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Recent studies have highlighted the potential of Mesenchymal Stem Cells (MSCs) as an alternative treatment for Alopecia Areata (AA) due to their immunosuppressive properties. While MSCs have shown promise in cell experiments, their effectiveness in vivo remains uncertain. This study aims to validate local administration of MSC therapy’s efficacy in AA treatment through animal experiments. AA was induced through Interferon-gamma (IFN-γ) administration in mice, and MSC treatment (MSCT)’s effects were assessed visually and through tissue analysis. The MSC-treated group showed more hair regrowth compared to the control (CTL) group. MSCT notably reduced local inflammatory cytokines (JAK1, JAK2, STAT1, STAT3, IFN-γR, IL-1β, IL-16, IL-17α, and IL-18) in AA-induced mice’s skin, but systemic cytokine levels remained unchanged. Furthermore, MSC treatment normalized the expression of Wnt/β-catenin signaling pathway genes (LEF1 and β-catenin) and growth factors (FGF7 and FGF2), which are crucial for hair cycle regulation. This study lays the groundwork for further exploring MSCs as a potential treatment for AA, but more research is needed to fully understand their therapeutic potential.

GV1001, an anticancer vaccine, exhibits other biological functions, including anti-inflammatory and antioxidant activity. It also suppresses the development of ligature-induced periodontitis in mice. Porphyromonas gingivalis (Pg), a major human oral bacterium implicated in the development of periodontitis, is associated with various systemic disorders, such as atherosclerosis and Alzheimer’s disease (AD). This study aimed to explore the protective effects of GV1001 against Pg-induced periodontal disease, atherosclerosis, and AD-like conditions in Apolipoprotein (ApoE)-deficient mice. GV1001 effectively mitigated the development of Pg-induced periodontal disease, atherosclerosis, and AD-like conditions by counteracting Pg-induced local and systemic inflammation, partly by inhibiting the accumulation of Pg DNA aggregates, Pg lipopolysaccharides (LPS), and gingipains in the gingival tissue, arterial wall, and brain. GV1001 attenuated the development of atherosclerosis by inhibiting vascular inflammation, lipid deposition in the arterial wall, endothelial to mesenchymal cell transition (EndMT), the expression of Cluster of Differentiation 47 (CD47) from arterial smooth muscle cells, and the formation of foam cells in mice with Pg-induced periodontal disease. GV1001 also suppressed the accumulation of AD biomarkers in the brains of mice with periodontal disease. Overall, these findings suggest that GV1001 holds promise as a preventive agent in the development of atherosclerosis and AD-like conditions associated with periodontal disease.

Blackberries (Rubus fruticosus), which are known to include a variety of bioactive substances, have been extensively studied for their antioxidant properties. Blackberries possess multiple health beneficial effects, including anti-inflammation, anti-atherosclerosis, anti-tumor and immunomodulatory activity. However, the potential biological effects and precise molecular mechanisms of the fermented extracts remain largely unexplored. In this research, we demonstrate the effect of blackberries fermented with Lactobacillus for addressing obesity. We investigated the effect of blackberries fermented by Lactobacillus on mice fed a high-fat (60% kcal) diet for 12 weeks. Fermented blackberry administration reduced the body weight and epididymal fat caused by a high-fat diet compared to the obese group. The triglyceride and total cholesterol, which are blood lipid indicators, and the levels of leptin, which is an insulin resistance indicator, were significantly increased in the obese group but were significantly decreased in the fermented blackberries-treated group. Additionally, the expression of adipogenesis marker proteins, such as CEBPα, PPAR-γ and SREBP-1, was significantly increased in the obese group, whereas it was decreased in the fermented blackberries-treated group. These results suggest that fermented blackberries have a protective effect against high-fat-diet-induced obesity by inhibiting adipogenesis and are a potential candidate for the treatment of obesity.

Acute rejection (AR) is critical for long-term graft survival in kidney transplant recipients (KTRs). This study aimed to evaluate the efficacy of the integrated risk score of omics-based biomarkers in predicting AR in KTRs. This prospective, randomized, controlled, multicenter, pilot study enrolled 40 patients who recently underwent high-immunologic-risk kidney transplantation (KT). Five omics biomarkers were measured, namely, blood mRNA (three-gene signature), urinary exosomal miRNA (three-gene signature), urinary mRNA (six-gene signature), and two urinary exosomal proteins (hemopexin and tetraspanin-1) at 2 weeks and every 4 weeks after KT for 1 year. An integrated risk score was generated by summing each biomarker up. The biomarker group was informed about the integrated risk scores and used to adjust immunosuppression, but not the control group. The outcomes were graft function and frequency of graft biopsy. Sixteen patients in the biomarker group and nineteen in the control group completed the study. The mean estimated glomerular filtration rate after KT did not differ between the groups. Graft biopsy was performed in two patients (12.5%) and nine (47.4%) in the biomarker and control groups, respectively, with the proportion being significantly lower in the biomarker group (p = 0.027). One patient (6.3%) in the biomarker group and two (10.5%) in the control group were diagnosed with AR, and the AR incidence did not differ between the groups. The tacrolimus trough level was significantly lower in the biomarker group than in the control group at 1 year after KT (p = 0.006). Integrated omics biomarker monitoring may help prevent unnecessary or high-complication-risk biopsy and enables tailored immunosuppression by predicting the risk of AR in KTRs.

Side streams and byproducts of food are established sources of natural ingredients in cosmetics. In the present study, we obtained upcycled low-molecular-weight anionic peptides (LMAPs) using byproducts of the post-yuzu-juicing process by employing an enzyme derived from Bacillus sp. For the first time, we isolated anionic peptides less than 500 Da in molecular weight from Citrus junos TANAKA seeds via hydrolysis using this enzyme. The protective effect of LMAPs against UVR-induced photoaging was evaluated using a reconstructed skin tissue (RST) model and keratinocytes. The LMAPs protected the keratinocytes by scavenging intracellular reactive oxygen species and by reducing the levels of paracrine cytokines (IL-6 and TNF-α) in UVR (UVA 2 J/cm2 and UVB 15 mJ/cm2)-irradiated keratinocytes. Additionally, the increase in melanin synthesis and TRP-2 expression in RST caused by UVR was significantly inhibited by LMAP treatment. This treatment strongly induced the expression of filaggrin and laminin-5 in UVR-irradiated RST. It also increased type I collagen expression in the dermal region and in fibroblasts in vitro. These results suggest that a hydrolytic system using the enzyme derived from Bacillus sp. can be used for the commercial production of LMAPs from food byproducts and that these LMAPs can be effective ingredients for improving photoaging-induced skin diseases.

Cannabidiol (CBD) is a chemical obtained from Cannabis sativa; it has therapeutic effects on anxiety and cognition and anti-inflammatory properties. Although pharmacological applications of CBD in many types of tumors have recently been reported, the mechanism of action of CBD is not yet fully understood. In this study, we perform an mRNA-seq analysis to identify the target genes of CBD after determining the cytotoxic concentrations of CBD using an MTT assay. CBD treatment regulated the expression of genes related to DNA repair and cell division, with metallothionein (MT) family genes being identified as having highly increased expression levels induced by CBD. It was also found that the expression levels of MT family genes were decreased in colorectal cancer tissues compared to those in normal tissues, indicating that the downregulation of MT family genes might be highly associated with colorectal tumor progression. A qPCR experiment revealed that the expression levels of MT family genes were increased by CBD. Moreover, MT family genes were regulated by CBD or crude extract but not by other cannabinoids, suggesting that the expression of MT family genes was specifically induced by CBD. A synergistic effect between CBD and MT gene transfection or zinc ion treatment was found. In conclusion, MT family genes as novel target genes could synergistically increase the anticancer activity of CBD by regulating the zinc ions in human colorectal cancer cells.

Neoadjuvant chemotherapy (NAC) is widely used as a standard treatment for early-stage triple-negative breast cancer (TNBC). While patients who achieve pathologic complete response (pCR) have a highly favorable outcome, patients who do not achieve pCR have variable prognoses. It is important to identify patients who are most likely to have poor survival outcomes to identify candidates for more aggressive therapeutic approaches after NAC. Many studies have demonstrated that cytokines and growth factors packaged into extracellular vesicles (EVs) have an essential role in tumor progression and drug resistance. In this study, we examined the role of serum-derived EV-associated cytokines as prognostic biomarkers for long-term outcomes in patients who underwent anthracycline–taxane-based NAC. We isolated extracellular vesicles from the serum of 190 TNBC patients who underwent NAC between 2015 and 2018 at Samsung Medical Center. EV-associated cytokine concentrations were measured with ProcartaPlex Immune Monitoring 65-plex panels. The prognostic value of EV-associated cytokines was studied. We found that patients with high EV_APRIL, EV_CXCL13, and EV_VEGF-A levels had shorter overall survival (OS). We further evaluated the role of these selected biomarkers as prognostic factors in patients with residual disease (RD) after NAC. Even in patients with RD, high levels of EV_APRIL, EV_CXCL13, and EV_VEGF-A were correlated with poor OS. In all subgroup analyses, EV_CXCL13 overexpression was significantly associated with poor overall survival. Moreover, multivariate analysis indicated that a high level of EV_CXCL13 was an independent predictor of poor OS. Correlation analysis between biomarker levels in EVs and serum showed that EV_VEGF-A positively correlated with soluble VEGF-A but not CXCL13. An elevated level of soluble VEGF-A was also associated with poor OS. These findings suggest that EV_APRIL, EV_CXCL13, and EV_VEGF-A may be useful in identifying TNBC patients at risk of poor survival outcomes after NAC.

Src is emerging as a promising target in triple-negative breast cancer (TNBC) treatment because it activates survival signaling linked to the epidermal growth factor receptor. In this study, the effect of calcium supply on Src degradation was investigated to confirm underlying mechanisms and anticancer effects targeting TNBC. MDA-MB-231 cells, the TNBC cell line, were used. Calcium supply was feasible through lactate calcium salt (CaLac), and the applicable calcium concentration was decided by changes in the viability with different doses of CaLac. Expression of signaling molecules mediated by calcium-dependent Src degradation was observed by Western blot analysis and immunocytochemistry, and the recovery of the signaling molecules was confirmed following calpeptin treatment. The anticancer effect was investigated in the xenograft animal model. Significant suppression of Src was induced by calcium supply, followed by a successive decrease in the expression of epithelial growth factor receptor, RAS, extracellular signal-regulated kinase, and nuclear factor kappa B. Then, the suppression of cyclooxygenase-2 contributed to a significant deactivation of the prostaglandin E2 receptors. These results suggest that calcium supply has the potential to reduce the risk of TNBC. However, as this study is at an early stage to determine clinical applicability, close consideration is needed.

Urban particulate matter (UPM) is a high-hazard cause of various diseases in humans, including in the respiratory tract, skin, heart, and even brain. Unfortunately, there is no established treatment for the damage caused by UPM in the respiratory epithelium. In addition, although RIPK3 is known to induce necroptosis, its intracellular role as a negative regulator in human lungs and bronchial epithelia remains unclear. Here, the endogenous expression of RIPK3 was significantly decreased 6 h after exposure to UPM. In RIPK3-ovexpressed cells, RIPK3 was not moved to the cytoplasm from the nucleus. Interestingly, the overexpression of RIPK3 dramatically decreased TEER and F-actin formation. Its overexpression also decreased the expression of genes for pro-inflammatory cytokines (IL-6 and IL-8) and tight junctions (ZO-1, -2, -3, E-cadherin, and claudin) during UPM-induced airway inflammation. Importantly, overexpression of RIPK3 inhibited the UPM-induced ROS production by inhibiting the activation of iNOS and eNOS and by regulating mitochondrial fission processing. In addition, UPM-induced activation of the iκB and NF-κB signaling pathways was dramatically decreased by RIPK3, and the expression of pro-inflammatory cytokines was decreased by inhibiting the iκB signaling pathway. Our data indicated that RIPK3 is essential for the UPM-induced inflammatory microenvironment to maintain homeostasis. Therefore, we suggest that RIPK3 is a potential therapeutic candidate for UPM-induced pulmonary inflammation.

GV1001, a 16 amino acid peptide derived from the catalytic segment of human telomerase reverse transcriptase, was developed as an anti-cancer vaccine. Subsequently, it was found to exhibit anti-inflammatory and anti-Alzheimer’s disease properties. Periodontitis is a risk factor for a variety of systemic diseases, including atherosclerosis, a process in which chronic systemic and vascular inflammation results in the formation of plaques containing lipids, macrophages, foam cells, and tissue debris on the vascular intima. Thus, we investigated the effect of GV1001 on the severity of ligature-induced periodontitis, vascular inflammation, and arterial lipid deposition in mice. GV1001 notably reduced the severity of ligature-induced periodontitis by inhibiting gingival and systemic inflammation, alveolar bone loss, and vascular inflammation in wild-type mice. It also significantly lowered the amount of lipid deposition in the arterial wall in ApoE-deficient mice receiving ligature placement without changing the serum lipid profile. In vitro, we found that GV1001 inhibited the Receptor Activator of NF-κB ligand (RANKL)-induced osteoclast formation and tumor necrosis factor-α (TNF-α)-induced phenotypic changes in endothelial cells. In conclusion, our study suggests that GV1001 prevents the exacerbation of periodontitis and atherosclerosis associated with periodontitis partly by inhibiting local, systemic, and vascular inflammation and phenotypic changes of vascular endothelial cells.

Cervi cornu extracts have been used in traditional medicine for the treatment of various disorders, including osteoporosis. However, since it is not easy to separate the active ingredients, limited research has been conducted on their functional properties. In this study, we extracted the low-molecular-weight (843 Da) collagen NP-2007 from cervi cornu by enzyme hydrolyzation to enhance absorption and evaluated the therapeutic effect in monosodium iodoacetate-induced rat osteoarthritis (OA) model. NP-2007 was orally administered at 50, 100, and 200 mg/kg for 21 days. We showed that the production of matrix metalloproteinase-2, -3, and -9, decreased after NP-2007 treatment. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and prostaglandin E2 were also reduced after treatment of NP-2007. Furthermore, the administration of NP-2007 resulted in effective preservation of both the synovial membrane and knee cartilage and significantly decreased the transformation of fibrous tissue. We verified that the treatment of NP-2007 significantly reduced the production of nitric oxide and pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 in lipopolysaccharides-stimulated RAW 264.7 cells by regulation of the NF-kB and MAPK signaling pathways. This study indicates that NP-2007 can alleviate symptoms of osteoarthritis and can be applied as a novel treatment for OA treatment.

Platelet-derived growth factor type BB (PDGF-BB) regulates vascular smooth muscle cell (VSMC) migration and proliferation, which play critical roles in the development of vascular conditions. p90 ribosomal S6 kinase (p90RSK) can regulate various cellular processes through many different target substrates in several cell types, but the regulatory function of p90RSK on PDGF-BB-mediated cell migration and proliferation and subsequent vascular neointima formation has not yet been extensively examined. In this study, we investigated whether p90RSK inhibition protects VSMCs against PDGF-BB-induced cellular phenotypic changes and the molecular mechanisms underlying the effect of p90RSK inhibition on neointimal hyperplasia in vivo. Pretreatment of cultured primary rat VSMCs with FMK or BI-D1870, which are specific inhibitors of p90RSK, suppressed PDGF-BB-induced phenotypic changes, including migration, proliferation, and extracellular matrix accumulation, in VSMCs. Additionally, FMK and BI-D1870 repressed the PDGF-BB-induced upregulation of cyclin D1 and cyclin-dependent kinase-4 expression. Furthermore, p90RSK inhibition hindered the inhibitory effect of PDGF-BB on Cdk inhibitor p27 expression, indicating that p90RSK may induce VSMC proliferation by regulating the G0/G1 phase. Notably, treatment with FMK resulted in attenuation of neointima development in ligated carotid arteries in mice. The findings imply that p90RSK inhibition mitigates the phenotypic switch and neointimal hyperplasia induced by PDGF-BB.

Several studies have reported the pathogenic role of Malassezia in atopic dermatitis (AD); the significance of Malassezia’s influence on AD needs to be further investigated. Dupilumab, a monoclonal antibody to anti-Interleukin (IL) 4Rα, and ruxolitinib, a Janus kinase (JAK)1/2 inhibitor, are the first approved biologics and inhibitors widely used for AD treatment. In this study, we aimed to investigate how Malassezia Restricta (M. restricta) affects the skin barrier and inflammation in AD and interacts with the AD therapeutic agents ruxolitinib and anti-IL4Rα. To induce an in vitro AD model, a reconstructed human epidermis (RHE) was treated with IL-4 and IL-13. M. restricta was inoculated on the surface of RHE, and anti-IL4Rα or ruxolitinib was supplemented to model treated AD lesions. Histological and molecular analyses were performed. Skin barrier and ceramide-related molecules were downregulated by M. restricta and reverted by anti-IL4Rα and ruxolitinib. Antimicrobial peptides, VEGF, Th2-related, and JAK/STAT pathway molecules were upregulated by M. restricta and suppressed by anti-IL4Rα and ruxolitinib. These findings show that M. restricta aggravated skin barrier function and Th2 inflammation and decreased the efficacy of anti-IL4Rα and ruxolitinib.

Obese psoriatic patients experience higher disease severity and exhibit poorer treatment responses and clinical outcomes. It has been proposed that proinflammatory cytokines produced by adipose tissue exacerbate psoriasis; however, the role of obesity in psoriasis remains unclear. This study aimed to elucidate the role of obesity in the pathogenesis of psoriasis, focusing on immunological changes. To induce obesity, mice were fed a high-fat diet for 20 weeks. We then applied imiquimod to the skin on a mouse’s back for seven consecutive days to induce psoriasis and scored lesion severity every day for seven days. Cytokine levels in serum and the Th17 cell population in the spleen and draining lymph nodes were studied to identify immunological differences. The clinical severity was more remarkable, and histologically the epidermis was also significantly thicker in the obese group. Increased levels of IL-6 and TNF-α were observed in serum after psoriasis. They were elevated to a greater degree, with greater expansion of the functional Th17 cell population in the obese group. It is concluded that obesity could exacerbate psoriasis through mechanisms that involve elevated proinflammatory cytokine secretion and an expanded Th17 cell population.

Regular exercise, especially aerobic exercise, is beneficial for increasing serum high-density lipoprotein-cholesterol (HDL-C) levels in the general population. In addition to the HDL-C quantity, exercise enhances HDL functionality, antioxidants, and cholesterol efflux. On the other hand, the optimal intensity and frequency of exercise to increase HDL quantity and enhance HDL quality in middle-aged women need to be determined. The current study was designed to compare the changes in HDL quantity and quality among middle-aged women depending on exercise intensity, frequency, and duration; participants were divided into a sedentary group (group 1), a middle-intensity group (group 2), and a high-intensity group (group 3). There were no differences in anthropometric parameters among the groups, including blood pressure, muscle mass, and handgrip strength. Although there was no difference in serum total cholesterol (TC) among the groups, the serum HDL-C and apolipoprotein (apo)A-I levels remarkably increased to 17% and 12%, respectively, in group 3. Serum low-density lipoprotein-cholesterol (LDL-C), glucose, triglyceride, and the apo-B/apoA-I ratio were remarkably decreased in the exercise groups depending on the exercise intensity; group 3 showed 13%, 10%, and 45% lower LDL-C, glucose, and triglyceride (TG), respectively, than group 1. The hepatic and muscle damage parameter, aspartate aminotransferase (AST), was significantly decreased in the exercise groups, but high-sensitivity C-reactive protein (CRP), alanine aminotransferase (ALT), and γ-glutamyl transferase (γ-GTP) were similar in the three groups. In LDL, the particle size was increased 1.5-fold (p < 0.001), and the oxidation extent was decreased by 40% with a 23% lower TG content in group 3 than in group 1. In the exercise groups (groups 2 and 3), LDL showed the slowest electromobility with a distinct band intensity compared to the sedentary group (group 1). In HDL2, the particle size was 2.1-fold increased (p < 0.001) in the exercise group (group 3) with a 1.5-fold increase in TC content compared to that in group 1, as well as significantly enhanced antioxidant abilities, paraoxonase (PON) activity, and ferric ion reduction ability (FRA). In HDL3, the particle size was increased 1.2-fold with a 45% reduction in TG in group 3 compared to group 1. With increasing exercise intensity, apoA-I expression was increased in HDL2 and HDL3, and PON activity and FRA were enhanced (p < 0.001). In conclusion, regular exercise in middle-aged women is associated with the elevation of serum HDL-C and apoA-I with the enhancement of HDL quality and functionality and an increase in the TC content, particle size, and antioxidant abilities. With the reduction in TG and oxidized products in LDL and HDL, lipoproteins could have more anti-atherogenic properties through regular exercise in an intensity-dependent manner.

Linosorbs (Los) are cyclic peptides from flaxseed oil composed of the LO mixture (LOMIX). The activity of LO has been reported as being anti-cancer and anti-inflammatory. However, the study of skin protection has still not proceeded. In particular, there are poorly understood mechanisms of melanogenesis to LO. Therefore, we investigated the anti-melanogenesis effects of LOMIX and LO, and its activity was examined in mouse melanoma cell lines. The treatment of LOMIX (50 and 100 μg/mL) and LO (6.25–50 μM) suppressed melanin secretion and synthesis, which were 3-fold increased, in a dose-dependent manner, up to 95%. In particular, [1–9-NαC]-linusorb B3 (LO1) and [1-9-NαC]-linusorb B2 (LO2) treatment (12.5 and 25 μM) highly suppressed the synthesis of melanin in B16F10 cell lines up to 90%, without toxicity. LOMIX and LOs decreased the 2- or 3-fold increased mRNA levels, including the microphthalmia-associated transcription factor (MITF), Tyrosinase, tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (TYRP2) at the highest concentration (25 μM). Moreover, the treatment of 25 μM LO1 and LO2 inhibited the expression of MITF and phosphorylation of upper regulatory proteins such as CREB and PKA. Taken together, these results suggested that LOMIX and its individual LO could inhibit melanin synthesis via downregulating the CREB-dependent signaling pathways, and it could be used for novel therapeutic materials in hyperpigmentation.

Alopecia areata (AA) is an autoimmune condition related to the collapse of the immune privilege of hair follicles. Certain AA populations present severe clinical manifestations, such as total scalp hair or body hair loss and a treatment refractory property. The aim of this study was to assess the effects of allogenic human mesenchymal stem cells (hMSCs) from healthy donors on the peripheral blood mononuclear cells (PBMCs) of severe AA patients, with a focus on the change in the cell fraction of Th1, Th17, and Treg cells and immunomodulatory functions. PBMCs of 10 AA patients and eight healthy controls were collected. Levels of Th17, Th1, and Treg subsets were determined via flow cytometry at baseline, activation status, and after co-culturing with hMSCs. All participants were severe AA patients with SALT > 50 and with a long disease duration. While the baseline Th1 and Treg levels of AA patients were comparable to those of healthy controls, their Th17 levels were significantly lower than those of the controls. When stimulated, the levels of CD4+IFN-γ+ T cells of the AA patients rose sharply compared to the baseline, which was not the case in those of healthy controls. The cell fraction of CD4+Foxp3+ regulatory T cells also abruptly increased in AA patients only. Co-culturing with allogenic hMSCs in activated AA PBMCs slightly suppressed the activation levels of CD4+INF-γ+ T cells, whereas it significantly induced the differentiation of CD4+Foxp3+ regulatory T cells. However, these changes were not prominent in the PBMCs of health controls. To examine the pathomechanisms, PBMCs of healthy donors were treated with IFN-γ to induce AA-like environment and then treated with allogenic grants and compared with ruxolitinib as a positive treatment control. hMSC treatment was shown to significantly inhibit the mRNA levels of proinflammatory cytokines, such as IFN-γ, TNF-α, IL-1α, IL-2R, IL-15, and IL-18, and chemokines, such as CCR7 and CCR10, in IFN-treated PBMCs. Interestingly, hMSCs suppressed the activation of JAK/STAT signaling by IFN in PBMCs with an effect that was comparable to that of ruxolitinib. Furthermore, the hMSC treatment showed stronger efficacy in inducing Foxp3, IL-10, and TGF-β mRNA transcription than ruxolitinib in IFN-treated PBMCs. This study suggests that allogenic hMSC treatments have therapeutic potential to induce immune tolerance and anti-inflammatory effects in severe AA patients.

Light-to-moderate alcohol drinking is associated with a low incidence of cardiovascular disease (CVD) via an elevation of high-density lipoproteins-cholesterol (HDL-C), particularly with the short-term supplementation of alcohol. However, there is no information on the change in the HDL qualities and functionalities between non-drinkers and mild drinkers in the long-term consumption of alcohol. This study analyzed the lipid and lipoprotein profiles of middle-aged Korean female non-drinkers, mild-drinkers, and binge-drinkers, who consumed alcohol for at least 10 years. Unexpectedly, the serum levels of HDL-C and apolipoprotein A-I (apoA-I) were decreased significantly depending on the alcohol amount; the binge-drinker group showed 18% and 13% lower HDL-C (p = 0.011) and apoA-I levels (p = 0.024), respectively, than the non-drinker group. Triglyceride (TG) and oxidized species, malondialdehyde (MDA), and low-density lipoproteins (LDL) levels were significantly elevated in the drinker groups. Interestingly, the binge-drinker group showed 1.4-fold higher (p = 0.020) cholesterol contents in HDL2 and 1.7-fold higher (p < 0.001) TG contents in HDL3 than those of the non-drinker group. The mild-drinker group also showed higher TG contents in HDL3 (p = 0.032) than the non-drinker group, while cholesterol contents were similar in the HDL3 of all groups. Transmission electron microscopy (TEM) showed that the non-drinker group showed a more distinct and clear particle shape of the LDL and HDL image with a larger particle size than the drinker group. Electrophoresis of LDL showed that the drinker group had faster electromobility with a higher smear band intensity and aggregation in the loading position than the non-drinker group. The HDL level of binge drinkers showed the lowest paraoxonase activity, the highest glycated extent, and the most smear band intensity of HDL and apoA-I, indicating that HDL quality and functionality were impaired by alcohol consumption. In conclusion, long-term alcohol consumption in middle-aged women, even in small amounts, caused a significant decrease in the serum HDL-C and apoA-I with atherogenic changes in LDL and HDL, such as an increase in TG and MDA content with a loss of paraoxonase activity.

Alcohol consumption is associated with an increased risk of several cancers, including oral/oropharyngeal squamous cell carcinoma (OSCC). Alcohol also enhances the progression and aggressiveness of existing cancers; however, its underlying molecular mechanism remains elusive. Especially, the local carcinogenic effects of alcohol on OSCC in closest contact with ingestion of alcohol are poorly understood. We demonstrated that chronic ethanol exposure to OSCC increased cancer stem cell (CSC) populations and their stemness features, including self-renewal capacity, expression of stem cell markers, ALDH activity, and migration ability. The ethanol exposure also led to a significant increase in aerobic glycolysis. Moreover, increased aerobic glycolytic activity was required to support the stemness phenotype of ethanol-exposed OSCC, suggesting a molecular coupling between cancer stemness and metabolic reprogramming. We further demonstrated that chronic ethanol exposure activated NFAT (nuclear factor of activated T cells) signaling in OSCC. Functional studies revealed that pharmacological and genetic inhibition of NFAT suppressed CSC phenotype and aerobic glycolysis in ethanol-exposed OSCC. Collectively, chronic ethanol exposure promotes cancer stemness and aerobic glycolysis via activation of NFAT signaling. Our study provides a novel insight into the roles of cancer stemness and metabolic reprogramming in the molecular mechanism of alcohol-mediated carcinogenesis.

Recently, the role of kidney pericytes in kidney fibrosis has been investigated. This study aims to evaluate the effect of paricalcitol on hypoxia-induced and TGF-β1-induced injury in kidney pericytes. The primary cultured pericytes were pretreated with paricalcitol (20 ng/mL) for 90 min before inducing injury, and then they were exposed to TGF-β1 (5 ng/mL) or hypoxia (1% O2 and 5% CO2). TGF-β1 increased α-SMA and other fibrosis markers but reduced PDGFRβ expression in pericytes, whereas paricalcitol reversed the changes. Paricalcitol inhibited the TGF-β1-induced cell migration of pericytes. Hypoxia increased TGF-β1, α-SMA and other fibrosis markers but reduced PDGFRβ expression in pericyte, whereas paricalcitol reversed them. Hypoxia activated the HIF-1α and downstream molecules including prolyl hydroxylase 3 and glucose transporter-1, whereas paricalcitol attenuated the activation of the HIF-1α-dependent molecules and TGF-β1/Smad signaling pathways in hypoxic pericytes. The gene silencing of HIF-1α vanished the hypoxia-induced TGF-β1, α-SMA upregulation, and PDGFRβ downregulation. The effect of paricalcitol on the HIF-1α-dependent changes of fibrosis markers was not significant after the gene silencing of HIF-1α. In addition, hypoxia aggravated the oxidative stress in pericytes, whereas paricalcitol reversed the oxidative stress by increasing the antioxidant enzymes in an HIF-1α-independent manner. In conclusion, paricalcitol improved the phenotype changes of pericyte to myofibroblast in TGF-β1-stimulated pericytes. In addition, paricalcitol improved the expression of fibrosis markers in hypoxia-exposed pericytes both in an HIF-1α-dependent and independent manner.

The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS- and Aβ-induced neuroinflammatory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 microglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proinflammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflammasome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroinflammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphology, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and morphology. Taken together, our findings indicate that donepezil significantly downregulates LPS- and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD.

Theasinensin A (TSA) is a major group of catechin dimers mainly found in oolong tea and black tea. This compound is also manufactured with epigallocatechin gallate (EGCG) as a substrate and is refined after the enzyme reaction. In previous studies, TSA has been reported to be effective against inflammation. However, the effect of these substances on skin melanin formation remains unknown. In this study, we unraveled the role of TSA in melanogenesis using mouse melanoma B16F10 cells and normal human epidermal melanocytes (NHEMs) through reverse transcription polymerase chain reaction (RT-PCR), Western blotting analysis, luciferase reporter assay, and enzyme-linked immunosorbent assay analysis. TSA inhibited melanin formation and secretion in α-melanocyte stimulating hormone (α-MSH)-induced B16F10 cells and NHEMs. TSA down-regulated the mRNA expression of tyrosinase (Tyr), tyrosinase-related protein 1 (Tyrp1), and Tyrp2, which are all related to melanin formation in these cells. TSA was able to suppress the activities of certain proteins in the melanocortin 1 receptor (MC1R) signaling pathway associated with melanin synthesis in B16F10 cells: cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), protein kinase A (PKA), tyrosinase, and microphthalmia-associated transcription factor (MITF). We also confirmed α-MSH-mediated CREB activities through a luciferase reporter assay, and that the quantities of cAMP were reduced by TSA in the enzyme linked immunosorbent assay (ELISA) results. Based on these findings, TSA should be considered an effective inhibitor of hyperpigmentation.

The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1β production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.

Mesenchymal stem cell therapy (MSCT) has been shown to be a new therapeutic option for treating alopecia areata (AA). Outer root sheath cells (ORSCs) play key roles in maintaining the hair follicle structure and supporting the bulge area. In human ORSCs (hORSCs), the mechanism for this process has not been extensively studied. In this study, we aimed to examine the influence of human hematopoietic mesenchymal stem cells (hHMSCs) in the hORSCs in vitro model of AA and determine the mechanisms controlling efficacy. Interferon-gamma (IFN-γ) pretreatment was used to induce an in vitro model of AA in hORSCs. The effect of MSCT on the viability and migration of hORSCs was examined using co-cultures, the MTT assay, and migration assays. We investigated the expression of molecules related to the Wnt/β-catenin pathway, JAK/STAT pathway, and growth factors in hHMSC-treated hORSCs by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses. hHMSCs increased hORSC viability and migration when they were co-cultured. hHMSCs reverted IFN-γ-induced expression—including NLRP3, ASC, caspase-1, CXCL-9 through 11, IL-1β, and IL-15—and upregulated several growth factors and hair stem cell markers. hHMSCs activated several molecules in the Wnt/β-catenin signaling pathway, such as in the Wnt families, β-catenin, phosphorylated GSK-3β and cyclin D1, and suppressed the expression of DKK1 induced by IFN-γ in hORSCs. hHMSCs suppressed the phosphorylation of JAK1 to 3, STAT1, and STAT3 compared to the controls and IFN-γ-pretreated hORSCs. These results demonstrate that hHMSCs increased hORSC viability and migration in the in vitro AA model. Additionally, MSCT definitely stimulated anagen survival and hair growth in an HF organ culture model. MSCT appeared to be associated with the Wnt/β-catenin and JAK/STAT pathways in hORSCs.

Genome-wide studies focusing on elucidating the effects on cancer progression have enabled the consequent identification of a distinct subpopulation of pancreatic cancer cells with unstable genomic characteristics. Based on this background, deleterious changes by poly (adenosine diphosphate (ADP)-ribose) polymerase-1 (PARP)-1 have been concentrated in oncology. One of the critical functions of PARP-1 is the response to DNA damage, which plays a pivotal role in DNA repair in cancers. PARP-1 also has widespread functions that are essential for the survival and growth of cancer cells. It regulates oxidative stress in mitochondria through the regulation of superoxide and oxidation. PARP-1 is in charge of regulating mitosis, which is a crucial role in tumorigenesis and remodels histones and chromatin enzymes related to transcriptional regulation, causing alterations in epigenetic markers and chromatin structure. Given the significance of these processes, it can be understood that these processes in cancer cells are at the frontline of the pathogenetic changes required for cancer cell survival, and these contributions can result in malignant transformation. Therefore, this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 in pancreatic cancer related to the aforementioned roles, along with the summary of recent approaches with PARP-1 inhibition in clinical studies targeting pancreatic cancer. This understanding could help to embrace the importance of targeting PARP-1 in the treatment of pancreatic cancer, which may present the potential to find out a variety of research topics that can be both challenged clinically and non-clinically.

The protective effects of alpha-1 antitrypsin (AAT) in tacrolimus (TAC)-induced renal injury was evaluated in a rat model. The TAC group rats were subcutaneously injected with 2 mg/kg TAC every day for four weeks. The TAC with AAT group was cotreated with daily subcutaneous injections of TAC and intraperitoneal injections of AAT (80 mg/kg) for four weeks. The effects of AAT on TAC-induced renal injury were evaluated using serum biochemistry, histopathology, and Western blotting. The TAC injection significantly increased renal interstitial fibrosis, inflammation, and apoptosis as compared to the control treatment. The histopathological examination showed that cotreatment of TAC and AAT attenuated interstitial fibrosis (collagen, fibronectin, and α-SMA staining), and α-SMA expression in Western blotting was also decreased. Immunohistochemical staining for inflammation (osteopontin and ED-1 staining) revealed improved interstitial inflammation in the TAC with AAT group compared to that in the TAC group. The TAC treatment increased renal apoptosis compared to the control treatment, based on the results of increased immunohistochemical staining of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), increased caspase-3 activity, and lower Bcl-2 to Bad expression ratio. However, AAT cotreatment significantly changed these markers and consequently showed decreased apoptosis. AAT protects against TAC-induced renal injury via antifibrotic, anti-inflammatory, and antiapoptotic effects.

In the present study, we investigated the effects of xanthine oxidase (XO) inhibition on cholesterol-induced renal dysfunction in chronic kidney disease (CKD) mice, and in low-density lipoprotein (LDL)-treated human kidney proximal tubule epithelial (HK-2) cells. ApoE knockout (KO) mice underwent uninephrectomy to induce CKD, and were fed a normal diet or high-cholesterol (HC) diet along with the XO inhibitor topiroxostat (1 mg/kg/day). HK-2 cells were treated with LDL (200 µg/mL) and topiroxostat (5 µM) or small interfering RNA against xanthine dehydrogenase (siXDH; 20 nM). In uninephrectomized ApoE KO mice, the HC diet increased cholesterol accumulation, oxidative stress, XO activity, and kidney damage, while topiroxostat attenuated the hypercholesterolemia-associated renal dysfunction. The HC diet induced cholesterol accumulation by regulating the expressions of genes involved in cholesterol efflux (Nr1h3 and Abca1) and synthesis (Srebf2 and Hmgcr), which was reversed by topiroxostat. Topiroxostat suppressed the expressions of genes related to hypercholesterolemia-associated inflammation and fibrosis in the unilateral kidney. LDL stimulation evoked changes in the cholesterol metabolism, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and NF-κB pathways in HK-2 cells, which were mitigated by XO inhibition with topiroxostat or siXDH. These findings suggest that XO inhibition exerts renoprotective effects against hypercholesterolemia-associated kidney injury. XO could be a novel therapeutic target for hypercholesterolemia-associated kidney injury in uninephrectomized patients.

Keloid is a representative chronic fibroproliferative condition that occurs after tissue injury. Emerging evidence showed that activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is involved in the pro-inflammatory response in injured tissues. However, the role of NLRP3 inflammasome in keloid progression remains unclear. Notch signaling, which activates NLRP3 inflammasome, is known to contribute to scar formation in keloid, but the cause of enhanced Notch signaling in keloid is not clear. We sought to investigate whether autophagy regulates Notch1 signaling in keloid fibroblasts and determine whether Notch1 signaling might regulate NLRP3 inflammasomes and myofibroblast differentiation. An in vitro model of keloid was established by culturing primary keloid fibroblasts from patients. Expression levels of Notch1, NLRP3 inflammasome proteins, pro-inflammatory cytokines, and myofibroblast markers in keloid fibroblasts were examined and compared with those in normal fibroblasts. Autophagy known to mediate Notch1 degradation was also monitored in fibroblasts. Small interfering RNA (siRNA) targeting Notch1 was used to transfect keloid fibroblasts to further examine the role of Notch signaling in NLRP3 inflammasome activation. Expression levels of Notch1 and NLRP3 inflammasome in keloid fibroblasts increased compared to those in normal fibroblasts. Such increases were accompanied by increased LC3 levels and reduced autophagic flux. Notch1 silencing in keloid fibroblasts by siRNA transfection significantly suppressed increased levels of overall NLRP3 inflammasome complex proteins, NF-kB, and α-smooth muscle actin. Autophagy induction by rapamycin treatment in keloid fibroblasts effectively suppressed expression levels of Notch1 and NLRP3 inflammasome proteins. Decreased autophagy activity in keloid can result in Notch1-mediated myofibroblast activation and NLRP3 inflammasome signaling activation which is critical for chronic inflammation. Collectively, these results identify Notch1 as a novel activator of NLRP3 inflammasome signaling leading to chronic tissue damage and myofibroblast differentiation in keloid progression.

The protective effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 1 inhibition against kidney ischemia-reperfusion injury (IRI) remain uncertain. The bilateral kidney pedicles of C57BL/6 mice were clamped for 30 min to induce IRI. Madin–Darby Canine Kidney (MDCK) cells were incubated with H2O2 (1.4 mM) for 1 h to induce oxidative stress. ML171, a selective NOX1 inhibitor, and siRNA against NOX1 were treated to inhibit NOX1. NOX expression, oxidative stress, apoptosis assay, and mitogen-activated protein kinase (MAPK) pathway were evaluated. The kidney function deteriorated and the production of reactive oxygen species (ROS), including intracellular H2O2 production, increased due to IRI, whereas IRI-mediated kidney dysfunction and ROS generation were significantly attenuated by ML171. H2O2 evoked the changes in oxidative stress enzymes such as SOD2 and GPX in MDCK cells, which was mitigated by ML171. Treatment with ML171 and transfection with siRNA against NOX1 decreased the upregulation of NOX1 and NOX4 induced by H2O2 in MDCK cells. ML171 decreased caspase-3 activity, the Bcl-2/Bax ratio, and TUNEL-positive tubule cells in IRI mice and H2O2-treated MDCK cells. Among the MAPK pathways, ML171 affected ERK signaling by ERK phosphorylation in kidney tissues and tubular cells. NOX1-selective inhibition attenuated kidney IRI via inhibition of ROS-mediated ERK signaling.

p62/sequestosome-1 is a scaffolding protein involved in diverse cellular processes such as autophagy, oxidative stress, cell survival and death. It has been identified to interact with atypical protein kinase Cs (aPKCs), linking these kinases to NF-κB activation by tumor necrosis factor α (TNFα). The diverse functions of p62 are regulated through post-translational modifications of several domains within p62. Among the enzymes that mediate these post-translational modifications, little is known about the deubiquitinating enzymes (DUBs) that remove ubiquitin chains from p62, compared to the E3 ligases involved in p62 ubiquitination. In this study, we first demonstrate a role of ubiquitin-specific protease USP20 in regulating p62 stability in TNFα-mediated NF-κB activation. USP20 specifically binds to p62 and acts as a positive regulator for NF-κB activation by TNFα through deubiquitinating lysine 48 (K48)-linked polyubiquitination, eventually contributing to cell survival. Furthermore, depletion of USP20 disrupts formation of the atypical PKCζ-RIPK1-p62 complex required for TNFα-mediated NF-κB activation and significantly increases the apoptosis induced by TNFα plus cycloheximide or TNFα plus TAK1 inhibitor. These findings strongly suggest that the USP20-p62 axis plays an essential role in NF-κB-mediated cell survival induced by the TNFα-atypical PKCζ signaling pathway.

Genetic variability can modulate individual drug responses. A significant portion of pharmacogenetic variants reside in the noncoding genome yet it is unclear if the noncoding variants directly influence protein function and expression or are present on a haplotype including a functionally relevant genetic variation (synthetic association). Gene-wise variant burden (GVB) is a gene-level measure of deleteriousness, reflecting the cumulative effects of deleterious coding variants, predicted in silico. To test potential associations between noncoding and coding pharmacogenetic variants, we computed a drug-level GVB for 5099 drugs from DrugBank for 2504 genomes of the 1000 Genomes Project and evaluated the correlation between the long-known noncoding variant-drug associations in PharmGKB, with functionally relevant rare and common coding variants aggregated into GVBs. We obtained the area under the receiver operating characteristics curve (AUC) by comparing the drug-level GVB ranks against the corresponding pharmacogenetic variants-drug associations in PharmGKB. We obtained high overall AUCs (0.710 ± 0.022–0.734 ± 0.018) for six different methods (i.e., SIFT, MutationTaster, Polyphen-2 HVAR, Polyphen-2 HDIV, phyloP, and GERP++), and further improved the ethnicity-specific validations (0.759 ± 0.066–0.791 ± 0.078). These results suggest that a significant portion of the long-known noncoding variant-drug associations can be explained as synthetic associations with rare and common coding variants burden of the corresponding pharmacogenes.

UVB irradiation can induce generation of reactive oxygen species (ROS) that cause skin aging or pigmentation. Lactobacillus acidophilus is a well-known probiotic strain that regulates skin health through antimicrobial peptides and organic products produced by metabolism and through immune responses. In this study, we investigated the antioxidative, antiwrinkle, and antimelanogenesis effects of tyndallized Lactobacillus acidophilus KCCM12625P (AL). To analyze the effects of AL on UV irradiation-induced skin wrinkle formation in vitro, human keratinocytes and human dermal fibroblasts were exposed to UVB. Subsequent treatment with AL induced antiwrinkle effects by regulating wrinkle-related genes such as matrix metalloproteinases (MMPs), SIRT-1, and type 1 procollagen (COL1AL). In addition, Western blotting assays confirmed that regulation of MMPs by AL in keratinocytes was due to regulation of the AP-1 signaling pathway. Furthermore, we confirmed the ability of AL to regulate melanogenesis in B16F10 murine melanoma cells treated with α-melanocyte-stimulating hormone (α-MSH). In particular, AL reduced the mRNA expression of melanogenesis-related genes such as tyrosinase, TYRP-1, and TYRP-2. Finally, we used Western blotting assays to confirm that the antimelanogenesis role of AL was due to its regulation of the cyclic adenosine monophosphate (cAMP) signaling pathway. Collectively, these results indicate that AL has an antiwrinkle activity in damaged skin and can inhibit melanogenesis. Thus, AL should be considered an important substance for potential use in anti-aging drugs or cosmetics.

Orchids are one of the most significant plants that have ecologically adapted to every habitat on earth. Orchids show a high level of variation in their floral morphologies, which makes them popular as ornamental plants in the global market. Floral scent and color are key traits for many floricultural crops. Volatile organic compounds (VOCs) play vital roles in pollinator attraction, defense, and interaction with the environment. Recent progress in omics technology has led to the isolation of genes encoding candidate enzymes responsible for the biosynthesis and regulatory circuits of plant VOCs. Uncovering the biosynthetic pathways and regulatory mechanisms underlying the production of floral scents is necessary not only for a better understanding of the function of relevant genes but also for the generation of new cultivars with desirable traits through molecular breeding approaches. However, little is known about the pathways responsible for floral scents in orchids because of their long life cycle as well as the complex and large genome; only partial terpenoid pathways have been reported in orchids. Here, we review the biosynthesis and regulation of floral volatile compounds in orchids. In particular, we focused on the genes responsible for volatile compounds in various tissues and developmental stages in Cymbidium orchids. We also described the emission of orchid floral volatiles and their function in pollination ecology. Taken together, this review will provide a broad scope for the study of orchid floral scents.

In humans, aging is associated with endothelial dysfunction and an increased risk of venous thromboembolism. Although intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at a ratio of 6:1 by old rats improved the endothelial dysfunction in arteries, the impact on veins remains unclear. Eight-month-old male Wistar rats were either untreated or orally administered corn oil, EPA:DHA 1:1, or EPA:DHA 6:1 (500 mg/kg/d) for seven days. Vascular reactivity was studied by myography. In middle-aged femoral artery rings, acetylcholine caused a partial relaxation at low concentrations and a contractile response at high concentrations, whereas in the old femoral vein only a partial relaxation was observed. The EPA:DHA 6:1 treatment blunted the contractile response to acetylcholine in the middle-aged femoral artery and both EPA:DHA 6:1 and 1:1 increased the relaxation to acetylcholine in the old femoral vein. No such effects were observed with corn oil. Both the non-selective cyclooxygenase inhibitor indomethacin and the COX-1 inhibitor SC-560 increased the relaxation to acetylcholine in the middle-aged femoral artery whereas the COX-2 inhibitor NS-398 increased that in the middle-aged femoral vein. In conclusion, our results indicate that aging is associated with an endothelial dysfunction in the femoral artery and vein, which can be improved by EPA:DHA 6:1 treatment—most likely via a cyclooxygenase-dependent mechanism.

Loliolide is a monoterpenoid hydroxylactone present in freshwater algae that has anti-inflammatory and antiaging activity; however, its effects on ultraviolet-damaged skin have yet to be elucidated. This study investigated the antiapoptosis and wound-healing effects of loliolide using HaCaT cells (a human keratinocyte cell line). Loliolide inhibited the expression of reactive oxygen species (ROS) induced by ultraviolet radiation as well as wrinkle formation-related matrix metalloproteinase genes and increased the expression of the damage repair-related gene SIRT1. The apoptosis signaling pathway was confirmed by Western blot analysis, which showed that loliolide was able to reduce the expression of caspases 3, 8, and 9, which are related to ROS-induced apoptosis. In addition, Western blotting, reverse-transcription polymerase chain reaction (PCR), and real-time PCR analyses showed that loliolide enhanced the expression of the epidermal growth factor receptor signaling pathway (PI3K, AKT) and migration factors, such as K6, K16, and K17; keratinocyte growth factor; and inflammatory cytokines, such as interleukin (IL)-1, IL-17, and IL-22 expressed during the cellular scratching process, suggesting a putative wound-healing ability. Because of the antiapoptosis and antiscratching effects on skin of both loliolide and loliolide-rich Prasiola japonica ethanol extract, we consider the former to be an important compound used in the cosmeceutical industry.

Loliolide is a monoterpenoid hydroxylactone found in many algae, including fresh water green algae, Prasiola japonica. To date, loliolide and compounds in P. japonica have not been studied systematically with respect to skin pharmacology. In this study, we investigated oxidative stress-protective and anti-melanogenic effects of loliolide and P. japonica ethanol extract (Pj-EE), known to contain loliolide, in human keratinocyte (HaCaT) cells and mouse melanoma (B16F10) cells. Loliolide suppressed the transcription of genes encoding matrix metalloproteinases (MMPS), which were induced in HaCaT cells by hydrogen peroxide (H2O2) treatment. Loliolide and Pj-EE not only reduced the melanin secretion and content in B16F10 cells but also increased the expression of the antioxidant proteins nuclear factor (erythroid-derived 2)-like 2 (NRF2) and heme oxygenase-1 (HO-1) in HaCaT cells subjected to H2O2 treatment. Furthermore, loliolide and Pj-EE decreased expression of the anti-melanogenic protein microphthalmia-associated transcription factor (MITF) and tyrosinase in B16F10 cells subjected to α-melanocyte-stimulating hormone (α-MSH) treatment. Our findings demonstrate that loliolide and Pj-EE have antioxidant and anti-melanogenic effects on skin.

Lung injury is characterized by diffuse lung inflammation, alveolar-capillary destruction, and alveolar flooding, resulting in respiratory failure. Polydexyribonucleotide (PDRN) has an anti-inflammatory effect, decreasing inflammatory cytokines, and suppressing apoptosis. Thus, we investigated its efficacy in the treatment of lung injury, which was induced in rats using lipopolysaccharide (LPS). Rats were randomly divided into three groups according to sacrifice time, and each group split into control, lung injury-induced, and lung injury-induced + PDRN-treated groups. Rats were sacrificed 24 h and 72 h after PDRN administration, according to each group. Lung injury was induced by intratracheal instillation of LPS (5 mg/kg) in 0.2 mL saline. Rats in PDRN-treated groups received a single intraperitoneal injection of 0.3 mL distilled water including PDRN (8 mg/kg), 1 h after lung injury induction. Percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive, cleaved caspase-3-, -8-, and -9-positive cells, the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2), and expressions of inflammatory cytokines (tumor necrosis factor-α, interleukin-6) were decreased by PDRN treatment in the LPS-induced lung injury rats. Therefore, treatment with PDRN reduced lung injury score. This anti-apoptotic effect of PDRN can be ascribed to the enhancing effect of PDRN on adenosine A2A receptor expression. Based on these results, PDRN might be considered as a new therapeutic agent for the treatment of lung injury.

Despite the critical role of melanin in the protection of skin against UV radiation, excess production of melanin can lead to hyperpigmentation and skin cancer. Pear fruits are often used in traditional medicine for the treatment of melasma; therefore, we investigated the effects of pear extract (PE) and its component, protocatechuic acid (PCA), on melanogenesis in mouse melanoma cells. We found that PE and PCA significantly suppressed melanin content and cellular tyrosinase activity through a decrease in the expression of melanogenic enzymes and microphthalmia-associated transcription factor (Mitf) in α-melanocyte stimulating hormone-stimulated mouse melanoma cells. Moreover, PCA decreased cyclic adenosine monophosphate (cAMP) levels and cAMP-responsive element-binding protein phosphorylation, which downregulated Mitf promoter activation and subsequently mediated the inhibition of melanogenesis. These results suggested that pear may be an effective skin lightening agent that targets either a tyrosinase activity or a melanogenic pathway.

Disease prevention through vaccination is considered to be the greatest contribution to public health over the past century. Every year more than 100 million children are vaccinated with the standard World Health Organization (WHO)-recommended vaccines including hepatitis B (HepB). HepB is the most serious type of liver infection caused by the hepatitis B virus (HBV), however, it can be prevented by currently available recombinant vaccine, which has an excellent record of safety and effectiveness. To date, recombinant vaccines are produced in many systems of bacteria, yeast, insect, and mammalian and plant cells. Among these platforms, the use of plant cells has received considerable attention in terms of intrinsic safety, scalability, and appropriate modification of target proteins. Research groups worldwide have attempted to develop more efficacious plant-derived vaccines for over 30 diseases, most frequently HepB and influenza. More inspiring, approximately 12 plant-made antigens have already been tested in clinical trials, with successful outcomes. In this study, the latest information from the last 10 years on plant-derived antigens, especially hepatitis B surface antigen, approaches are reviewed and breakthroughs regarding the weak points are also discussed.

High salt intake causes and aggravates arterial hypertension and vascular dysfunction. We investigated the effect of Salicornia europaea extracts (SE) on vascular function and blood pressure. SE constituents were analyzed using high performance liquid chromatography, and SE’s effect on vascular function was evaluated in isolated porcine coronary arteries. SE’s vascular protective effect was also evaluated in vivo using normotensive and spontaneous hypertensive rats (SHRs). SE mainly contained sodium chloride (55.6%), 5-(hydroxymethyl)furfural, p-coumaric acid, and trans-ferulic acid. High sodium (160 mmol/L) induced vascular dysfunction; however, SE containing the same quantity of sodium did not cause vascular dysfunction. Among the compounds in SE, trans-ferulic acid accounts for the vascular protective effect. Normotensive rats fed a high-salt diet showed significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), which decreased significantly in the SE-treated groups. In SHRs, high edible salt intake significantly increased SBP, DBP, and MAP, but SE intake was associated with a significantly lower MAP. Thus, SE did not induce vascular dysfunction, and trans-ferulic acid might be at least partly responsible for the vasoprotective effect of SE. Taken together, SE could be used as an alternative to purified salt to prevent and ameliorate hypertension.