Discovery of organosulfur-based selective HDAC8 inhibitors with anti-neuroblastoma activity.

Histone deacetylases (HDACs) are important epigenetic regulators of gene expression and various cellular processes, and are potential targets for anticancer therapy. In particular, HDAC8 is a promising therapeutic target for childhood neuroblastoma. To date, five HDAC inhibitors have been approved as anticancer drugs; however, all are non-selective HDAC inhibitors with various side effects. Furthermore, many promising HDAC inhibitors incorporate hydroxamic acid as a zinc binding group (ZBG), which may be associated with toxicity. Therefore, identification of isoform-selective HDAC inhibitors with novel ZBG is crucial. Here, a series of sulfur-based selective HDAC8 inhibitors featuring a novel ZBG were identified by modifying the early hit, ajoene, a component of garlic. Structure-activity relationship studies uncovered potent and selective HDAC8 inhibitors, and docking studies provided a structural rationale for HDAC8 inhibitory activity. One of the potent compounds, (Z)-1-phenyl-7-(4-methoxyphenyl)-2,3,7-trithiahepta-4-ene-7-oxide (15c), exhibited antiproliferative activity, with a GI50 of 2 µM, against neuroblastoma cell lines. 15c also showed significant in vivo efficacy in a neuroblastoma BE(2)-C xenograft model.

Mitophagy Defects Exacerbate Inflammation and Aberrant Proliferation in Lymphocytic Thyroiditis.

Background: Mitochondrial dysfunction in the thyroid due to defective mitophagy has been observed in lymphocytic thyroiditis (LT). However, the effect of impaired mitophagy on the pathogenesis of LT is not well understood. The aim of this study is to investigate the role of mitophagy dysregulation in the thyroid gland. Methods: We analyzed RNA sequencing data of human thyroid glands with/without LT from Genotype-Tissue Expression (GTEx; n = 653) and performed RNA sequencing in thyroid glands of phosphatase and tensin homolog-induced putative protein kinase 1 (Pink1) knock-out and wild-type mice. We evaluated the phenotypic and histopathologic characteristics of the human (n = 16) and mouse thyroids. Additionally, we assessed cell proliferation, reactive oxygen species (ROS) production, and cytokine secretion of human thyroid epithelial cells (HTori-3) treated with PINK1 siRNA or a mitophagy inhibitor. Results: We found that expression of PINK1, a key regulator of mitophagy, was compromised in human thyroids with LT. Thyroid glands of Pink1-deficient mice exhibited increased inflammatory responses and nodular hyperplasia. Furthermore, mitophagy defects led to the production of pro-inflammatory cytokines and ROS in thyroid cells, resulting in immune cell recruitment. Notably, these mitophagy defects upregulated both the RNA expression and protein secretion of amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, in thyroid cells, while decreasing the protein expression of cAMP response element-binding protein (CREB), a transcription factor that suppresses AREG transcription. Finally, we demonstrated that aberrant cell proliferation in thyroid cells, driven by mitophagy defects, was mitigated after treatment with cetuximab, an EGFR inhibitor. Conclusions: In this study, we observed that mitophagy defects in the thyroid not only intensify inflammation through the accumulation of ROS, cytokine production, and immune cell recruitment but also contribute to hyperplasia via the EGFR pathway, facilitated by increased secretion of AREG from thyroid cells.

Higher serum phosphate within the normal range is associated with the development of calcified aortic valve disease.

Background: Despite the essential role of ectopic osteogenic calcium-phosphate metabolism in the development of calcific aortic valve disease (CAVD), the implications of high serum phosphate levels in CAVD development are not fully understood. Methods: Asymptomatic individuals who underwent health screening using serial cardiac computed tomography (CT) and echocardiography were selected from a multicenter registry. CAVD was identified and quantified on CT images using the aortic valve calcification (AVC) score. The associations between initial serum phosphate levels and the presence of baseline CAVD, development of new CAVD, and the AVC score progression rate were investigated using multivariable regression models. Results: A total of 736 individuals were selected for analysis, and the median interscan duration was 36.4 months. On initial CT, 83 (13.7%) participants had baseline CAVD, while 52 (7.0%) individuals developed new CAVD during follow-up. Serum phosphate levels were not associated with a higher probability of baseline CAVD but were predictive of newly developed CAVD (odds ratio per 1 mg/dl, 1.05; 95% confidence interval, 1.01-1.10; p = 0.02). Higher phosphate levels were also associated with a faster AVC score progression in those with baseline CAVD (regression coefficient per 1 mg/dl, 15.55 Agatston units/year; 95% confidence interval, 6.02-25.07; p < 0.01), an association which remained significant when the analysis was extended to include newly developed CAVD. Conclusion: Even slight elevations in serum phosphate are associated with accelerated CAVD progression from an early stage. Further studies are needed to investigate whether the regulation of phosphate metabolism can slow the progression of CAVD to aortic stenosis.

Refractory solar lentigines successfully treated with 532-nm nanosecond Nd:YAG Vasculature Salvage Laser Surgery (VSLS) system: Case series.

BACKGROUND: Solar lentigo, a common epidermal hyperpigmented lesion found in sun-exposed areas, results from the proliferation of melanocytes and the accumulation of melanin. Although various treatments for solar lentigo have been explored, they often lead to complications, including prolonged erythema and post-inflammatory hyperpigmentation (PIH), posing significant concerns. OBJECTIVES AND METHODS: This study evaluated the safety and efficacy of the Vasculature Salvage Laser Surgery (VSLS) system. We treated six Korean patients, each with solar lentigo, in a single session using the 532-nm nanosecond neodymium-doped yttrium aluminum garnet (Nd:YAG) VSLS system, with follow-up periods ranging from 3 to 10 weeks. RESULTS: The treatment led to the complete removal of pigmented lesions in all patients without resulting in PIH, even in cases where previous laser treatments had failed. The only side effect observed was mild erythema, which resolved over the long term in most instances. CONCLUSIONS: The VSLS system emerges as a safe and effective treatment for pigmented lesions, including refractory solar lentigines. Nonetheless, additional studies are required to verify its long-term efficacy.

First Trial of a Novel Caseous Lymphadenitis Inactivated Vaccine in South Korea: Experimental Evaluation across Various Animal Models.

Caseous lymphadenitis (CLA) is a chronic and subclinical bacterial disease of ruminants caused by Corynebacterium pseudotuberculosis (C. pseudotuberculosis) infection. Until 2014, there were no reports of CLA outbreaks in South Korea; however, the prevalence of CLA cases has steadily increased. In this study, we used recently obtained field isolates to develop the first inactivated CLA vaccine in South Korea and evaluated it in various animal models. The inactivated vaccine was evaluated for virulence and effectiveness. Mice were tested for virulence and immunization challenges, and guinea pigs and Korean Native Black Goats (KNBGs) evaluated various vaccine concentrations to determine the optimal dose and effectiveness. In the case of KNBGs, clinical symptoms were not observed after vaccination. In addition, CLA-specific IgG was detected at a significantly (p < 0.05) high level and was maintained. In histopathological evaluations, inflammation was predominantly observed in the prefemoral lymph nodes in the non-vaccinated+CHAL group. The genetic diversity of C. pseudotuberculosis, which has become widespread in South Korea, is less than 0.5% our vaccine is expected to prevent infection by a wide range of strains effectively. In summary, our CLA vaccine can potentially prevent CLA and foster the growth of South Korea's domestic KNBG industry.

Fermented Fish Collagen Attenuates Melanogenesis via Decreasing UV-Induced Oxidative Stress.

Excessive melanogenesis leads to hyperpigmentation-related cosmetic problems. UV exposure increases oxidative stress, which promotes melanogenesis-related signal pathways such as the PKA, microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein-1 (TRP1), and tyrosinase-related protein-2 (TRP2) pathways. Glycine is a source of endogenous antioxidants, including glutathione. Fermented fish collagen (FC) contains glycine; thus, we evaluated the effect of FC on decreasing melanogenesis via decreasing oxidative stress. The glycine receptor (GlyR) and glycine transporter-1 (GlyT1) levels were decreased in UV-irradiated keratinocytes; however, the expression levels of these proteins increased upon treatment with FC. The FC decreased oxidative stress, as indicated by the decreasing expression of NOX1/2/4, increased expression of GSH/GSSG, increased SOD activity, and decreased 8-OHdG expression in UV-irradiated keratinocytes. Administration of conditioned media from FC-treated keratinocytes to melanocytes led to decreased p38, PKC, MITF, TRP1, and TRP2 expression. These changes induced by the FC were also observed in UV-irradiated animal skin. FC treatment increased the expression of GlyR and GlyT, which was accompanied by decreased oxidative stress in the UV-irradiated skin. Moreover, the FC negatively regulated the melanogenesis signaling pathways, leading to decreased melanin content in the UV-irradiated skin. In conclusion, FC decreased UV-induced oxidative stress and melanogenesis in melanocytes and animal skin. FC could be used in the treatment of UV-induced hyperpigmentation problems.

Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer.

BACKGROUND: Increased cancer stem cell (CSC) content and SOX2 overexpression are common features in the development of resistance to therapy in hormone-dependent breast cancer, which remains an important clinical challenge. SOX2 has potential as biomarker of resistance to treatment and as therapeutic target, but targeting transcription factors is also challenging. Here, we examine the potential inhibitory effect of different polyoxometalate (POM) derivatives on SOX2 transcription factor in tamoxifen-resistant breast cancer cells. METHODS: Various POM derivatives were synthesised and characterised by infrared spectra, powder X-ray diffraction pattern and nuclear magnetic resonance spectroscopy. Estrogen receptor (ER) positive breast cancer cells, and their counterparts, which have developed resistance to the hormone therapy tamoxifen, were treated with POMs and their consequences assessed by gel retardation and chromatin immunoprecipitation to determine SOX2 binding to DNA. Effects on proliferation, migration, invasion and tumorigenicity were monitored and quantified using microscopy, clone formation, transwell, wound healing assays, flow cytometry and in vivo chick chorioallantoic membrane (CAM) models. Generation of lentiviral stable gene silencing and gene knock-out using CRISPR-Cas9 genome editing were applied to validate the inhibitory effects of the selected POM. Cancer stem cell subpopulations were quantified by mammosphere formation assays, ALDEFLUOR activity and CD44/CD24 stainings. Flow cytometry and western blotting were used to measure reactive oxygen species (ROS) and apoptosis. RESULTS: POMs blocked in vitro binding activity of endogenous SOX2. [P2W18O62]6- (PW) Wells-Dawson-type anion was the most effective at inhibiting proliferation in various cell line models of tamoxifen resistance. 10 µM PW also reduced cancer cell migration and invasion, as well as SNAI2 expression levels. Treatment of tamoxifen-resistant cells with PW impaired tumour formation by reducing CSC content, in a SOX2-dependent manner, which led to stem cell depletion in vivo. Mechanistically, PW induced formation of reactive oxygen species (ROS) and inhibited Bcl-2, leading to the death of tamoxifen-resistant cells. PW-treated tamoxifen-resistant cells showed restored sensitivity to tamoxifen. CONCLUSIONS: Together, these observations highlight the potential use of PW as a SOX2 inhibitor and the therapeutic relevance of targeting SOX2 to treat tamoxifen-resistant breast cancer.

Enhancing Growth and Health in Weanling Pigs: The Impact of Monzogranite Supplementation.

Monzogranite is known for its high surface area and cation exchange capacity, which play a crucial role in ameliorating the challenges by enhancing nutrient adsorption and facilitating nutrient availability during the weaning period. Weaned crossbred piglets (Duroc × Yorkshire × Landrace), initially weighing 5.36 ± 0.26 kg, were allocated into four treatments with 6 replicates each (10 pigs per replicate). The treatments encompassed CON (basal diet), Z0.1 (0.1% monzogranite supplementation in basal diet), Z0.2 (0.2% monzogranite supplementation), and Z0.3 (0.3% monzogranite supplementation). In phase 1, a linear increase in total average daily gain (ADG) was observed across treatment groups, with a concomitant linear increase in ADG and gain-to-feed ratio (G/F). The overall results showed a linear increase in ADG and G/F. A linear decrease in aspartate aminotransferase and lactate dehydrogenase levels was observed across treatment groups. Conversely, no significant differences were noted in the levels of albumin, alkaline phosphatase, alanine aminotransferase, high-density lipoprotein, low-density lipoprotein, total cholesterol, blood urea nitrogen, triglycerides, and gamma-glutamyl transferase among the treatment groups. Faecal scoring indicated a linear reduction in scores at Day 7 among the treatment groups. However, no significant differences were observed at Days 14 and 28. The assessment of immunoglobulins demonstrated a significant increase in both immunoglobulin G and immunoglobulin A levels in the Z0.1 treatment group compared to the CON. In both phase 1 and phase 2, a linear decrease in cortisol levels was evident. In conclusion, a linear increase in total ADG and G/F during phase 1, sustained across both phases, suggests monzogranite potential to enhance growth performance. Moreover, stress mitigation was shown through a consistent linear decrease in cortisol levels across phases. These findings underscore monzogranite multifaceted impact, emphasizing its potential as a dietary supplement to enhance growth, liver health, and stress resilience in weanling pigs.

Pogostemon cablin Extract Promotes Wound Healing through OR2AT4 Activation and Exhibits Anti-Inflammatory Activity.

Skin healing occurs through an intricate process called wound healing which comprises four phases: coagulation and hemostasis, inflammation, cellular proliferation, and remodeling. Chronic wounds often arise because of prolonged or excessive inflammation, which hinders the healing process and wound closure. Despite the recognized efficacy of Pogostemon cablin (patchouli) in wound healing, the precise mechanism of action of Pogostemon cablin extract (PCE) on inflammation and wound healing remains poorly understood. In this study, we investigated the effects of PCE on cell proliferation and wound healing, as well as its anti-inflammatory activity, using in vitro experiments. We found that PCE increased cell proliferation and expression of the cell proliferation marker Ki67 and accelerated wound healing in human keratinocytes through the activation of OR2AT4. Furthermore, PCE exhibited anti-inflammatory effects by decreasing the levels of pro-inflammatory cytokines interleukin-6 and -8 in lipopolysaccharide-treated and TNF-α-exposed THP-1 and HaCaT cells, respectively. Overall, these findings suggest that PCE holds therapeutic potential by promoting cell proliferation, facilitating wound healing, and exerting anti-inflammatory effects.

Characterization of high-affinity antibodies against the surface Gc protein of Dabie bandavirus / severe fever with thrombocytopenia syndrome virus.

Severe fever with thrombocytopenia syndrome virus (SFTSV) or Dabie bandavirus is an emerging pathogen responsible for SFTS. It is considered a novel threat to human health, given the high associated fatality. SFTSV is a segmented negative-strand RNA virus containing three single-stranded RNAs, with the M segment encoding the glycoproteins Gn and Gc. Gc is vital for viral entry into the host cell surface, along with the Gn protein. As the Gc is the surface-exposable antigen from virions, it is a critical diagnostic marker of infection. Although various SFTSV Gn or N protein-based sero-diagnostic methods have been developed, there are no commercially available sero-diagnostic kits. Therefore, we generated monoclonal antibodies (mAbs) against SFTSV Gc and explored their application in serum diagnostic tests to develop sensitive serodiagnostic tools covering broad-range genotypes (A to F). First, 10 SFTSV Gc antibody-binding fragments (Fabs) were isolated using a phage display system and converted into human IgGs. Enzyme-linked immunosorbent assays (ELISA) of the SFTSV and Rift Valley fever virus (RVFV: same genus as SFTSV) Gc antigens showed that all antibodies attached to the SFTSV Gc protein had high affinity. An immunofluorescence assay (IFA), to verify the cross-reactivity of seven antibodies with high affinities for various SFTSV genotypes (A, B2, B3, D, and F) and detect mAb binding with intact Gc proteins, revealed that five IgG type mAbs were bound to intact Gc proteins of various genotypes. Six high-affinity antibodies were selected using ELISA and IFA. The binding capacity of the six antibodies against the SFTSV Gc antigen was measured using surface plasmon resonance. All antibodies had high binding capacity. Consequently, these antibodies serve as valuable markers in the serological diagnosis of SFTSV.

The Mental Health Outcomes and Cost Estimates of Korean Medicine for Anxiety Disorder Patients.

Korean medicine (KM) is used to treat anxiety disorders, but there is limited research on its effects. This study aimed to examine the associations between improved QoL and reduced clinical symptoms and KM in patients with anxiety disorders. The medical records of patients with anxiety who were treated with KM (acupuncture, psychotherapy, Chuna therapy, aromatherapy, or herbal medicine) for at least 4 weeks were retrospectively analyzed. Clinical, QoL, and cost outcomes were measured at baseline and at weeks 4 and 12 (Anxiety: State-Trait Anxiety Inventory [STAI X-1 (state), X-2 (trait)], Beck Anxiety Inventory [BAI]; anger: State-Trait Anger Expression Inventory State [STAXI-S (state), T (trait)], Anger Expression Inventory [AXI-K-I (anger-in), AXI-K-O (anger-out), AXI-K-C (anger-control); depression: Beck Depression Inventory-II [BDI II], QoL: QoL-related instruments Euro Quality of Life 5 Dimensions utility score [EQ-5D], Euro QoL Visual Analog Scale [EQ-VAS]). The total costs for each item were calculated in terms of NHIS-covered costs and patients' out-of-pocket costs from the perspective of the healthcare system. The medical records of 67 patients were evaluated. The KM treatments were found to be associated with decreased anxiety (STAI X-1; STAI X-2; BAI, p < 0.0001), depression (BDI-II, p < 0.0001), and anger (AKI-K-I; AKI-K-O, p < 0.05) and increased QoL (EQ-5D; EQ-VAS, p < 0.0001). An average of USD 1360 was paid for the KM treatments for 4 weeks. The study findings suggested that KM may improve clinical symptoms and QoL outcomes in patients with anxiety disorders.

Socioeconomic status and cardiovascular mortality in over 170,000 cancer survivors.

AIMS: Cardiovascular health is acknowledged as a crucial concern among cancer survivors. Socioeconomic status (SES) is an essential but often neglected risk factor for cardiovascular disease (CVD). We conducted this study to identify the relationship between SES and CVD mortality in cancer survivors. METHODS AND RESULTS: Using the National Health Insurance Service-National Health Examinee database, we identified cancer survivors diagnosed and surviving beyond 5 years post-diagnosis. SES was assessed based on insurance premiums and classified into 5 groups. The primary outcome was overall CVD mortality. This study analyzed 170 555 individuals (mean age 60.7 ± 11.9 years, 57.8% female). A gradual increase in risk was observed across SES groups: adjusted hazard ratios (95% confidence intervals) for overall CVD mortality were 1.15 (1.04-1.26), 1.28 (1.15-1.44), 1.31 (1.18-1.46), and 2.13 (1.30-3.49) for the second, third, and fourth quartile, and medical aid group (the lowest SES group) compared to the highest SES group, respectively (p for trend < 0.001). The lowest SES group with hypertension exhibited a 3.4-fold higher risk of CVD mortality compared to the highest SES group without hypertension. Interaction analyses revealed that low SES synergistically interacts with hypertension, heightening the risk of CVD mortality (synergy index 1.62). CONCLUSION: This study demonstrates a significant correlation between low SES and increased CVD mortality among cancer survivors. Particularly, the lowest SES group, when combined with hypertension, significantly escalates CVD mortality. Our findings underscore the critical importance of recognizing SES as a significant risk factor for CVD mortality in this population of cancer survivors.

Our population-based cohort study, involving over 170 000 cancer survivors, demonstrates a significant association between socioeconomic status (SES) and cardiovascular disease (CVD) mortality.

Can Older Adult Patients with Hip Fractures Have Their Discharge Destination Predicted by Physical Performance Measures?

Background and Objectives: The majority of patients who undergo hip fracture surgery do not recover their former level of physical function; hence, it is essential to establish a specific rehabilitation strategy for maximal functional recovery of patients after a hip fracture. Knowing which indicators of physical function in hip fracture patients have a significant impact on the decision regarding the place or timing of discharge would make it possible to plan and prepare for discharge as soon as possible. Therefore, this study aimed to investigate the relationship between physical function and discharge destination for older adult patients with hip fracture. Materials and Methods: In this retrospective cohort study, 150 hip fracture patients (mean age 78.9 ± 10.6 years) between January 2019 and June 2021 were enrolled. Patients were categorized into two groups according to their discharge destination, either home or facility. Demographic and disease-related characteristic data were collected from the medical records. All the patients completed performance-based physical function tests including the 10 Meter Walk Test (10MWT), Timed Up and Go test (TUG), Koval's grade, and Berg Balance Scale (BBS) at the start of rehabilitation and at discharge. A backward stepwise binary logistic regression analysis was then performed to determine the independent factors of the discharge destination. Results: The home discharge group had a significantly lower Koval's grade, lower TUG, higher BBS both at baseline and discharge, and younger age. Backward stepwise logistic binary regression analysis showed that TUG, BBS, and 10MWT at baseline and discharge were significant variables affecting the discharge destination after hip fracture. Conclusions: These results demonstrate that balance and gait in older adult patients with hip fractures are highly influential factors in the determining the discharge destination.

Lactococcus lactis KF140 Ameliorates Nonalcoholic Fatty Liver Disease Induced by Nε-Carboxymethyl-Lysine and High-Fat Diet.

SCOPE: Long-term consumption of excessive dietary advanced glycation end-products such as Nε-carboxymethyl-lysine (CML), which are produced by the Maillard reaction during food thermal processing, leads to nonalcoholic fatty liver disease (NAFLD) along with high fat consumption. The study previously finds that administration of Lactococcus lactis KF140 (LL-KF140) detoxifies CML by decreasing CML absorption both in a rat model and clinical trial. METHODS AND RESULTS: The present study evaluates the ameliorative effect of LL-KF140 on NAFLD and fatty liver-related biomarkers in a mouse model induced by CML and high fat. LL-KF140 is orally administered to mice at a concentration of 1 × 107 or 1 × 108 colony-forming unit (CFU) per mouse for 8 weeks. LL-KF140 administration ameliorates the NAFLD-related symptoms by reducing body weight and fat mass gain along with levels of serum aspartate transaminase, alanine transferase, and lipids as well as glucose intolerance and insulin resistance in CML-treated mice. In addition, histological analysis including staining and western blotting shows that LL-KF140 suppresses the lipogenesis pathway and CML absorption, thereby suppressing CML-induced NAFLD. CONCLUSION: These findings suggest that LL-KF140 attenuates dietary CML-induced NAFLD by suppressing the de novo lipogenesis pathway, and it may be used as a probiotic strain.

Piezo1 Activation Drives Enhanced Collagen Synthesis in Aged Animal Skin Induced by Poly L-Lactic Acid Fillers.

Poly L-lactic acid (PLLA) fillers stimulate collagen synthesis by activating various immune cells and fibroblasts. Piezo1, an ion channel, responds to mechanical stimuli, including changes in extracellular matrix stiffness, by mediating Ca2+ influx. Given that elevated intracellular Ca2+ levels trigger signaling pathways associated with fibroblast proliferation, Piezo1 is a pivotal regulator of collagen synthesis and tissue fibrosis. The aim of the present study was to investigate the impact of PLLA on dermal collagen synthesis by activating Piezo1 in both an H2O2-induced cellular senescence model in vitro and aged animal skin in vivo. PLLA elevated intracellular Ca2+ levels in senescent fibroblasts, which was attenuated by the Piezo1 inhibitor GsMTx4. Furthermore, PLLA treatment increased the expression of phosphorylated ERK1/2 to total ERK1/2 (pERK1/2/ERK1/2) and phosphorylated AKT to total AKT (pAKT/AKT), indicating enhanced pathway activation. This was accompanied by upregulation of cell cycle-regulating proteins (CDK4 and cyclin D1), promoting the proliferation of senescent fibroblasts. Additionally, PLLA promoted the expression of phosphorylated mTOR/S6K1/4EBP1, TGF-ß, and Collagen I/III in senescent fibroblasts, with GsMTx4 treatment mitigating these effects. In aged skin, PLLA treatment similarly upregulated the expression of pERK1/2/ERK1/2, pAKT/AKT, CDK4, cyclin D1, mTOR/S6K1/4EBP1, TGF-ß, and Collagen I/III. In summary, our findings suggest Piezo1's involvement in PLLA-induced collagen synthesis, mediated by heightened activation of cell proliferation signaling pathways such as pERK1/2/ERK1/2, pAKT/AKT, and phosphorylated mTOR/S6K1/4EBP1, underscoring the therapeutic potential of PLLA in tissue regeneration.

Association between Height and Functional Outcomes of Patients 6 Months after a Stroke: A Multicenter Prospective Observational Cohort Study.

Many physical factors influence post-stroke functional outcomes. However, few studies have examined the influence of height on these outcomes. Here, data from the Korean Stroke Cohort for Functioning and Rehabilitation were used and patients' height was categorized into three groups: short (lower 25%), middle (middle 50%), and tall (upper 25%). Differences in the modified Rankin scale (mRS), functional ambulatory category (FAC), and Korean-translated version of the Modified Barthel Index (K-MBI) scores were analyzed for each group at 6 months post-stroke. A subgroup analysis was conducted based on the initial Fugl-Meyer Assessment (FMA) score. We analyzed functional outcomes in 5296 patients at 6 months post-stroke, adjusting for age and body mass index. The short-height group exhibited higher mRS scores (1.88 ± 0.043), lower FAC scores (3.74 ± 0.045), and lower K-MBI scores (82.83 ± 0.748) than the other height groups (p < 0.05). In the subgroup analysis, except for the very severe FMA group, the short-height group also exhibited worse outcomes in terms of mRS, FAC, and K-MBI scores (p < 0.05). Taken together, the short-height group exhibited worse outcomes related to disability, gait function, and ADLs at 6 months post-stroke.

Analysis of particulate matter-induced alteration of genes and related signaling pathways in the respiratory system.

Airborne particulate matter (PM) is a global environmental risk factor threatening human health and is a major cause of cardiovascular and respiratory disease-associated death. Current studies on PM exposure have been limited to large-scale cohort and epidemiological investigations, emphasizing the need for detailed individual-level studies to uncover specific differentially expressed genes and their associated signaling mechanisms. Herein, we revealed that PM exposure significantly upregulated inflammatory and immune responses, such as cytokine-mediated signaling pathways, complement system, and the activation and migration of immune cells in gene set enrichment analysis of our RNA sequencing (RNAseq) data. Remarkably, we discovered that the broad gene expression and signaling pathways mediated by macrophages were predominantly expressed in the respiratory system following PM exposure. Consistent with these observations, individual PMs, classified by aerodynamic size and origin, significantly promoted macrophage recruitment to the lungs in the mouse lung inflammation model. Additionally, we confirmed that RNAseq observations from the respiratory system were reproduced in murine bone marrow-derived macrophages and the alveolar macrophage cell line MH-S after individual PM exposure. Our findings demonstrated that PM exposure augmented broad inflammatory and immune responses in the respiratory system and suggested the reinforcement of global strategies for reducing particulate air pollution to prevent respiratory diseases and their exacerbation.

Pediococcus pentosaceus KF159 alleviates house dust mite-induced atopic dermatitis by promoting IL10 production and regulatory T cell induction.

Atopic dermatitis (AD) is a chronic immune disease that requires long-term management owing to its relative ease of recurrence. However, steroid treatment is limited owing to the side effects. Therefore, research on therapeutics with proven safety is required. Here, we evaluated the anti-allergic activity of the probiotic strain Pediococcus pentosaceus KF159 (PPKF159) with an ex vivo mouse model sensitized with ovalbumin (OVA) and a mouse model of AD induced by house dust mites. Changes in pathological symptoms were confirmed based on the clinical status of the AD-induced lesion site and the levels of T helper type 2 (Th2)-derived cytokines and immunoglobulin E (IgE). In addition, cell-mediated responses and related mechanisms were elucidated using various kinds of primary cells including splenocytes, mesenteric lymph nodes, Peyer's patch, and bone marrow-derived dendritic cells (BMDCs) in vitro and ex vivo. Oral administration of PPKF159 alleviated AD-like clinical symptoms such as erythema, edema, hemorrhage, and increased tissue thickness, and suppressed the production of Th2-associated cytokines and serum IgE while increasing T helper type 1 (Th1)-mediated cytokine production. PPKF159 induced tolerogenic dendritic cells (tol-DCs) by increasing the expression of ICOS-L, PD-L1, and IDO which were closely related to Treg induction in PPKF159-treated BMDCs. In addition, BMDCs and naive T cells co-cultured in the presence of PPKF159 had elevated IL10 production and increased proportions of CD4+CD25+Foxp3+ Tregs compared to the absence of PPKF159. This study showed that PPKF159 relieved AD-like clinical symptoms, modulated the Th1/Th2 immune balance, and inhibited IgE production in a mouse AD model. PPKF159 induced the transformation of dendritic cells into tolerogenic versions. These induced tol-DCs directly enhanced the production of IL10 or improved the secretion of IL10 through the induction of CD4+CD25+Foxp3+ Treg cells, thereby improving AD. These results suggest that PPKF159 can be applied as a functional food material for the treatment and prevention of AD.

Effect of Heat-Treated Lactiplantibacillus plantarum nF1 on the Immune System Including Natural Killer Cell Activity: A Randomized, Placebo-Controlled, Double-Blind Study.

Heat-treated Lactiplantibacillus plantarum nF1 (HT-nF1) increases immune cell activation and the production of various immunomodulators (e.g., interleukin (IL)-12) as well as immunoglobulin (Ig) G, which plays an important role in humoral immunity, and IgA, which activates mucosal immunity. To determine the effect of HT-nF1 intake on improving immune function, a randomized, double-blind, placebo-controlled study was conducted on 100 subjects with normal white blood cell counts. The HT-nF1 group was administered capsules containing 5 × 1011 cells of HT-nF1 once a day for 8 weeks. After 8 weeks of HT-nF1 intake, significant changes in IL-12 were observed in the HT-nF1 group (p = 0.045). In particular, the change in natural killer (NK) cell activity significantly increased in subjects with low secretory (s) IgA (≤49.61 µg/mL) and low NK activity (E:T = 10:1) (≤3.59%). These results suggest that HT-nF1 has no safety issues and improves the innate immune function by regulating T helper (Th)1-related immune factors. Therefore, we confirmed that HT-nF1 not only has a positive effect on regulating the body's immunity, but it is also a safe material for the human body, which confirms its potential as a functional health food ingredient.

Understanding the Korean Dialysis Cohort for Mineral, Vascular Calcification, and Fracture (ORCHESTRA) Study: Design, Method, and Baseline Characteristics.

INTRODUCTION: End-stage renal disease (ESRD) is a growing disease worldwide, including Korea. This is an important condition that affects patient outcome. To provide optimal management for mineral disturbance, vascular calcification, and bone disease in ESRD patients, the Korean dialysis cohort for mineral, vascular calcification, and fracture (ORCHESTRA) study was conducted by enrolling Korean dialysis patients. METHODS: Sixteen university-affiliated hospitals and one Veterans' Health Service Medical Center participated in this study. This prospective cohort study enrolled approximately 900 consecutive patients on dialysis between May 2019 and January 2021. Enrolled subjects were evaluated at baseline for demographic information, laboratory tests, radiologic imaging, and bone mineral densitometry (BMD) scans. After enrollment, regular assessments of the patients were performed, and their biospecimens were collected according to the study protocol. The primary outcomes were the occurrence of major adverse cardiovascular events, invasive treatment for peripheral artery disease, and osteoporotic fractures. The secondary outcomes were hospitalization for cerebrovascular disease or progression of abdominal aortic calcification. Participants will be assessed for up to 3 years to determine whether primary or secondary outcomes occur. RESULTS: Between May 2019 and January 2021, all participating centers recruited 900 consecutive dialysis patients, including 786 undergoing hemodialysis (HD) and 114 undergoing peritoneal dialysis (PD). The mean age of the subjects was 60.4 ± 12.3 years. Males accounted for 57.7% of the total population. The mean dialysis vintage was 6.1 ± 6.0 years. The HD group was significantly older, had a longer dialysis vintage, and more comorbidities. Overall, the severity of vascular calcification was higher and the level of BMD was lower in the HD group than in the PD group. CONCLUSION: This nationwide, multicenter, prospective cohort study focused on chronic kidney disease-mineral and bone disorder and aimed to provide clinical evidence to establish optimal treatment guidelines for Asian dialysis patients.