Recent advances and future perspectives in the therapeutics of prostate cancer.

Prostate cancer (PC) is one of the most common cancers in males and the fifth leading reason of death. Age, ethnicity, family history, and genetic defects are major factors that determine the aggressiveness and lethality of PC. The African population is at the highest risk of developing high-grade PC. It can be challenging to distinguish between low-risk and high-risk patients due to the slow progression of PC. Prostate-specific antigen (PSA) is a revolutionary discovery for the identification of PC. However, it has led to an increase in over diagnosis and over treatment of PC in the past few decades. Even if modifications are made to the standard PSA testing, the specificity has not been found to be significant. Our understanding of PC genetics and proteomics has improved due to advances in different fields. New serum, urine, and tissue biomarkers, such as PC antigen 3 (PCA3), have led to various new diagnostic tests, such as the prostate health index, 4K score, and PCA3. These tests significantly reduce the number of unnecessary and repeat biopsies performed. Chemotherapy, radiotherapy, and prostatectomy are standard treatment options. However, newer novel hormone therapy drugs with a better response have been identified. Androgen deprivation and hormonal therapy are evolving as new and better options for managing hormone-sensitive and castration-resistant PC. This review aimed to highlight and discuss epidemiology, various risk factors, and developments in PC diagnosis and treatment regimens.

Multicomponent-Loaded Vesosomal Drug Carrier for Controlled and Sustained Compound Release.

Liposomes have been extensively adopted in drug delivery systems with clinically approved formulations. However, hurdles remain in terms of loading multiple components and precisely controlling their release. Herein, we report a vesosomal carrier composed of liposomes encapsulated inside the core of another liposome for the controlled and sustained release of multiple contents. The inner liposomes are made of lipids with different compositions and are co-encapsulated with a photosensitizer. Upon induction of reactive oxygen species (ROS), the contents of the liposomes are released, with each type of liposome displaying distinct kinetics due to the variance in lipid peroxidation for differential structural deformation. In vitro experiments demonstrated immediate content release from ROS-vulnerable liposomes, followed by sustained release from ROS-nonvulnerable liposomes. Moreover, the release trigger was validated at the organismal level using Caenorhabditis elegans. This study demonstrates a promising platform for more precisely controlling the release of multiple components.

Redirection of CAR-T Cell Cytotoxicity Using Metabolic Glycan Labeling with Unnatural Sugars.

T cells expressing chimeric antigen receptors (CAR-T cells) have shown unprecedented clinical responses against hematological malignancies. However, some patients relapse after CAR-T cell therapy due to antigen-negative escape variants. Additionally, CAR-T cell therapies showed limited clinical efficacy in solid tumors with high antigen heterogeneity. To overcome this, we metabolically labeled the glycans on cancer cells to redirect CAR-T cell cytotoxicity regardless of the endogenous antigen expression status of the cancer cells. We found that modifying cancer cells with N-azidoacetylmannosamine and bicyclo[6.1.0]non-4-yne-fluorescein isothiocyanate can elicit selective and durable cytotoxicity of anti-FITC CAR-T cells. Furthermore, we demonstrated that dinitrophenyl-conjugated sialic acid (Sia-DNP) generated DNP-modified glycans on cancer cells in situ that could be effectively targeted by anti-DNP CAR-T cells to eradicate established tumors in xenograft models. Our study illustrates that metabolic glycan labeling using unnatural sugars can be combined with CAR-T cell therapy to provide novel cancer immunotherapy for solid tumors that lack viable target antigens.

Therapeutic targeting of the tumor microenvironments with cannabinoids and their analogs: Update on clinical trials.

Cancer is a major global public health concern that affects both industrialized and developing nations. Current cancer chemotherapeutic options are limited by side effects, but plant-derived alternatives and their derivatives offer the possibilities of enhanced treatment response and reduced side effects. A plethora of recently published articles have focused on treatments based on cannabinoids and cannabinoid analogs and reported that they positively affect healthy cell growth and reverse cancer-related abnormalities by targeting aberrant tumor microenvironments (TMEs), lowering tumorigenesis, preventing metastasis, and/or boosting the effectiveness of chemotherapy and radiotherapy. Furthermore, TME modulating systems are receiving much interest in the cancer immunotherapy field because it has been shown that TMEs have significant impacts on tumor progression, angiogenesis, invasion, migration, epithelial to mesenchymal transition, metastasis and development of drug resistance. Here, we have reviewed the effective role of cannabinoids, their analogs and cannabinoid nano formulations on the cellular components of TME (endothelial cells, pericytes, fibroblast and immune cells) and how efficiently it retards the progression of carcinogenesis is discussed. The article summarizes the existing research on the molecular mechanisms of cannabinoids regulation of the TME and finally highlights the human studies on cannabinoids' active interventional clinical trials. The conclusion outlines the need for future research involving clinical trials of cannabinoids to demonstrate their efficacy and activity as a treatment/prevention for various types of human malignancies.

Antioxidant and antiproliferative activity of Basella alba against colorectal cancer.

Basella alba, a green leafy vegetable with remarkable nutraceutical potential is widely used since ancient times to maintain a healthy colon. This plant has been investigated for its medicinal potential due to the increase in young adult cases of colorectal cancer each year. This study was accomplished to investigate Basella alba methanolic extract (BaME) antioxidant and anticancer properties. BaME consisted of a substantial amount of both phenolic and flavonoid compounds which exhibited significant antioxidant reactivity. Both colon cancer cell lines experienced a cell cycle arrest at the G0/G1 phase after receiving treatment with BaME, which inhibited pRb and cyclin D1 and raised p21 expression levels. This was associated with the survival pathway molecule inhibition and downregulation of E2F-1. The results of the current investigation confirm that BaME inhibits CRC cell survival and expansion. To conclude, the bioactive principles in the extract act as potential antioxidants and antiproliferative agents against colorectal cancer.

Red clover (Trifolium pratense L.) extract inhibits ferroptotic cell death by modulating cellular iron homeostasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Red clover (Trifolium pratense L.) is a traditional Chinese medicine and use as herbal medicine which has the effects of regulating menopausal symptoms, heart problem, inflammatory disease, psoriasis and cognitive deficits. In previous reported, the studies of red clover were mainly focused on clinical practice. the pharmacological functions of red clover not fully elucidated. AIM OF THE STUDY: To identify the molecules that regulate ferroptosis, we examined whether red clover (Trifolium pratense L.) extracts (RCE) affected ferroptosis induced by chemical treatment or cystine/glutamate antiporter (xCT) deficiency. MATERIALS AND METHODS: Cellular models for ferroptosis were induced by erastin/Ras-selectiv lethal 3 (RSL3) treatment or xCT deficiency in mouse embryonic fibroblasts (MEFs). Intracellular iron and peroxidized lipid levels were determined using Calcein-AM and BODIPY-C11 fluorescence dyes, respectively. Protein and mRNA were quantified by Western blot and real-time polymerase chain reaction, respectively. RNA sequencing analysis was performed on xCT-/- MEFs. RESULTS: RCE significantly suppressed ferroptosis induced by both erastin/RSL3 treatment and xCT deficiency. The anti-ferroptotic effects of RCE correlated to ferroptotic phenotypic changes such as cellular iron accumulation and lipid peroxidation in cellular ferroptosis models. Importantly, RCE affected levels of iron metabolism-related proteins including iron regulatory protein 1, ferroportin 1 (FPN1), divalent metal transporter 1, and transferrin receptor. RNA sequencing analysis of xCT-/- MEFs identified that expression of cellular defense genes was upregulated, while expression of cell death-related genes was downregulated, by RCE. CONCLUSION: RCE potently suppressed ferroptosis triggered both by erastin/RSL3 treatment and xCT deficiency by modulating cellular iron homeostasis. This is the first report that RCE has therapeutic potential in diseases associated with ferroptotic cell death, particularly ferroptosis induced by dysregulation of cellular iron metabolism.

Zinc finger protein 251 deficiency impairs glucose metabolism by inducing adipocyte hypertrophy.

Zinc finger protein (ZFP) 251 is a member of the C2H2 ZFP family containing a Krüppel-associated box domain that might mainly act as a transcriptional repressor. However, its cellular function remains largely unknown. Here, we discovered that ZFP251 deficiency caused glucose intolerance in mice. This phenotype was associated with impaired insulin signaling due to hypertrophic changes in white adipose tissue (WAT). Gene ontology analysis revealed that ZFP251 deficiency affected the expression of genes associated with adipocyte differentiation and lipid and fatty acid metabolism. Consistent with in vivo results, hypertrophic changes were observed in Zfp251 knockdown (KD) 3T3-L1 adipocytes. In addition, Zfp251 KD 3T3-L1 preadipocytes exhibited cell cycle arrest in G0/G1 phase, leading to impaired differentiation into mature adipocytes, upon which abnormal mitotic clonal expansion and reduced expression of adipogenic markers were exhibited. These results suggest that ZFP251 deficiency causes impaired adipogenesis and adipocyte hypertrophy, leading to dysfunction of WAT.

Highly Specific Peptide-Mediated Cuvette-Form Localized Surface Plasmon Resonance (LSPR)-Based Fipronil Detection in Egg.

Herein, we have developed peptide-coated gold nanoparticles (AuNPs) based on localized surface plasmon resonance (LSPR) sensor chips that can detect fipronil with high sensitivity and selectivity. The phage display technique has been exploited for the screening of highly specific fipronil-binding peptides for the selective detection of the molecule. LSPR sensor chips are fabricated initially by attaching uniformly synthesized AuNPs on the glass substrate, followed by the addition of screened peptides. The parameters, such as the peptide concentration of 20 µg mL-1 and the reaction time of 30 min, are further optimized to maximize the efficacy of the fabricated LSPR sensor chips. The sensing analysis is performed systematically under standard fipronil solutions and spike samples from eggs. The developed sensor has shown excellent sensitivity towards both standard solutions and spike samples with limit of detection (LOD) values of 0.01 ppb, respectively. Significantly, the developed LSPR sensor chips offer distinct features, such as a facile fabrication approach, on-site sensing, rapid analysis, cost-effectiveness, and the possibility of mass production, in which the chips can be effectively used as a promising and potential on-site detection tool for the estimation of fipronil.

PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1.

Emerging evidence shows that peroxisome proliferator-activated receptor delta (PPARδ) plays a pivotal role in cellular aging. However, its function in retinal disease processes such as hyperglycemia-associated diabetic retinopathy is unclear. Here, we demonstrate that PPARδ inhibits premature senescence of retinal pigment epithelial (RPE) cells induced by high glucose (HG) through SIRT1 upregulation. A specific ligand GW501516-activation of PPARδ suppressed premature senescence and production of reactive oxygen species induced by HG in ARPE-19 cells, a spontaneously arising human RPE cell line. These effects were accompanied by the regulation of the premature senescence-associated genes p53, p21, and SMP-30. Furthermore, GW501516-activated PPARδ almost completely abolished the effects of HG treatment on the formation of phosphorylated H2A histone family member X (γ-H2A.X) foci, a molecular marker of aging. These inhibitory effects of GW501516 were significantly reversed in ARPE-19 cells stably expressing small hairpin RNA targeting PPARδ. Notably, GW501516 significantly increased the mRNA and protein levels of SIRT1, indicating that GW501516-activated PPARδ exerted its beneficial effects through SIRT1. In addition, GW501516 restored HG-suppressed SIRT1 expression, corroborating the role of SIRT1 in the anti-senescence function of PPARδ. The effects of PPARδ on HG-induced premature senescence and the expression of the senescence-associated genes p53, p21, and SMP-30 were mimicked by the SIRT1 activator resveratrol, but blocked by the SIRT1 inhibitor sirtinol. Collectively, these results indicate that GW501516-activated PPARδ inhibits HG-triggered premature senescence of RPE cells by modulating SIRT1 signaling.

PPARδ Activation Mitigates 6-OHDA-Induced Neuronal Damage by Regulating Intracellular Iron Levels.

Intracellular iron accumulation in dopaminergic neurons contributes to neuronal cell death in progressive neurodegenerative disorders such as Parkinson's disease. However, the mechanisms of iron homeostasis in this context remain incompletely understood. In the present study, we assessed the role of the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) in cellular iron homeostasis. We identified that PPARδ inhibited 6-hydroxydopamine (6-OHDA)-triggered neurotoxicity in SH-SY5Y neuroblastoma cells. PPARδ activation with GW501516, a specific PPARδ agonist, mitigated 6-OHDA-induced neuronal damage. Further, PPARδ activation also suppressed iron accumulation, which contributes to 6-OHDA-induced neuronal damage. PPARδ activation attenuated 6-OHDA-induced neuronal damage in a similar manner to that of the iron chelator deferoxamine. We further elucidated that PPARδ modulated cellular iron homeostasis by regulating expression of divalent metal transporter 1, ferroportin 1, and ferritin, but not transferrin receptor 1, through iron regulatory protein 1 in 6-OHDA-treated cells. Interestingly, PPARδ activation suppressed 6-OHDA-triggered generation of reactive oxygen species and lipid peroxides. The effects of GW501516 were abrogated by shRNA knockdown of PPARδ, indicating that the effects of GW501516 were PPARδ-dependent. Taken together, these findings suggest that PPARδ attenuates 6-OHDA-induced neurotoxicity by preventing intracellular iron accumulation, thereby suppressing iron overload-associated generation of reactive oxygen species and lipid peroxides, key mediators of ferroptotic cell death.

Testis development in the Japanese eel is affected by photic signals through melatonin secretion.

OBJECTIVE: According to reported spawning characteristics of Japanese eel, Anguilla japonica, which exhibit spawning and migration patterns that are synchronized with lunar cycles and photoperiod, we hypothesized that a close association exists between specific photic signals (daylight, daylength, and moonlight) and endocrinological regulation. Given the photic control in melatonin secretion, this hypothesis was tested by investigating whether melatonin signals act as mediators relaying photic signals during testis development in the eel. METHODS: We examined changes in melatonin-secretion patterns using time-resolved fluorescence immunoassays in sexually immature and mature male Japanese eels under the condition of a new moon (NM) and a full moon (FM). RESULTS: The eye and plasma melatonin levels exhibited a nocturnal pattern under a 12-h light: dark cycle (12L12D) or under constant darkness (DD), but not with constant light (LL). Eye melatonin levels were similar under the 12L12D and short-day (9L15D) conditions. In the long-day condition (15L9D), secreted plasma melatonin levels were stable, whereas short-day melatonin secretion began when darkness commenced. Sexual maturation began at 8 weeks following intraperitoneal injection of human chorionic gonadotropin (hCG), and NM exposure led to significantly higher eye and plasma melatonin levels compared with those detected under FM exposure.

Peroxisome proliferator-activated receptor δ rescues xCT-deficient cells from ferroptosis by targeting peroxisomes.

Ferroptosis is a recently recognized process of cell death characterized by accumulation of iron-dependent lipid peroxides. Herein, we demonstrate that peroxisome proliferator-activated receptor δ (PPARδ) inhibits ferroptosis of mouse embryonic fibroblasts (MEFs) derived from cysteine/glutamate transporter (xCT)-knockout mice. Activation of PPARδ by the specific ligand GW501516 led to a dose-dependent decrease in ferroptotic cell death triggered by xCT deficiency, along with decreased levels of intracellular iron accumulation and lipid peroxidation. These effects of GW501516 were abolished by PPARδ-targeting small interfering RNA (siRNA) and the PPARδ inhibitor GSK0660, indicating that PPARδ inhibits xCT deficiency-induced ferroptosis. In addition, GW501516-activated PPARδ time- and dose-dependently upregulated catalase expression at both the mRNA and protein levels. This PPARδ-mediated upregulation of catalase was markedly attenuated in cells treated with PPARδ-targeting siRNA and GSK0660, indicating that expression of catalase is dependent on PPARδ. Consistently, the effects of GW501516 on ferroptosis of xCT-deficient MEFs were counteracted in the presence of 3-amino-1,2,4-triazole, a specific inhibitor of catalase, suggesting that catalase is essential for the effect of PPARδ on ferroptosis triggered by xCT deficiency. GW501516-activated PPARδ stabilized peroxisomes through catalase upregulation by targeting peroxisomal hydrogen peroxide-mediated lysosomal rupture, which led to ferroptosis of xCT-deficient MEFs. Collectively, these results demonstrate that PPARδ modulates ferroptotic signals in xCT-deficient MEFs by regulating catalase expression.

Associations of regional-level perceived stress and depression with health-related quality of life in Korean adults: a multilevel analysis of 2017 Korea Community Health Survey data.

OBJECTIVES: We examined the associations of individual and regional-level perceived stress and depression with health-related quality of life (HRQOL) in Korean adults. METHODS: We used data from the 2017 Korea Community Health Survey, which included 216,713 adults living within 254 municipal districts. As individual-level independent variables, perceived stress (higher vs. lower) and depression (Patient Health Questionnaire-9 ≥10) were defined. Regional-level age-adjusted rates of perceived stress (%) and depression (%) were created for 254 municipal districts and categorized into quartiles to generate regional levels of stress and depression. HRQOL was defined as the individual-level EuroQol 5-dimensional index×100. A multilevel analysis was performed to identify the relationship between individual or regional-level independent variables and individual HRQOL. RESULTS: In the null model, the proportions of individual variation in the HRQOL explained by region were 1.7% and 2.7% for men and women, respectively. When adjusted with all individual-level variables, regional stress and depression, as well as individual-level perceived stress and depression, were significantly related to HRQOL for both genders. In the full model including all variables, the decrease in HRQOL from the first to the fourth quartile group of regional stress was greater in women (-1.09; 95% confidence interval [CI], -1.87 to -0.31) than in men (-0.65; 95% CI, -1.04 to -0.26). CONCLUSIONS: Our results suggest that regional-level perceived stress and depression, as well as individual-level perceived stress and depression, are inversely associated with individual HRQOL.

The anti-cancerous activity of adaptogenic herb Astragalus membranaceus.

BACKGROUND: Cancer is the most dreadful disease increasing rapidly causing an economic burden globally. A standardized chemotherapy regimen planned with curative intent weakens the immune system and damages healthy cells making the patient prone to infections and severe side effects with pain and fatigue. PURPOSE: Astragalus membranaceus (AM) has a long history of use in the treatment of severe adverse diseases. For thousands of years, it has been used in mixed herbal decoctions for the treatment of cancer. Due to growing interest in this plant root for its application to treat various types of cancers and tumors, has attracted researcher's interest. METHOD: The literature search was done from core collections of electronic databases such as Web of Science, Google Scholar, PubMed and Science Direct using keywords given below and terms like pharmacological and phytochemical details of this plant. OUTCOME: Astragalus membranaceus has demonstrated the ability to modulate the immune system during drug therapy making the patient physically fit and prolonged life. It has become a buzzword of herbalists as it is one of the best of seven important adaptogenic herbs with a protective effect against chronic stress and cancer. It demonstrated significant amelioration of the perilous toxic effects induced by concurrently administered chemo onco-drugs. CONCLUSION: The natural phytoconstituents of this plant formononetin, astragalus polysaccharide, and astragalosides which show high potential anti-cancerous activity are studied and discussed in detail. One of them are used in clinical trials to overcome cancer related fatigue. Overall, this review aims to provide an insight into Astragalus membranaceus status in cancer therapy.

Catalase Mediates the Inhibitory Actions of PPARδ against Angiotensin II-Triggered Hypertrophy in H9c2 Cardiomyocytes.

Hypertrophy of myocytes has been implicated in cardiac dysfunctions affecting wall stress and patterns of gene expression. However, molecular targets potentially preventing cardiac hypertrophy have not been fully elucidated. In the present study, we demonstrate that upregulation of catalase by peroxisome proliferator-activated receptor δ (PPARδ) is involved in the anti-hypertrophic activity of PPARδ in angiotensin II (Ang II)-treated H9c2 cardiomyocytes. Activation of PPARδ by a specific ligand GW501516 significantly inhibited Ang II-induced hypertrophy and the generation of reactive oxygen species (ROS) in H9c2 cardiomyocytes. These effects of GW501516 were almost completely abolished in cells stably expressing small hairpin (sh)RNA targeting PPARδ, indicating that PPARδ mediates these effects. Significant concentration and time-dependent increases in catalase at both mRNA and protein levels were observed in GW501516-treated H9c2 cardiomyocytes. In addition, GW501516-activated PPARδ significantly enhanced catalase promoter activity and protein expression, even in the presence of Ang II. GW501516-activated PPARδ also inhibited the expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which are both marker proteins for hypertrophy. The effects of GW501516 on the expression of ANP and BNP were reversed by 3-amino-1,2,4-triazole (3-AT), a catalase inhibitor. Inhibition or downregulation of catalase by 3-AT or small interfering (si)RNA, respectively, abrogated the effects of PPARδ on Ang II-induced hypertrophy and ROS generation, indicating that these effects of PPARδ are mediated through catalase induction. Furthermore, GW501516-activated PPARδ exerted catalase-dependent inhibitory effects on Ang II-induced hypertrophy by blocking p38 mitogen-activated protein kinase. Taken together, these results indicate that the anti-hypertrophic activity of PPARδ may be achieved, at least in part, by sequestering ROS through fine-tuning the expression of catalase in cardiomyocytes.

Peroxisome proliferator-activated receptor-δ-mediated upregulation of catalase helps to reduce ultraviolet B-induced cellular injury in dermal fibroblasts.

BACKGROUND: Previous studies suggested that the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-δ plays an essential role in cellular responses against oxidative stress. OBJECTIVE: To investigate how PPAR-δ elicits cellular responses against oxidative stress in primary human dermal fibroblasts (HDFs) exposed to ultraviolet B (UVB). METHODS: The present study was undertaken in HDFs by performing real-time polymerase chain reaction, gene silencing, cytotoxicity and reporter gene assay, analyses for catalase and reactive oxygen species, and immunoblot analyses. RESULTS: The PPAR-δ activator GW501516 upregulated expression of catalase and this upregulation was attenuated by PPAR-δ-targeting siRNA. GW501516-activated PPAR-δ induced catalase promoter activity through a direct repeat 1 response element. Mutation of this response element completely abrogated transcriptional activation, indicating that this site is a novel type of PPAR-δ response element. In addition, GW501516-activated PPAR-δ counteracted the reductions in activity and expression of catalase induced by UVB irradiation. These recovery effects were significantly attenuated in the presence of PPAR-δ-targeting siRNA or the specific PPAR-δ antagonist GSK0660. GW501516-activated PPAR-δ also protected HDFs from cellular damage triggered by UVB irradiation, and this PPAR-δ-mediated reduction of cellular damage was reversed by the catalase inhibitor or catalase-targeting siRNA. These effects of catalase blockade were positively correlated with accumulation of reactive oxygen species in HDFs exposed to UVB. Furthermore, GW501516-activated PPAR-δ targeted peroxisomal hydrogen peroxide through catalase in UVB-irradiated HDFs. CONCLUSION: The gene encoding catalase is a target of PPAR-δ, and this novel catalase-mediated pathway plays a critical role in the cellular response elicited by PPAR-δ against oxidative stress.

Ginseng leaf extract ameliorates the survival of endotoxemic mice by inhibiting the release of high mobility group box 1.

High mobility group box 1 (HMGB1) is a well-defined mediator involved in the pathophysiologic response to endotoxemia and sepsis. However, the mechanisms and therapeutic agents that could prevent its release are not fully elucidated. Here, the present study demonstrates that the ginseng leaf extract (GLE) regulates lipopolysaccharide (LPS)-triggered release of HMGB1 in macrophages and endotoxemic animal model. Treatment of RAW264.7 macrophages with GLE significantly inhibited the release of HMGB1 stimulated by LPS. GLE also suppressed the generation of nitric oxide (NO) and expression of inducible NO synthase (iNOS) in a dose-dependent manner. These effects of GLE were accompanied by inhibition of HMGB1 release stimulated by LPS, indicating a potential mechanism by which GLE regulates HMGB1 release through NO signaling. Furthermore, induction of suppressor of cytokine signaling 1 by GLE-mediated GLE-dependent suppression of HMGB1 release and NO/iNOS induction by inhibiting Janus kinase 2/signal transducer and activator of transcription 1 signal in RAW 264.7 cells exposed to LPS. Finally, administration of the GLE ameliorated the survival rate of LPS-injected endotoxemic mice in a NO-dependent manner. Thus, GLE may block the LPS-stimulated release of HMGB1 by regulating cellular signal networks, thereby providing a therapeutic strategy for endotoxemia as a functional food. PRACTICAL APPLICATIONS: High mobility group box 1 (HMGB1) is released into the extracellular milieu when immune cells are exposed to pathogen-related molecules such as lipopolysaccharide (LPS), in which it acts as a critical mediator of lethality in sepsis and endotoxemia. The extract of ginseng leaf, which is a part that can be easily thrown away, ameliorated the survival rate of endotoxemic mice by inhibiting HMGB1 secretion in a NO-dependent manner. Thus, this study suggests that ginseng leaf can be used as a functional food by resolving the immune responses in the pathology of endotoxemia.

Risk Assessment of Importation and Local Transmission of COVID-19 in South Korea: Statistical Modeling Approach.

BACKGROUND: Despite recent achievements in vaccines, antiviral drugs, and medical infrastructure, the emergence of COVID-19 has posed a serious threat to humans worldwide. Most countries are well connected on a global scale, making it nearly impossible to implement perfect and prompt mitigation strategies for infectious disease outbreaks. In particular, due to the explosive growth of international travel, the complex network of human mobility enabled the rapid spread of COVID-19 globally. OBJECTIVE: South Korea was one of the earliest countries to be affected by COVID-19. In the absence of vaccines and treatments, South Korea has implemented and maintained stringent interventions, such as large-scale epidemiological investigations, rapid diagnosis, social distancing, and prompt clinical classification of severely ill patients with appropriate medical measures. In particular, South Korea has implemented effective airport screenings and quarantine measures. In this study, we aimed to assess the country-specific importation risk of COVID-19 and investigate its impact on the local transmission of COVID-19. METHODS: The country-specific importation risk of COVID-19 in South Korea was assessed. We investigated the relationships between country-specific imported cases, passenger numbers, and the severity of country-specific COVID-19 prevalence from January to October 2020. We assessed the country-specific risk by incorporating country-specific information. A renewal mathematical model was employed, considering both imported and local cases of COVID-19 in South Korea. Furthermore, we estimated the basic and effective reproduction numbers. RESULTS: The risk of importation from China was highest between January and February 2020, while that from North America (the United States and Canada) was high from April to October 2020. The R0 was estimated at 1.87 (95% CI 1.47-2.34), using the rate of α=0.07 for secondary transmission caused by imported cases. The Rt was estimated in South Korea and in both Seoul and Gyeonggi. CONCLUSIONS: A statistical model accounting for imported and locally transmitted cases was employed to estimate R0 and Rt. Our results indicated that the prompt implementation of airport screening measures (contact tracing with case isolation and quarantine) successfully reduced local transmission caused by imported cases despite passengers arriving from high-risk countries throughout the year. Moreover, various mitigation interventions, including social distancing and travel restrictions within South Korea, have been effectively implemented to reduce the spread of local cases in South Korea.

Taurine and Ginsenoside Rf Induce BDNF Expression in SH-SY5Y Cells: A Potential Role of BDNF in Corticosterone-Triggered Cellular Damage.

This study shows that taurine and ginsenoside Rf act synergistically to increase the expression of brain-derived neurotrophic factor (BDNF) in SH-SY5Y human neuroblastoma cells in a dose- and time-dependent manner. The increase of BDNF mRNA by taurine and ginsenoside Rf was markedly attenuated by inhibitors of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. In addition, taurine and ginsenoside Rf protected cells from corticosterone-induced BDNF suppression and reduced cell viability and lactate dehydrogenase release. The results from this study showed that combined treatment with both taurine and ginsenoside Rf enhanced BDNF expression and protected cells against corticosterone-induced damage.

Ring finger protein 219 regulates inflammatory responses by stabilizing sirtuin 1.

BACKGROUND AND PURPOSE: Ring finger protein 219 (RNF219), a protein containing the C3 HC4 -type RING-HC motif, has been identified as a binding partner of the histone deacetylase sirtuin 1 (SIRT1). To explore the functions of RNF219, we examined its possible roles in the cellular responses to inflammation. EXPERIMENTAL APPROACH: Effects of RNF219 on SIRT1 were studied in vitro using RAW264.7 cells and in male BALB/c mice, treated with LPS or IFN-γ. Western blots, RT-PCR, co-immunoprecipitation and ubiquitination assays were used, along with LC-MS/MS analysis. In vivo, survival and serum cytokines and tissue levels of RNF219 and SIRT1 were measured. KEY RESULTS: Binding of RNF219 to SIRT1 inhibited degradation of SIRT1 by preventing its ubiquitination, thereby prolonging SIRT1-mediated anti-inflammatory signalling. LPS caused RNF219 deacetylation, leading to instability of RNF219 and preventing its association with SIRT1. Accordingly, the acetylation status of RNF219 is a critical determinant in its interaction with SIRT1, affecting the response to inflammatory stimuli. The deacetylase inhibitor trichostatin A, increased acetylation and stability of RNF219 and survival of mice injected with LPS, through the interaction of RNF219 with SIRT1. CONCLUSION AND IMPLICATIONS: RNF219 is involved in a novel mechanism to stabilize SIRT1 protein by protein-protein interaction, leading to the resolution of cellular inflammation. These observations provide new insights into the function of RNF219 in modulation of cellular inflammation, and may aid and encourage the development of new anti-inflammatory drugs.