas; however, planners appear to ignore the possibility that rural residents with lower incomes may not be able to afford such high medical consultation costs. Therefore, the government should consider providing incentives to encourage urban doctors to provide discounts to rural residents or directly offer appropriate subsidies.
Thioredoxin‐interacting protein (TXNIP), also known as Vitamin‐D upregulated protein‐1 (VDUP‐1), interacts with thioredoxin to regulate redox responses and participates in diverse disorders including ...metabolic, cardiovascular, inflammatory and malignant diseases. Psoriasis is characterized by chronic skin inflammation and an aberrant pattern of keratinocyte differentiation. Clinically, psoriasis is associated with various cardiometabolic comorbidities but studies on TXNIP's biological role in skin disorders are limited. In this study, we investigated TXNIP expression in psoriasis and its regulation in normal human epidermal keratinocytes (NHEKs), and then explored how TXNIP regulated skin keratinocyte differentiation to determine its role in psoriasis pathogenesis. Our immunohistochemical study demonstrated extensive TXNIP expression in the upper and lower epidermis of psoriasis compared to predominant TXNIP expression in the basal layer of normal skin. 1, 25‐dihydroxyvitamin D3 suppressed but TGF‐α and EGF enhanced TXNIP expression in NHEKs. An inducer of keratinocyte differentiation, phorbol 12‐myristate 13‐acetate (PMA), also diminished TXNIP expression, which was reversed by PKC‐δ knockdown. TXNIP knockdown reduced PMA‐induced involucrin and transglutaminse‐1 expression, and increased p63 expression in NHEKs but did not significantly affect cell proliferation. H2O2‐induced ROS production and EGFR phosphorylation decreased in NHEKs with TXNIP knockdown. Furthermore, PMA‐induced PKC‐δ phosphorylation, TGF‐α, and EGF‐triggered EGFR phosphorylation were attenuated by TXNIP knockdown. Our results unraveled the regulation and function of TXNIP expression in skin keratinocytes and the cross‐regulation between TXNIP and EGFR signaling. These findings imply a role of TXNIP in psoriasis and provide insight into the possible impact of TXNIP regulators on the skin or psoriasis.
It has been reported that nanoparticles (NPs) prepared by hydrophobically-modified polymers could accumulate passively in the tumor tissue; however, their cellular uptake mechanism and intercellular ...trafficking pathway have never been understood. This study was designed to address these concerns, using NPs prepared by a hydrophobically-modified chitosan (
N-palmitoyl chitosan, NPCS). Molecular dynamic simulations found that a degree of substitution (DS) of 5% of palmitoyl groups on its backbone was sufficient to allow NPCS to form NPs, due to a significant increase in the intra- and intermolecular hydrophobic interactions. With an increase of DS, there were more palmitoyl groups present on the surface of NPs which were then able to interact with the cell membranes. A greater extent of cellular uptake of NPCS NPs was observed with increasing the DS on NPCS. The internalization of NPCS NPs was clearly related with the lipid raft-mediated routes; with increasing the DS on NPCS, the caveolae-mediated endocytosis became more important. The results obtained in the intracellular trafficking study showed that NPCS NPs entered cells via caveolae and transiently localized to caveosomes before trafficking to the endosomal pathway. These results suggest that the prepared NCPS NPs may serve as a carrier for intracellular delivery of therapeutic agents.
Display omitted
This study extends brand community research by proposing and testing a model of user participation in brand communities. The authors conceptualize three levels of antecedents of brand community ...participation (individual, relationship, and group) based on qualitative results and an extensive literature review. The empirical analysis derives from data pertaining to car brand communities in Taiwan and supports most of the hypotheses. However, some differences emerge between Taiwanese and Western car brand users with regard to relationship-level factors. In addition, perceived critical mass accounts for some social mechanisms that underlie members' decisions to participate in the brand community. Finally, a quantile regression analysis extends prior literature by showing that different rules of exchange motivate brand users, depending on their participation levels. The paper discusses the managerial implications of these findings as well as several important research issues and avenues.
In this paper, we study the min–max programming problem with
n
addition-min fuzzy relational inequality constraints. We prove that when the problem is feasible, an optimal solution always exists with ...all variables being of the same value. Based on this result, the min–max programming problem can be simplified as a single-variable optimization problem with the same optimal objective value. To solve the corresponding single-variable optimization problem, we propose an analytical method and an iterative method by successively approximating the lower bound of the optimal value. Numerical examples are given to illustrate our methods.
PDF
