G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35-STARD4 axis is a promising therapeutic target for NAFLD.

Kynurenic acid ameliorates NLRP3 inflammasome activation by blocking calcium mobilization via GPR35.

The inflammasome has been linked to diverse inflammatory and metabolic diseases, and tight control of inflammasome activation is necessary to avoid excessive inflammation. Kynurenic acid (KA) is a tryptophan metabolite in the kynurenine pathway. However, the roles and mechanisms of the regulation of inflammasome activation by KA have not yet been fully elucidated. Here, we found that KA suppressed caspase-1 activation and IL-1ß production in macrophages by specifically inhibiting canonical and noncanonical activation of the NLRP3 inflammasome. Mechanistically, KA reduced calcium mobilization through G-protein receptor 35 (GPR35), resulting in reduced mitochondrial damage and decreased mtROS production, thus blocking NLRP3 inflammasome assembly and activation. Importantly, KA prevented lipopolysaccharide-induced systemic inflammation, monosodium urate-induced peritoneal inflammation, and high-fat diet-induced metabolic disorder. Thus, KA ameliorated inflammation and metabolic disorders by blocking calcium mobilization-mediated NLRP3 inflammasome activation via GPR35. Our data reveal a novel mechanism for KA in the modulation of inflammasome activation and suggest that GPR35 might be a promising target for improving NLRP3 inflammasome-associated diseases by regulating calcium mobilization.

Hepatocyte-specific deletion of cellular repressor of E1A-stimulated genes 1 exacerbates alcohol-induced liver injury by activating stress kinases.

Alcohol-associated liver disease (ALD) encompasses a wide range of pathologies from simple steatosis to cirrhosis and hepatocellular carcinoma and is a global health problem. Currently, there are no effective pharmacological treatments for ALD. We have previously demonstrated that aging exacerbates the pathogenesis of ALD, but the underlying mechanisms are still poorly understood. Cellular repressor of E1A-stimulated genes 1 protein (CREG1) is a recently identified small glycoprotein that has been implicated in aging process by promoting cellular senescence and activating stress kinases. Thus, the current study aimed to explore the role of aging associated CREG1 in ALD pathogenesis and CREG1 as a potential therapeutic target. Hepatic and serum CREG1 protein levels were elevated in ALD patients. Elevation of hepatic CREG1 protein and mRNA was also observed in a mouse model of Gao-binge alcohol feeding. Genetic deletion of the Creg1 gene in hepatocytes (Creg1∆hep ) markedly exacerbated ethanol-induced liver injury, apoptosis, steatosis and inflammation. Compared to wild-type mice, Creg1∆hep mice had increased phosphorylation of hepatic stress kinases such as apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38 but not TGF-ß-activated kinase 1 (TAK1) or extracellular signal-regulated kinase (ERK) after alcohol feeding. In vitro, ethanol treatment elevated the phosphorylation of ASK1, JNK, and p38 in mouse hepatocyte AML-12 cells. This elevation was further enhanced by CREG1 knockdown but alleviated by CREG1 overexpression. Last, treatment with an ASK1 inhibitor abolished ethanol-induced liver injury and upregulated hepatic lipogenesis, proinflammatory genes and stress kinases in Creg1∆hep mice. Taken together, our data suggest that CREG1 protects against alcoholic liver injury and inflammation by inhibiting the ASK1-JNK/p38 stress kinase pathway and that CREG1 is a potential therapeutic target for ALD.

Hepatic NCoR1 deletion exacerbates alcohol-induced liver injury in mice by promoting CCL2-mediated monocyte-derived macrophage infiltration.

Nuclear receptor corepressor 1 (NCoR1) is a corepressor of the epigenetic regulation of gene transcription that has important functions in metabolism and inflammation, but little is known about its role in alcohol-associated liver disease (ALD). In this study, we developed mice with hepatocyte-specific NCoR1 knockout (NCoR1Hep-/-) using the albumin-Cre/LoxP system and investigated the role of NCoR1 in the pathogenesis of ALD and the underlying mechanisms. The traditional alcohol feeding model and NIAAA model of ALD were both established in wild-type and NCoR1Hep-/- mice. We showed that after ALD was established, NCoR1Hep-/- mice had worse liver injury but less steatosis than wild-type mice. We demonstrated that hepatocyte-specific loss of NCoR1 attenuated liver steatosis by promoting fatty acid oxidation by upregulating BMAL1 (a circadian clock component that has been reported to promote peroxisome proliferator activated receptor alpha (PPARα)-mediated fatty ß-oxidation by upregulating de novo lipid synthesis). On the other hand, hepatocyte-specific loss of NCoR1 exacerbated alcohol-induced liver inflammation and oxidative stress by recruiting monocyte-derived macrophages via C-C motif chemokine ligand 2 (CCL2). In the mouse hepatocyte line AML12, NCoR1 knockdown significantly increased ethanol-induced CCL2 release. These results suggest that hepatocyte NCoR1 plays distinct roles in controlling liver inflammation and steatosis, which provides new insights into the development of treatments for steatohepatitis induced by chronic alcohol consumption.

Progress in public health risk communication in China: lessons learned from SARS to H7N9.

BACKGROUND: Following the SARS outbreak, the World Health Organization revised the International Health Regulations to include risk communication as one of the core capacity areas. In 2006, the U.S. Centers for Disease Control and Prevention's Global Disease Detection [GDD] program began collaborating with China to enhance China's risk communication capacity to address gaps in the SARS communication response. This article describes tangible improvements in China's public health emergency risk communication capacity between the SARS and H7N9 outbreaks; documents U.S. CDC GDD cooperative technical assistance during 2006-2017; and shares lessons learnt to benefit other countries and contribute to enhance global health security. METHOD: A questionnaire based on the WHO Joint External Evaluation tool [Risk Communication section] was developed. A key communications official from the China National Health Commission [NHC] completed the questionnaire retrospectively to reflect China's capacity to manage communication response before, during and after the outbreaks of SARS in 2003, influenza H1N1 in 2009, and influenza H7N9 in 2013. A literature search was also conducted in English and Chinese to further substantiate the results of the questionnaire completed by NHC. RESULTS: China demonstrated significantly improved risk communication capacities of pre-event, during event and post event responses to H7N9 when compared to the SARS response. China NHC improved its response through preparedness, availability of dedicated staff and resources for risk communication, internal clearance mechanisms, standard operating procedures with national response parties external to NHC, rumor management, communication with international agencies and consistent messaging with healthcare and private sectors. Correspondingly, the perceived level of trust that the public had in the NHC following outbreaks rose between the SARS and H7N9 response. CONCLUSION: Risk communication capacities in China have increased during the ten years between the SARS outbreak of 2003 and the H7N9 outbreak of 2013. Long-term risk communication capacity building efforts in bilateral collaborations are uncommon. The U.S. CDC GDD project was one of the first such collaborations worldwide. The lessons learned from this project may benefit lower and middle-income countries as they build their national emergency risk communication capacity.

Identifying ways to increase seasonal influenza vaccine uptake among pregnant women in China: A qualitative investigation of pregnant women and their obstetricians.

BACKGROUND: Pregnant women are at higher risk for complications from influenza infection. Nevertheless, seasonal influenza vaccination among pregnant women in China is low. A better understanding of perceptions of pregnant women and their physicians, and factors influencing decisions about receiving seasonal influenza vaccine could be used to develop effective strategies for improving seasonal influenza vaccine uptake during pregnancy. METHODS: We recruited pregnant women from 9 hospitals located in 5 cities across China to participate in focus group interviews. Obstetricians from the same hospitals were recruited for one on one in-depth interviews. We collected information about perceptions of barriers and motivating factors for utilizing seasonal influenza vaccine during pregnancy. We systematically analyzed the information using qualitative methods. RESULTS: We conducted 18 focus groups with 108 pregnant women and interviewed 18 obstetricians. Awareness about the use of influenza vaccine during pregnancy was minimal in both subject groups. None of the pregnant women had received influenza vaccine during pregnancy and none of the obstetricians had recommended influenza vaccine for their patients. Both groups noted insufficient knowledge about influenza infection and benefits of the vaccine, concerns about vaccine safety, and lack of local data related to vaccine use in Chinese pregnant women. Obstetricians cited the lack of a national policy as a major barrier to recommending seasonal influenza vaccine to pregnant women. Pregnant women cited not receiving a recommendation for vaccination from healthcare workers as an additional barrier. CONCLUSION: Our findings highlight the immediate need to increase awareness and knowledge about the risks of influenza infection and the benefits and safety of seasonal influenza vaccination among both pregnant women and obstetricians in China. Obstetricians interviewed stated that the development and implementation of a national policy prioritizing pregnant women for seasonal influenza vaccination would facilitate their willingness to recommend seasonal influenza vaccine to pregnant women.

Perceptions on the risk communication strategy during the 2013 avian influenza A/H7N9 outbreak in humans in China: a focus group study.

OBJECTIVE: To identify the general public's perceptions of the overall risk communication strategy carried out by Chinese public health agencies during the first wave of avian influenza A(H7N9) outbreak in humans in 2013. METHODS: Participants were recruited from communities in Beijing, Lanzhou and Hangzhou, China in May and June 2013 by convenience sampling. Demographics and other relevant information were collected using a self-administered questionnaire. Focus group interviews were conducted using a set of nine pre-developed questions and a tested moderator guide. The interviews were audio recorded and were transcribed verbatim. The constant comparative method was used to identify trends and themes. RESULTS: A total of nine focus group interviews, with 94 participants recruited from nine communities, were conducted. Most participants received H7N9 information via television and the Internet. Most the participants appreciated the transparency and timeliness of the information released by the government. They expressed a sense of trust in the recommended public health advice and followed most of them. The participants suggested that the government release more information about clinical treatment outcomes, have more specific health recommendations that are practical to their settings and expand the use of new media channels for risk communication. CONCLUSION: The public perceived the overall risk communication strategy by the Chinese public health agencies as effective, though the moderator had a governmental agency title that might have biased the results. There is a need to expand the use of social media for risk communication in the future.

A practical community-based response strategy to interrupt Ebola transmission in sierra Leone, 2014-2015.

BACKGROUND: The Ebola virus disease spread rapidly in West Africa in 2014, leading to the loss of thousands of lives. Community engagement was one of the key strategies to interrupt Ebola transmission, and practical community level measures needed to be explored in the field and tailored to the specific context of communities. METHODS: First, community-level education on Ebola virus disease (EVD) prevention was launched for the community's social mobilizers in six districts in Sierra Leone beginning in November 2014. Then, from January to May of 2015, in three pilot communities, local trained community members were organized to engage in implementation of EVD prevention and transmission interruption measures, by involving them in alert case report, contact tracing, and social mobilization. The epidemiological indicators of transmission interruption in three study communities were evaluated. RESULTS: A total of 6 016 community social mobilizers from 185 wards were trained by holding 279 workshops in the six districts, and EVD message reached an estimated 631 680 residents. In three pilot communities, 72 EVD alert cases were reported, with 70.8 % of them detected by trained local community members, and 14 EVD cases were finally identified. Contact tracing detected 64.3 % of EVD cases. The median duration of community infectivity for the cases was 1 day. The secondary attack rate was 4.2 %, and no third generation of infection was triggered. No health worker was infected, and no unsafe burial and noncompliance to EVD control measures were recorded. The community-based measures were modeled to reduce 77 EVD cases, and the EVD-free goal was achieved four months earlier in study communities than whole country of Sierra Leone. CONCLUSIONS: The community-based strategy of social mobilization and community engagement was effective in case detection and reducing the extent of Ebola transmission in a country with weak health system. The successfully practical experience to reduce the risk of Ebola transmission in the community with poor resources would potentially be helpful for the global community to fight against the EVD and the other diseases in the future.

Assessing knowledge and application of emergency risk communication principles among public health workers in China.

OBJECTIVE: Since 2003, the Chinese National Health and Family Planning Commission (formerly the Ministry of Health) has implemented changes to more effectively communicate risk during public health emergencies. In spite of ongoing improvements, provincial and sub-provincial leaders face barriers, such as established modes of operation, lack of training, shortage of trained risk communicators, and limited understanding and willingness of recipients to mitigate risks. METHODS: We assessed the current status of and barriers to risk communication knowledge and practice among public health practitioners in China. We designed the survey questionnaire to capture information related to the risk communication core capacities required by international health regulations and common risk communication principles. RESULTS: Our findings showed that risk communication training has successfully developed an awareness of risk communication principles and the ability to implement those principles in practice in China. CONCLUSIONS: Future efforts should focus on areas such as a dedicated risk communication workforce, requirements that public health agencies develop a risk communication plan, and additional training for public health practitioners and their partners. It is critical that the infectious diseases prevention and control law be amended to grant provincial and local public health agencies more autonomy to release information.

Measuring health literacy regarding infectious respiratory diseases: a new skills-based instrument.

BACKGROUND: There is no special instrument to measure skills-based health literacy where it concerns infectious respiratory diseases. This study aimed to explore and evaluate a new skills-based instrument on health literacy regarding respiratory infectious diseases. METHODS: This instrument was designed to measure not only an individual's reading and numeracy ability, but also their oral communication ability and their ability to use the internet to seek information. Sixteen stimuli materials were selected to enable measurement of the skills, which were sourced from the WHO, China CDC, and Chinese Center of Health Education. The information involved the distribution of epidemics, immunization programs, early symptoms, means of disease prevention, individual's preventative behavior, use of medications and thermometers, treatment plans and the location of hospitals. Multi-stage stratified cluster sampling was employed to collect participants. Psychometric properties were used to evaluate the reliability and validity of the instrument. RESULTS: The overall degree of difficulty and discrimination of the instrument were 0.693 and 0.482 respectively. The instrument demonstrated good internal consistency reliability with a Cronbach's alpha of 0.864. As for validity, six factors were extracted from 30 items, which together explained 47.3% of the instrument's variance. And based on confirmatory factor analysis, the items were grouped into five subscales representing prose, document, quantitative, oral and internet based information seeking skills (χ(2) = 9.200, P>0.05, GFI = 0.998, TLI = 0.988, AGFI = 0.992, RMSEA = 0.028). CONCLUSION: The new instrument has good reliability and validity, and it could be used to assess the health literacy regarding respiratory infectious disease status of different groups.

Determinants of health literacy and health behavior regarding infectious respiratory diseases: a pathway model.

BACKGROUND: Health literacy has been defined as the degree to which individuals have the capacity to obtain, process, and understand the basic health information and services needed to make appropriate health decisions. Currently, few studies have validated the causal pathways of determinants of health literacy through the use of statistical modeling. The purpose of the present study was to develop and validate a health literacy model at an individual level that could best explain the determinants of health literacy and the associations between health literacy and health behaviors even health status. METHODS: Skill-based health literacy test and a self-administrated questionnaire survey were conducted among 3222 Chinese adult residents. Path analysis was applied to validate the model. RESULTS: The model explained 38.6% of variance for health literacy, 11.7% for health behavior and 2.3% for health status: (GFI = 0.9990; RMR = 0.0521; χ(2) = 10.2151, P = 0.1159). Education has positive and direct effect on prior knowledge (ß = 0.324) and health literacy (ß = 0.346). Health literacy is also affected by prior knowledge (ß = 0.245) and age (ß = -0.361). Health literacy is a direct influencing factor of health behavior (ß = 0.101). The most important factor of health status is age (ß = 0.107). Health behavior and health status have a positive interaction effect. CONCLUSION: This model explains the determinants of health literacy and the associations between health literacy and health behaviors well. It could be applied to develop intervention strategies to increase individual health literacy, and then to promote health behavior and health status.

[Comparative study of the factors in tuberculosis treatment between immigrant workers and local residents in Shenzhen].

OBJECTIVE: To study the factors affecting the management and treatment of immigrant workers with tuberculosis, to determine the most effective measures and to provide an academic basis for tuberculosis control and prevention strategies targeting the immigrant population. METHODS: A self-designed questionnaire was administered to 1364 immigrant workers with tuberculosis (study group) and 436 local residents (control group) with tuberculosis. RESULTS: Whether a patient's tuberculosis status was discovered or not was related to the medical facilities initially visited, job mobility, and the individual worker's economic condition. The percentage of cases discovered was relatively low among those who made their first visit to a private clinic (39.0%), and 58.4% (796) of immigrant workers delayed their first consultation mainly due to neglecting symptoms (55.9%, 445), subjective perception of symptoms being not severe enough (19.3%, 154) to visit a physician and the inconvenience of visiting a hospital because of its being far away from home (15.8%, 47). As comparing immigrant workers with local residents, the differences of the delay reason between the two groups were statistically significant (chi(2) = 21.49, P < 0.01). And 39.9% (544) of immigrant workers and 49.1% (214) of local residents had had late confirmation. The differences of the delay reasons between the two groups were insignificant (chi(2) = 7.31, P = 0.293). And 17.6% (240) patients of immigrant workers and 13.1% (57) patients of local residents did not keep to their drug regimens in a timely fashion. The differences of the reasons between the two groups were insignificant (chi(2) = 6.66, P > 0.05). And 77.5% (1057) of immigrant workers and 31.8% (138) of local residents were considered that taking medicine in supervision spot might have impact on their lives and work. The differences of the reasons between the two groups were significant (chi(2) = 9.71, P < 0.05). All 79.2% (1080) of immigrant workers and 63.3% (276) of local residents did not obtain medicine according to prescriptions. The differences of reasons between the two groups were statistically significant (chi(2) = 24.84, P < 0.01). And 51.2% (699) of immigrant workers and 46.1% (201) of the registered population did not follow up with doctors' directions for lab tests. The differences of the reasons between the two groups were insignificant (chi(2) = 3.26, P > 0.05). CONCLUSION: The influential factors in tuberculosis management and treatment were complex. Prevention strategies should focus on health education and promotion activities to improve awareness in seeking medical services. Also, developing and standardizing reference mechanisms for patients, and alleviating the economic burden of the workers will be critical to reduce the tuberculosis incidence.