Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.

OBJECTIVES: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation. METHODS: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. RESULTS: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. INTERPRETATION: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040-1054.

Time Window for Induced Hypertension in Acute Small Vessel Occlusive Stroke With Early Neurological Deterioration.

BACKGROUND: Therapeutic-induced hypertension treatment (iHTN) is helpful for alleviating early neurological deterioration (END) in acute small vessel occlusive stroke. We examined the time parameters related to iHTN effectiveness in these patients. METHODS: We retrospectively reviewed patients with acute small vessel occlusive stroke who underwent iHTN for END, defined as an increase of ≥2 points in total National Institutes of Health Stroke Scale (NIHSS) score or ≥1 point in motor items of NIHSS. The primary outcome was an early neurological improvement (ENI; a decrease of ≥2 points in total NIHSS score or ≥1 point in motor items of NIHSS), and the secondary outcome was any neurological improvement (a decrease of ≥1 point in the total NIHSS score). We conducted a multivariable logistic regression analysis, adjusting for demographics, risk factors, baseline clinical status, and intervention-related variables. We also generated a restricted cubic spline curve for the END-to-iHTN time cutoff. RESULTS: Among the 1062 patients with small vessel occlusive stroke screened between 2017 and 2021, 136 patients who received iHTN within 24 hours from END were included. The mean age was 65.1 (±12.0) years, and 61.0% were male. Sixty-five (47.8%) patients showed ENI and 77 (56.6%) patients showed any neurological improvement. END-to-iHTN time was significantly shorter in patients with ENI (150 [49-322] versus 290 [97-545] minutes; P=0.018) or any neurological improvement (150 [50-315] versus 300 [130-573] minutes; P=0.002). A 10-minute increase in the time between END and iHTN decreased the odds of achieving ENI (odds ratio, 0.984 [95% CI, 0.970-0.997]; P=0.019) or any neurological improvement (odds ratio, 0.978 [95% CI, 0.964-0.992]; P=0.002). The restricted cubic spline curve showed that the odds ratio of ENI reached its minimum at ≈3 hours. CONCLUSIONS: Among patients with small vessel occlusive stroke with END, a shorter interval between END and the initiation of iHTN was associated with increased odds of achieving neurological improvement. The efficacy of iHTN may be limited to induction within the first 3 hours of END.

Effect of antiviral therapy in patients with low HBV DNA level on transarterial chemoembolization for hepatocellular carcinoma.

Antiviral therapy improves survival in patients with hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC). However, the effect of antiviral therapy in patients with low-level viremia HBV-HCC receiving non-curative therapy remains unclear. We aimed to evaluate the role of antiviral therapy in patients with low-level viremia and treated with transarterial chemoembolization (TACE). This retrospective study evaluated 206 patients with HBV-HCC who underwent TACE as an initial treatment. Of those, 135 patients received antiviral therapy (antiviral group), and 71 did not (non-antiviral group). The definition of low-level viremia was an HBV DNA level <2000 IU/ml. Kaplan-Meier curves, log-rank tests and Cox regression analysis were used for statistical analyses. The median follow-up duration was 39 months (1-174 months). Overall survival (OS) did not differ between groups (P = .227). Barcelona Clinic Liver Cancer stage (BCLC), Child-Pugh (CP) class and α-fetoprotein level were independent prognostic factors for OS. Antiviral therapy (hazard ratio [HR], 0.503, P = .022) was a prognostic factor for 2-year survival. On subgroup analysis, antiviral therapy improved short-term survival in patients with BCLC stage 0 and A (P = .037) and CP class A (P = .04). In patients with low-level viremia, antiviral therapy yielded short-term survival benefits, particularly in patients with early-stage HCC.

Effectiveness and safety of herbal medicine for cancer-related fatigue in lung cancer survivors: A systematic review and meta-analysis.

Approximately half of lung cancer patients (LCP) receiving chemotherapy are experiencing cancer-related fatigue (CRF). In East Asia, herbal medicines (HMs) have been used as tonics due to their anti-fatigue effect. This systematic review evaluated the effectiveness and safety of HMs for CRF in LCP. We comprehensively searched 12 electronic medical databases to search randomized controlled trials (RCTs) and quasi-RCTs investigating HMs for CRF in LCP, published up to September 2019. The primary outcome was the fatigue severity. Secondary outcomes included patients' quality of life (QOL), activities of daily life (ADL), and incidence of adverse events. Cochrane's risk of bias tool assessed the methodological quality of included RCTs. The risk ratio or mean difference was estimated with 95% confidence intervals by performing a meta-analysis. Twelve RCTs with 861 participants were included. Compared to conventional medicine alone, HM combined with conventional medicine significantly improved fatigue level, QOL, and ADL. As monotherapy, HM significantly improved ADL compared with megestrol. No serious HM-related adverse events were reported. Limited evidence suggests that HM could be effective and safe for CRF in LCP. However, further high-quality RCTs are needed to confirm these findings owing to the small number and low methodological quality of the included studies.

Inflammasomes and autoimmune and rheumatic diseases: A comprehensive review.

Inflammasomes are a multi-protein platform forming a part of the innate immune system. Inflammasomes are at standby status and can be activated when needed. Inflammasome activation is an important mechanism for the production of active interleukin (IL)-1ß and IL-18, which have important roles to instruct adaptive immunity. Active forms of inflammasomes trigger a series of inflammatory cascades and lead to the differentiation and polarization of naïve T cells and secretion of various cytokines, which can induce various kinds of autoimmune and rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), gout, Sjögren's syndrome, Behçet's disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgA vasculitis (former Henoch-Schönlein purpura ). In this review, we summarize studies published on inflammasomes and review their roles in various autoimmune diseases. Understanding of the role of inflammasomes may facilitate the diagnosis of autoimmune diseases and the development of tailored therapies in the future.

Suppression of lung inflammation by the ethanol extract of Chung-Sang and the possible role of Nrf2.

BACKGROUND: Asian traditional herbal remedies are typically a concoction of a major and several complementary herbs. While balancing out any adverse effect of the major herb, the complementary herbs could dilute the efficacy of the major herb, resulting in a suboptimal therapeutic effect of an herbal remedy. Here, we formulated Chung-Sang (CS) by collating five major herbs, which are used against inflammatory diseases, and tested whether an experimental formula composed of only major herbs is effective in suppressing inflammation without significant side effects. METHODS: The 50% ethanol extract of CS (eCS) was fingerprinted by HPLC. Cytotoxicity to RAW 264.7 cells was determined by an MTT assay and a flow cytometer. Nuclear NF-κB and Nrf2 were analyzed by western blot. Ubiquitinated Nrf2 was similarly analyzed following immunoprecipitation of Nrf2. Acute lung inflammation and sepsis were induced in C57BL/6 mice. The effects of eCS on lung disease were measured by HE staining of lung sections, a differential cell counting of bronchoalveolar lavage fluid, a myeloperoxidase (MPO) assay, a real-time qPCR, and Kaplan-Meier survival of mice. RESULTS: eCS neither elicited cytotoxicity nor reactive oxygen species. While not suppressing NF-κB, eCS activated Nrf2, reduced the ubiquitination of Nrf2, and consequently induced the expression of Nrf2-dependent genes. In an acute lung inflammation mouse model, an intratracheal (i.t.) eCS suppressed neutrophil infiltration, the expression of inflammatory cytokine genes, and MPO activity. In a sepsis mouse model, a single i.t. eCS was sufficient to significantly decrease mouse mortality. CONCLUSIONS: eCS could suppress severe lung inflammation in mice. This effect seemed to associate with eCS activating Nrf2. Our findings suggest that herbal remedies consisting of only major herbs are worth considering.

Anti-inflammatory effects of embelin in A549 cells and human asthmatic airway epithelial tissues.

OBJECTIVE: Allergic asthma is the most common type in asthma, which is defined as a chronic inflammatory disease of the lung. In this study, we investigated whether embelin (Emb), the major component of Ardisia japonica BL. (AJB), exhibits anti-inflammatory effects on allergic asthma via inhibition of NF-κB activity using A549 cells and asthmatic airway epithelial tissues. METHODS: Inflammation was induced in A549 cells, a human airway epithelial cell line, by IL-1ß (10 ng/ml) treatment for 4 h. The effects of Emb on NF-κB activity and COX-2 protein expression in inflamed airway epithelial cells and human asthmatic airway epithelial tissues were analyzed via western blot. The secretion levels of NF-κB-mediated cytokines/chemokines, including IL-4, 6, 9, 13, TNF-α and eotaxin, were measured by a multiplex assay. RESULTS: Emb significantly blocked NF-κB activity in IL-1ß-treated A549 cells and human asthmatic airway epithelial tissues. COX-2 expression was also reduced in both IL-1ß-treated A549 cells and asthmatic tissues Emb application. Emb significantly reduced the secretion of IL-4, IL-6 and eotaxin in human asthmatic airway epithelial tissues by inhibiting activity of NF-κB. CONCLUSIONS: The results of this study suggest that Emb may be used as an anti-inflammatory agent via inhibition of NF-κB and related cytokines.

Association Between Secretoglobin Family 3A Member 2 (SCGB3A2) Gene Polymorphisms and Asthma in a Korean Population.

BACKGROUND Secretoglobin family 3A member 2 (SCGB3A2) plays an important role in secreting lung surfactant protein, which is a downstream target of thyroid transcription factor. MATERIAL AND METHODS We investigated whether single-nucleotide polymorphisms (SNPs) of SCGB3A2 gene contribute to susceptibility to asthma. To explore this possible association, 2 promoter SNPs (rs6882292, 659 G/A and rs1368408, -112 G/A) and missense SNP (rs151333009, stop codon) were tested in SCGB3A2 gene in 101 asthma patients and 377 healthy control subjects. SNPStats was used to obtain odds ratio (OR), 95% confidence intervals (CI), and P value adjusted for age and sex as covariables. Logistic regression method in each model (dominant, recessive, and log-additive) was applied to analyze genetic data. RESULTS rs151333009 SNP showed a monomorphic genotype. Two promoter SNPs (rs6882292, -659 G/A and rs1368408, -112 G/A) showed significant association with asthma (rs6882292, OR=2.66, 95% CI=1.42-5.01, p=0.0033 in dominant model, OR=2.45, 95% CI=1.33-4.54, p=0.0055 in log-additive model; rs1368408, OR=1.59, 95% CI=1.02-2.49, p=0.041 in dominant model, OR=3.02, 95% CI=1.15-7.90, p=0.03 in recessive model, OR=1.63, 95% CI=1.63, 95% CI=1.12-2.37, p=0.012 in log-additive model). CONCLUSIONS These results suggest that the promoter SNPs (rs6882292 and rs1368408) of SCGB3A2 gene may contribute to susceptibility to asthma in a Korean population.

Decreased cysteine uptake by EAAC1 gene deletion exacerbates neuronal oxidative stress and neuronal death after traumatic brain injury.

Excitatory amino acid carrier type 1 (EAAC1), a high-affinity glutamate transporter, can expend energy to move glutamate into neurons. However, under normal physiological conditions, EAAC1 does not have a great effect on glutamate clearance but rather participates in the neuronal uptake of cysteine. This process is critical to maintaining neuronal antioxidant function by providing cysteine for glutathione synthesis. Previous study showed that mice lacking EAAC1 show increased neuronal oxidative stress following transient cerebral ischemia. In the present study, we sought to characterize the role of EAAC1 in neuronal resistance after traumatic brain injury (TBI). Young adult C57BL/6 wild-type or EAAC1 (-/-) mice were subjected to a controlled cortical impact model for TBI. Neuronal death after TBI showed more than double the number of degenerating neurons in the hippocampus in EAAC1 (-/-) mice compared with wild-type mice. Superoxide production, zinc translocation and microglia activation similarly showed a marked increase in the EAAC1 (-/-) mice. Pretreatment with N-acetyl cysteine (NAC) reduced TBI-induced neuronal death, superoxide production and zinc translocation. These findings indicate that cysteine uptake by EAAC1 is important for neuronal antioxidant function and survival following TBI. This study also suggests that administration of NAC has therapeutic potential in preventing TBI-induced neuronal death.

Palliative self-expandable metal stents for acute malignant colorectal obstruction: clinical outcomes and risk factors for complications.

OBJECTIVE: Self-expandable metal stents (SEMSs) have been used as palliative treatment or bridge to surgery for obstructions caused by colorectal cancer (CRC). We assessed the long-term outcomes of palliative SEMSs and evaluated the risk factors influencing complications. MATERIALS AND METHODS: One hundred and seventy-five patients underwent SEMS placement for acute malignant colorectal obstruction. Of the 72 patients who underwent palliative treatment for primary CRC, 30 patients received chemotherapy (CT) for primary cancer (CT group) and 42 underwent best supportive treatment (BST) without CT (BST group). RESULTS: There was a significant difference in late migration between the CT group and the BST group (20.0% in CT group, 2.4% in BST group, p = 0.018). Response to CT influenced the rate of late obstruction (0% in disease control, 35.7% in disease progression, p = 0.014). However, late obstruction was not associated with stent properties, such as diameter or type (≤22 mm vs. >22 mm, 13.5% vs. 14.3%, p = 1.00; uncovered stent vs. covered stent, 15.5% vs. 7.1%, p = 0.675) and migration (≤22 mm vs. >22 mm, 16.2% vs. 2.9%, p = 0.108; uncovered stent vs. covered stent, 8.6% vs. 14.3%, p = 0.615) in palliative SEMS. CONCLUSION: The administration of CT increases the rate of stent migration, and disease control by CT can reduce the risk of obstruction by maintaining the luminal patency of palliative SEMSs.

The Effectiveness and Safety of Chuna Manual Therapy Adjuvant to Western Medicine in Patients with Chronic Obstructive Pulmonary Disease: A Randomized, Single-Blind, Investigator-Initiated, Pilot Trial.

Recently, non-pharmacological treatments are gaining increasing importance for improving the quality of life in patients with chronic obstructive pulmonary disease (COPD). This pilot study aimed to evaluate the feasibility of conducting extensive research on Chuna manual therapy (CMT). This study investigated the effectiveness and safety of CMT adjuvant to Western medicine (WM) in patients with COPD. Forty patients with COPD were randomized into two groups in a 1:1 ratio: experimental (CMT plus WM) and control (WM only) groups. The CMT intervention was administered once a week for eight weeks. The primary outcome measured was the 6-min walk distance (6MWD). Secondary outcomes measured were: forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), assessments using the modified Medical Research Council (mMRC) scale and Visual Analog Scale (VAS) for dyspnea, the COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), and the EuroQoL five-dimensional questionnaire (EQ-5D). The mean differences in FEV1 (L) between Weeks 1 and 8 were statistically significant between the groups (p = 0.039). Additionally, the experimental group showed improved 6MWD, mMRC, VAS for dyspnea, CAT, SGRQ (total), and EQ-VAS scores than the control group. However, the differences between the two groups were not statistically significant. No adverse events were observed during this trial. CMT has the potential to alleviate symptoms, improve quality of life, and delay the decline in lung function in patients with COPD. The results of this pilot study could lead to large-scale clinical trials in the future.

Blood sphingolipid as a novel biomarker in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Sphingolipids are signaling molecules and structural components of the axolemma and myelin sheath. Plasma sphingolipid levels may reflect disease status of neuromyelitis optica spectrum disorder (NMOSD). We aimed to examine plasma sphingolipids as disease severity biomarkers for NMOSD and compare their characteristics with those of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP). METHODS: We measured plasma sphingolipids, sNfL, and sGFAP levels in NMOSD cases with anti-aquaporin-4-antibody. An unbiased approach, partial least square discriminant analysis (PLS-DA), was utilized to determine whether sphingolipid profiles differ according to the disease state of NMOSD (presence, moderate-to-severe disability [Expanded Disease Severity Scale, (EDSS) > 3.0], and relapses). RESULTS: We investigated 81 patients and 10 controls. PLS-DA models utilizing sphingolipids successfully differentiated patients with EDSS > 3.0, but failed to identify the presence of disease and relapses. Ceramide-C14-a significant contributor to differentiating EDSS > 3.0-positively correlated with EDSS, while its levels were independent of age and the presence of relapses. This characteristic was unique from those of sNfL and sGFAP, which were affected by age and relapses as well as EDSS. CONCLUSION: Plasma sphingolipids may be useful NMOSD biomarkers for disability with distinct characteristics compared to sNfL and sGFAP.

The multi-targeted effects of Chrysanthemum herb extract against Escherichia coli O157:H7.

The Chrysanthemum lavandulifolium extract, which includes chrysoeriol, sudachitin, and acacetin, has excellent antibiotic effects on Escherichia coli O157:H7 (E. coli O157). A notable point is that the antibiotic targets of the herb extract are similar to the targets of commonly used antibiotic drugs, including bacterial cell wall biosynthesis, bacterial protein synthesis, and bacterial DNA replication and repair. In addition, the herbal antibiotic inhibits the etiological factors that contribute to the pathogenic property. The herbal sample was extracted and fractionated and then inoculated through a disk diffusion method to confirm its antibiotic effect against E. coli O157. Total RNA was isolated from the affected bacterial cells, and its expression level was analyzed through a microarray analysis. To confirm the accuracy of the microarray data, a real-time PCR was performed. Three active compounds, chrysoeriol, sudachitin, and acacetin, were identified with a high-performance liquid chromatography-electrospray ionization/mass spectrometry chromatogram, and the disk diffusion study confirmed that chrysoeriol and sudachitin contribute to the antibiotic properties of the herb extract. The results demonstrate that the multi-target efficacy of the herbal sample may indicate the potential for the development of more effective and safer drugs that will act as substitutes for existing antibiotics.

Disease characteristics of idiopathic transverse myelitis with serum neuronal and astroglial damage biomarkers.

Despite its close association with CNS inflammatory demyelinating disorders (CIDDs), pathogenic characteristics of idiopathic transverse myelitis (ITM) remain largely unknown. Here, we investigated serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) in patients with ITM to unravel the disease characteristics of ITM. We prospectively recruited 70 patients with ITM, 62 with AQP4 + NMOSD and 85 with RRMS-including 31 patients with acute TM attacks-along with 30 HCs. We measured sNfL and sGFAP levels using single-molecular arrays and compared these levels per lesion volume between the disease groups during attacks. Compared to HCs, ITM patients showed higher sNfL and sGFAP during acute attacks (sNfL: p < 0.001, sGFAP: p = 0.024), while those in remission (sNfL: p = 0.944, sGFAP: p > 0.999) did not, regardless of lesion extents and presence of multiple attacks. ITM patients demonstrated lower sGFAP/volume (p = 0.011) during acute attacks and lower sGFAP (p < 0.001) in remission compared to AQP4 + NMOSD patients. These findings suggest that both neuronal and astroglial damages occur in patients with acute ITM attacks at a similar level to those with RRMS, distinct from AQP4 + NMOSD. However, active neuroinflammatory process was not remarkable during remission in this cohort.

Protective Effect of the Fruit Hull of Gleditsia sinensis on LPS-Induced Acute Lung Injury Is Associated with Nrf2 Activation.

The fruit hull of Gleditsia sinensis (FGS) has been prescribed as a traditional eastern Asian medicinal remedy for the treatment of various respiratory diseases, but the efficacy and underlying mechanisms remain poorly characterized. Here, we explored a potential usage of FGS for the treatment of acute lung injury (ALI), a highly fatal inflammatory lung disease that urgently needs effective therapeutics, and investigated a mechanism for the anti-inflammatory activity of FGS. Pretreatment of C57BL/6 mice with FGS significantly attenuated LPS-induced neutrophilic lung inflammation compared to sham-treated, inflamed mice. Reporter assays, semiquantitative RT-PCR, and Western blot analyses show that while not affecting NF-κB, FGS activated Nrf2 and expressed Nrf2-regulated genes including GCLC, NQO-1, and HO-1 in RAW 264.7 cells. Furthermore, pretreatment of mice with FGS enhanced the expression of GCLC and HO-1 but suppressed that of proinflammatory cytokines in including TNF-α and IL-1ß in the inflamed lungs. These results suggest that FGS effectively suppresses neutrophilic lung inflammation, which can be associated with, at least in part, FGS-activating anti-inflammatory factor Nrf2. Our results suggest that FGS can be developed as a therapeutic option for the treatment of ALI.

Therapeutic Potential of Chungsangboha-tang for the Treatment of Asthma: A Review of Preclinical and Clinical Studies.

In traditional Korean medicine, Chungsangboha-tang (CSBHT) and its modified forms are used to treat various respiratory disorders, including asthma. This study aimed to identify research trends, clarify the effectiveness of CSBHT and related prescriptions, and lay a foundation for future research. We conducted a literature review using PubMed, Embase, Google Scholar, Oriental Medicine Advanced Searching Integrated System, National Digital Science Links, Korean Medical Database, Wanfang Data, and Chinese National Knowledge Infrastructure databases. We analyzed 25 studies, including 5 in vitro studies, 6 animal studies, and 14 human studies. Many studies evaluated the efficacy of CSBHT and its related prescriptions, including experimental studies on its effectiveness in asthma. The main mechanism of action involves the anti-inflammatory effect caused by the regulation of various immune cells, cytokines, and chemokines. In addition, clinical trials on asthma reported the benefits of CSBHT and its related prescriptions. However, there has been no randomized controlled study of clinical trials on the clinical effectiveness of CSBHT in asthma. Therefore, large-scale randomized controlled studies should be conducted in the future.

Efficacy and Safety of Ojeok-San Plus Saengmaek-San for Gastroesophageal Reflux-Induced Chronic Cough: A Pilot, Randomized, Double-Blind, Placebo-Controlled Trial.

Introduction: Gastroesophageal reflux-induced chronic cough (GERC) is one of the most common etiologies of chronic cough. Despite the growing prevalence and interest in GERC, no effective treatment is currently available. In our study, we used a combination of herbal medicines, Ojeok-san (OJS) plus Saengmaek-san (SMS), for the treatment of GERC. Methods: We conducted a pilot, randomized, placebo-controlled, parallel-arm, single-center clinical trial to assess the feasibility of our study protocol, as our study is the first herbal medicine trial for GERC. All enrolled participants were randomly assigned to either the intervention or placebo group in a 1:1 ratio and were administered trial drugs three times a day for 6 weeks, with an evaluation visit performed every 2 weeks for their efficacy and safety assessment until the follow-up visit (week 8). We evaluated the severity and frequency of cough, cough-specific quality of life, airway hypersensitivity, and reflux-related gastrointestinal symptoms, as well as pattern identification, to investigate the complex mechanisms of reflux cough syndrome. Results: A total of 30 participants were enrolled, and 25 completed the study at Kyung Hee University Korean Medicine Hospital from 26 December 2018 to 31 May 2021. OJS plus SMS significantly improved the cough diary score (CDS), cough visual analog scale, Korean version of the Leicester Cough Questionnaire, Hull Airway Reflux Questionnaire, and Gastrointestinal Symptom Rating Scale after the treatment compared to the baseline. Notably, OJS plus SMS showed significant efficacy in the daytime and total CDS compared with the placebo. Only one adverse event was observed during the trial, and no serious adverse events occurred. Additionally, we achieved successful results in feasibility outcomes by exceeding the ratio of 80%. Conclusion: We confirmed the feasibility of our trial design and demonstrated the potential of OJS plus SMS in relieving the severity of cough and GI symptoms in GERC patients with safe and successful feasibility results. We anticipate that our study results will be used as the basis for further large-scale, well-designed, confirmatory trials to evaluate the safety and efficacy of OJS plus SMS in GERC. Clinical Trial Registration: [https://cris.nih.go.kr], identifier WHO International Clinical Trials Registry Platform, Clinical Research Information Service [KCT0003115].

Rosa laevigata Attenuates Allergic Asthma Exacerbated by Water-Soluble PM by Downregulating the MAPK Pathway.

Exposure to water-soluble particulate matter (WPM) containing heavy metals can cause severe inflammatory responses and trigger and exacerbate the onset of asthma. As a follow-up study of Rosa laevigata (RL), this study analyzed the therapeutic effects and mechanisms of oral and intratracheal administration of RL and demonstrated anti-inflammatory effects in asthma models. Worse T-helper cell type 2 (Th2)-related inflammatory and pro-inflammatory responses were observed after simultaneous challenge with ovalbumin (OVA) and WPM. To establish a model of asthma exacerbated by WPM, BALB/c mice were sensitized with OVA + aluminum hydroxide and challenged with OVA + WPM. To confirm the therapeutic efficacy of RL, it was administered both orally and intratracheally. Histopathological analysis of H&E staining confirmed that oral and intratracheal administration of RL alleviated inflammatory cell infiltration in the airways aggravated by OVA + WPM. RL effectively reduced the number of inflammatory cells obtained from the bronchoalveolar lavage fluid. In addition, enzyme-linked immunosorbent assay (ELISA) and multiplex analysis of serum samples confirmed that the administration of RL reduced the levels of immuno-globulin E (IgE), Th2-related cytokines, and pro-inflammatory cytokines. Furthermore, real-time PCR analysis of lung tissue samples confirmed that the release of MUC5AC (Mucin 5AC, Oligomeric Mucus/Gel-Forming) and pro-inflammatory cytokines was reduced by RL, and western blotting confirmed that the administration of RL reduced the phosphorylation of ERK and p38 in the MAPK pathway. In conclusion, oral and intratracheal administration of RL appears to have an anti-asthmatic effect by reducing the secretion of Th2-related cytokines, pro-inflammatory cytokines, and IgE by downregulating the MAPK pathway. Thus, RL has further demonstrated potential for development as an oral and inhaled therapeutic for asthma symptoms exacerbated by WPM exposure.

An Angiotensin I converting enzyme polymorphism is associated with clinical phenotype when using differentiation-syndrome to categorize korean bronchial asthma patients.

In this study, genetic analysis was conducted to investigate the association of angiotensin I converting enzyme (ACE) gene polymorphism with clinical phenotype based on differentiation-syndrome of bronchial asthma patients. Differentiation-syndrome is a traditional Korean medicine (TKM) theory in which patients are classified into a Deficiency Syndrome Group (DSG) and an Excess Syndrome Group (ESG) according to their symptomatic classification. For this study, 110 participants were evaluated by pulmonary function test. Among them, 39 patients were excluded because they refused genotyping. Of the remaining patients, 52 with DSG of asthma (DSGA) and 29 with ESG of asthma (ESGA), as determined by the differentiation-syndrome techniques were assessed by genetic analysis. ACE insertion/deletion (I/D) polymorphism analysis was conducted using polymerase chain reaction (PCR). Student's t, chi-square, Fisher and Hardy-Weinberg equilibrium tests were used to compare groups. No significant differences in pulmonary function were observed between DSGA and ESGA. The genotypic frequency of ACE I/D polymorphism was found to differ slightly between DSGA and ESGA (P = .0495). However, there were no significant differences in allelic frequency observed between DSGA and ESGA (P = .7006, OR = 1.1223). Interestingly, the allelic (P = .0043, OR = 3.4545) and genotypic (P = .0126) frequencies of the ACE I/D polymorphism in female patients differed significantly between DSGA and ESGA. Taken together, the results presented here indicate that the symptomatic classification of DSGA and ESGA by differentiation-syndrome in Korean asthma patients could be useful in evaluation of the pathogenesis of bronchial asthma.

The effectiveness and safety of Chuna manual therapy adjuvant to Western medicine in patients with chronic obstructive pulmonary disease: Study protocol for a randomized, single-blind, investigator-initiated, pilot trial.

BACKGROUND: In chronic obstructive pulmonary disease (COPD) management, greater emphasis has been placed on symptomatic improvement and enhanced quality of life in patients. Manual therapy among respiratory rehabilitation programs has received much attention recently, with the publication of numerous studies. In South Korea, a method known as Chuna Manual Therapy (CMT) has been applied in the management of COPD patients and in clinical practice, but the clinical basis for safety and effectiveness is yet to be established. Therefore, rigorously designed randomized controlled trials are required. We aimed to evaluate the feasibility of assessing the add-on effect and safety of CMT administered with standard Western medicine therapy for the treatment of COPD. METHODS: This is a randomized, single-blind, single-center clinical pilot trial. Patients with COPD receiving standard drug therapy are randomly divided into an experimental group (n = 20) and a control group (n = 20) at a 1:1 ratio. The experimental group receives CMT adding to the standard medical therapy once a week for 8 weeks. The control group receives only the standard drug treatment. The trial is conducted with an outcome assessor and statistician blinding. The primary outcome is the 6-minute walk test. The secondary outcomes include the pulmonary function test, the Modified Medical Research Council, visual analog scale for dyspnea, COPD assessment test, quality of life using the St. George's respiratory questionnaire, EuroQOL five dimensions questionnaire, and Korean pattern identification questionnaire. Adverse events are also be evaluated. CONCLUSIONS: The results of this study will provide the feasibility of a large-scale clinical trial to establish high-quality clinical evidence of CMT for COPD. TRIAL REGISTRATION: Korean Clinical Trial Registry (http://cris.nih.go.kr; registration number: KCT0006119).