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Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin barrier dysfunction and chronic inflammatory responses. Reynoutria japonica, known as Huzhang in traditional Chinese Medicine, can enhance blood circulation to eliminate wind pathogens and terminate coughing. Despite pharmacological evidence supporting the efficacy of R. japonica in suppressing edema-induced skin inflammation or connective tissue diseases, its pharmaceutical potential for treating AD-like skin inflammation remains unexplored. This study investigated the possible effects of R. japonica ethanol extract (RJE) on Dermatophagoides farinae extract (DfE)-induced AD-like skin inflammation in NC/Nga mice. To elucidate the underlying mechanisms by which RJE inhibits skin inflammation, we examined the effect of RJE on IFN-γ/TNF-α-induced signal transducer and activator of transcription (STAT) signaling in human epidermal keratinocytes (HEKs) and human dermal fibroblasts (HDFs). Our findings revealed that RJE mitigates DfE-induced AD-like symptoms and skin barrier disruptions in mouse skin lesions. Moreover, RJE attenuated DfE-induced mast cell infiltration and serum levels of inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-23, IFN-γ, TNF-α, and GM-CSF). RJE also inhibited IFN-γ/TNF-α-induced chemokine levels and STAT3 phosphorylation in HEKs and HDFs. Virtual binding analysis of the RJE components suggested that emodin-8-β-D-glucoside binds to Janus kinase (JAK) 1/2, thereby suppressing STAT signaling, which was confirmed by Western blot analysis. In conclusion, our results suggest that RJE may alleviate DfE-induced skin barrier dysfunction by inhibiting JAK/STAT signaling and the proinflammatory immune response through the suppression of inflammatory mediators in AD-like skin disease. These findings suggest that RJE has potential as an effective therapy for AD management.

Allergic rhinitis (AR), a chronic respiratory inflammatory disease, is among the most common chronic diseases reported worldwide. Mucus hypersecretion is a critical feature of AR pathogenesis. Although the Gleditsia sinensis extract has several beneficial effects on human health, its effects on allergic inflammation have not yet been investigated. In this study, we examined the effects of G. sinensis aqueous extract (GSAE) on nasal inflammation in an ovalbumin (OVA)-induced AR mouse model. GSAE was administered orally for 1 week and then the clinical nasal symptoms were evaluated. The levels of histamine, OVA-specific immunoglobulin (Ig) E, and interleukin (IL)-13 were measured in the serum using an enzyme-linked immunosorbent assay (ELISA). Inflammatory cells were then counted in the nasal lavage fluid (NALF) and histopathology in the nasal epithelium was evaluated. STAT3/STAT6 phosphorylation was examined in primary human nasal epithelial cells (HNEpCs) using western blot analysis. Oral administration of GSAE to OVA-induced AR mice alleviated nasal clinical symptoms and reduced OVA-specific immunoglobulin E, interleukin (IL)-13, and histamine levels. The accumulation of eosinophils in nasal lavage fluid, nasal mucosa, mast cells, goblet cells, and mucin 5AC (MUC5AC) in the nasal epithelium was also inhibited by GSAE. Treatment with GSAE inhibited the production of MUC5AC in IL-4/IL-13-stimulated primary human nasal epithelial cells through the signal transducer and activator of transcription (STAT)3/STAT6 signaling pathway. These results indicated that GSAE reduces nasal inflammation suggesting that it is a potential treatment option for AR.

A variety of isothiazolinone-containing small molecules have been registered and used as chemical additives in many household products. However, their biodistribution and potential harmful effects on human health, especially respiratory effects, were not yet identified in sufficient detail. The purpose of this study was to investigate whether a biocide comprising a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) could reach the lungs and induce lung injury when exposure occurs by two administration routes involving the respiratory tract: intratracheal and intranasal instillation. To investigate the biodistribution of CMIT/MIT, we quantified the uptake of 14C-labeled CMIT/MIT in experimental animals for up to seven days after intratracheal and intranasal instillation. In the toxicity study, lung injury was assessed in mice using total inflammatory cell count in bronchoalveolar lavage fluid (BALF) and lung histopathology. The results of the biodistribution study indicated that CMIT/MIT were rapidly distributed throughout the respiratory tract. Using quantitative whole-body autoradiogram analysis, we confirmed that following intranasal exposure, CMIT/MIT reached the lungs via the respiratory tract (nose–trachea–lung). After 5 min post intratracheal and intranasal instillation, the amount of radiotracer ([14C]CMIT/MIT) in the lungs was 2720 ng g−1 and 752 ng g−1 tissue, respectively, and lung damage was observed. A higher amount of the radiotracer resulted in higher toxicity. Both intratracheal and intranasal instillation of CMIT/MIT increased inflammatory cell counts in the BALF and induced injuries in the alveoli. The frequency and the severity scores of injuries caused by intratracheal instillation were approximately-four to five times higher than those induced by intranasal instillation. Therefore, we concluded that CMIT/MIT could reach the lungs following nasal and intratracheal exposure and cause lung injuries, and the extent of injury was dependent on the exposure dose.

Summary: Here, we found that heterozygous null of peroxisomal Nudt7 (Nudt7+/−) induced the typical NAFLD features, i.e. increased levels of hepatic triglyceride (TG) and fatty acid (FA), infiltration of inflammatory cells, impaired glucose tolerance and insulin sensitivity, and stimulation of lipolysis from adipose tissue. Particularly, in Nudt7+/− hepatocytes, de novo lipogenesis (DNL) was significantly increased. Ingenuity pathway analysis (IPA) and KEGG pathway analysis of RNA sequencing data suggested the activation of PPAR signaling in the liver of Nudt7+/− mice. Moreover, accumulation of palmitic acid in Nudt7+/− hepatocyte increased the level of H3K4me3 on the promoters of PPARγ resulting in the activation of PPARγ and induced the DNL in the hepatocytes of Nudt7+/− mice. Moreover, we found that liraglutide significantly reduced typical NAFLD features induced by NUDT7 deficiency. Our data suggest that dysregulation of peroxisomal NUDT7 is responsible for upregulation of hepatic DNL by accumulation of palmitic acid and PPARγ activation.

Veronica persica is a flowering plant belonging to the family Scrophulariaceae. Here, we aimed to evaluate the pharmacological activity of the ethanol extract of Veronica persica (EEVP) in an airway inflammation model. We examined airway responsiveness to aerosolized methacholine, serum immunoglobulin (Ig)E levels, and total cell numbers in the lung and bronchoalveolar lavage fluid (BALF). Histological analysis of the lung tissue was performed using hematoxylin–eosin, Masson trichrome, or periodic acid-Schiff staining. Fluorescence-activated cell sorting analysis in the lung and BALF was applied to clarify the changes in immune cell types. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction were applied to investigate cytokine levels and gene expression related to airway inflammation. STAT-3/6 phosphorylation was examined in primary bronchial/tracheal epithelial cells using western blot analysis. EEVP significantly suppressed total IgE levels and methacholine-induced increase of Penh value in the HDM-challenged mouse model. EEVP also attenuated the severity of airway remodeling in lung tissues and decreased eosinophil and neutrophil infiltration in the lungs and BALF. EEVP significantly reduced the production of cytokines in BAL and splenocyte culture medium, and the expression of mRNAs related to airway inflammation in the lung tissue. EEVP suppressed IL-4/13-induced STAT-3/6 phosphorylation in the epithelial cells. We showed for the first time that EEVP effectively inhibits eosinophilic airway inflammation by suppressing the expression of inflammatory factors for T cell activation and polarization, and inhibits MCP-1 production of bronchial/tracheal epithelial cells by suppressing STAT-3/6 activation. EEVP may be a potential pharmacological agent to prevent inflammatory airway diseases.

Patients with advanced chronic kidney disease (CKD) experience multiple bothersome symptoms, undermining their quality of life (QOL). With growing attention to the importance of symptom management in advanced CKD, the evidence regarding symptoms is increasing. In this review, we briefly summarize the current evidence of effective pharmacologic and nonpharmacologic interventions to improve symptoms and QOL in patients with advanced CKD, including those on dialysis. We focused on symptoms that are commonly experienced by patients, such as pain, fatigue, sleep disturbances, itching, nausea and vomiting, cognitive impairment, and anxiety and depression. We noted that research in symptom science focused on improving symptom management in CKD is still very limited. In addition to the lack of clinical practice guidelines to address those common symptoms, the major gaps in the current literature include the evidence regarding mechanistic pathways to inform the development of effective symptom management for CKD populations, the evidence to confirm effective pharmacologic interventions in other populations for CKD populations, and research on how to incorporate effective symptom management approaches into clinical care. Although improving mortality remains as an important area in the kidney community, there is an urgent need to focus on improving symptom management to improve QOL in advanced CKD.

Alpinia officinarum (AO) has been traditionally used in Asia as an herbal medicine to treat inflammatory and internal diseases. However, the therapeutic effect of AO on atopic dermatitis (AD) is unclear. Therefore, we examined whether Alpinia officinarum water extract (AOWex) affects AD in vivo and in vitro. Oral administration of AOWex to NC/Nga mice with Dermatophagoies farina extract (DfE)-induced AD-like symptoms significantly reduced the severity of clinical dermatitis, epidermal thickness, and mast cell infiltration into the skin and ear tissue. Decreased total serum IgE, macrophage-derived chemokine (MDC), and regulated on activation, normal T-cell expressed and secreted (RANTES) levels were observed in DfE-induced NC/Nga mice in the AOWex-treated group. These effects were confirmed in vitro using HaCaT cells. Treatment with AOWex inhibited the expression of proinflammatory chemokines such as MDC, RANTES, IP-10 and I-TAC in interferon-γ and tumor necrosis factor-α-stimulated HaCaT cells. The anti-inflammatory effects of AOWex were due to its inhibitory action on MAPK phosphorylation (ERK and JNK), NF-κB, and STAT1. Furthermore, galangin, protocatechuic acid, and epicatechin from AOWex were identified as candidate anti-AD compounds. These results suggest that AOWex exerts therapeutic effects against AD by alleviating AD-like skin lesions, suppressing inflammatory mediators, and inhibiting major signaling molecules.

We previously found that lung tumor development was reduced in a presenilin (PS) Alzheimer’s disease (AD) mouse model. Here, we investigated whether this reducing effect could occur in a different AD mouse model. We investigated urethane-induced (1 mg/g) lung tumor development and melanoma growth in Swedish amyloid precursor protein (SwAPP) transgenic mice. The expression of chitinase-3-like-1 (Chi3L1) increased during lung tumor development and melanoma growth, which was accompanied by an increase in the activity of signal transducer and activator of transcription 3 (STAT3) and the downregulation of miRNA342-3p in wild-type mice. Like tumor development, the expression of Chi3L1 and STAT3 activity was reduced in the SwAPP mice, whereas the expression of miRNA342-3p was upregulated. In addition, Chi3L1 knockdown in the lung cancer and melanoma tissues reduced cancer cell growth and STAT3 activity but enhanced miRNA342-3p expression. However, the miRNA342-3p mimic decreased Chi3L1 expression, cancer cell growth, and STAT3 activity. Moreover, a STAT3 inhibitor reduced Chi3L1 expression and cancer cell growth but enhanced miRNA342-3p expression. These data showed that lung tumor development was reduced through the decrease of Chi3L1 expression via the STAT3-dependent upregulation of miRNA342-3p. This study indicates that lung tumor development could be reduced in SwAPP AD mice. Keywords: chitinase-3-like-1, lung tumor development, miRNA342-3p, STAT3

Background: Dialysis patients manage not only the demand of dialysis but also other complex chronic conditions. These individuals may draw upon personal and social resources to cope with the demands of self-management and care coordination. This study was designed to describe social networks for self-management and care coordination among hemodialysis patients and explore the association between network characteristics and perceived treatment burden. Study Design: A cross-sectional study using social network analysis. Setting & Participants: 20 patients from an outpatient dialysis center. Factors: Social network characteristics (eg, size and connectivity) and perceived treatment burden. Measurements/Outcomes: Participants completed a battery of questionnaires, including the Patient Experience With Treatment and Self-management Questionnaire (measuring perceived treatment burden) and a social network survey asking the respondent to name up to 5 people to whom he or she turned for help with self-care and care coordination tasks and their characteristics and relationships. Results: Participants were aged 53.4 years on average, half were women, and 18 were African Americans. On average, network size was 3.1 members, most of whom were women and family members. 7 patient networks included at least 1 health care provider. The clustering coefficient (the overall connection between members) was 0.54, suggesting that not all members within the patient’s network were connected with each other. Multimorbidity was not associated with treatment burden domain scores, but greater network connectivity was associated with lower treatment-related financial burden (r = −0.61). Limitations: The small sample was racially homogeneous and precluded controlling for potential confounding factors. Conclusions: Dialysis patients used networks of people to manage self-care and coordination tasks, but interconnectedness between members of individual patients’ networks was limited, which might negatively affect their perceived treatment burden. The social context of dialysis patients could play an important role in their illness management and treatment burden and calls for future research. Index Words: Chronic illness management, kidney failure, dialysis, social network, care coordination

Background: Low back pain (LBP) is a major burden in Korea. Despite its high prevalence, the government and the public health sector do not address the specific evidences of symptom control and prevention of LBP to reduce long-term healthcare costs and increase the quality of life. Thus, the Korean medicine sector encourages to collection and analysis of the medical utilization pattern of patients with LBP in Korea to provide evidences of LBP control strategy as well as political decisions. Methods: KLOS, a prospective, multi-center, patient registry pilot study will collaborate with 7 traditional Korean medicine hospitals and recruit patients with LBP into the registry. A total of 150 eligible patients with new episodes of LBP, who visit a Korean hospital without any other treatment history, will be enrolled in the registry. After enrollment, we will collect the individual characteristics of each patient, such as pain intensity, LBP-related daily disability, anthropometrics, and Health-Related Quality of Life (HRQoL) at baseline and FU1 and FU2. We will also access the patients’ clinical and administrative electronic records to analyze the pattern of patients’ resource utilization. Overall, the aims of KLOS are to (1) explore the general characteristics of patients with new episodes of LBP and (2) evaluate the efficacy and safety of various Korean medicine treatments for LBP, based on nationwide registry outcome collecting process. Discussion: The first pilot study of prospective, multi-center registry of newly diagnosed LBP patients in traditional Korean medicine hospitals. The result of this study may show the current status of LBP patients who receive Korean medicine treatments and provide evidences for reasonable decision-making on Korean medicine healthcare policy in the future. Trial registration number: ClinicalTrials.gov Identifier: NCT02418286.

Background: Cold hypersensitivity in the hands and feet (CHHF) is a symptom patients usually feel cold in their hands and feet, but not dealt with a disease in western medicine. However, it is often appealed by patients at a clinic of Korean medicine (KM), considered to be a sort of key diagnostic indicator, and actively treated by physicians. Nevertheless, there is no standardized diagnostic definition for CHHF. Therefore, we surveyed KM experts’ opinions to address the clinical definition, diagnostic criteria, and other relevant things on CHHF. Methods: We developed a survey to assess the definition, diagnosis, causes, and accompanying symptoms on CHHF. 31 experts who work at specialized university hospitals affiliated with KM hospitals consented to participation. Experts responded to survey questions by selecting multiple-choice answers or stating their opinions. Results: Vast majority of experts (83.8%) agreed with our definition on CHHF (“a feeling of cold as a symptom; that one's hands or feet become colder than those of average people in temperatures that are not normally perceived as cold”). 77.4% of experts considered subjective symptoms on CHHF were more important than medical instrument results. Constitution or genetic factors (87.1%) and stress (64.5%) were the most common causes reported for CHHF. Conclusions: This study offers an expert consensus regarding the themes, opinions, and experiences of practitioners with CHHF. Our results underscore the need for standardized definitions and diagnostic criteria for CHHF. Keywords: Cold hypersensitivity, Cold extremities, Cold constitution

Embryonic stem cells hold great promise for various diseases because of their unlimited capacity for self-renewal and ability to differentiate into any cell type in the body. However, despite over 3 decades of research, there have been no reports on the safety and potential efficacy of pluripotent stem cell progeny in Asian patients with any disease. Here, we report the safety and tolerability of subretinal transplantation of human embryonic-stem-cell (hESC)-derived retinal pigment epithelium in four Asian patients: two with dry age-related macular degeneration and two with Stargardt macular dystrophy. They were followed for 1 year. There was no evidence of adverse proliferation, tumorigenicity, ectopic tissue formation, or other serious safety issues related to the transplanted cells. Visual acuity improved 9–19 letters in three patients and remained stable (+1 letter) in one patient. The results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine.

Insulin stimulates glucose uptake through the membrane translocation of GLUT4 and GLUT1. Peroxisome proliferator-activated receptor γ (PPARγ) enhances insulin sensitivity. Here, we demonstrate that insulin stimulates GLUT4 and GLUT1 translocation, and glucose uptake, by activating the signaling pathway involving nicotinic acid adenine dinucleotide phosphate (NAADP), a calcium mobilizer, in adipocytes. We also demonstrate that PPARγ mediates insulin sensitization by enhancing NAADP production through upregulation of CD38, the only enzyme identified for NAADP synthesis. Insulin produced NAADP by both CD38-dependent and -independent pathways, whereas PPARγ produced NAADP by CD38-dependent pathway. Blocking the NAADP signaling pathway abrogated both insulin-stimulated and PPARγ-induced GLUT4 and GLUT1 translocation, thereby inhibiting glucose uptake. CD38 knockout partially inhibited insulin-stimulated glucose uptake. However, CD38 knockout completely blocked PPARγ-induced glucose uptake in adipocytes and PPARγ-mediated amelioration of glucose tolerance in diabetic mice. These results demonstrated that the NAADP signaling pathway is a critical molecular target for PPARγ-mediated insulin sensitization.