Anti-Inflammatory Effects of Clematis terniflora Leaf on Lipopolysaccharide-Induced Acute Lung Injury.

For centuries, natural products are regarded as vital medicines for human survival. Clematis terniflora var. mandshurica (Rupr.) Ohwi is an ingredient of the herbal medicine, Wei Ling Xian, which has been used in Chinese medicine to alleviate pain, fever, and inflammation. In particular, C. terniflora leaves have been used to cure various inflammatory diseases, including tonsillitis, cholelithiasis, and conjunctivitis. Based on these properties, this study aimed to scientifically investigate the anti-inflammatory effect of an ethanol extract of leaves of C. terniflora (EELCT) using activated macrophages that play central roles in inflammatory response. In this study, EELCT inhibited the essential inflammatory mediators, such as nitric oxide, cyclooxygenase-2, tumor necrosis factor-α, interleukin- (IL-) 6, IL-1ß, and inducible nitric oxide synthase, by suppressing the nuclear factor-κB and mitogen-activated protein kinase activation in macrophages. Acute lung injury (ALI) is a fatal respiratory disease accompanied by serious inflammation. With high mortality rate, the disease has no effective treatments. Therefore, new therapeutic agents must be developed for ALI. We expected that EELCT can be a promising therapeutic agent for ALI by reducing inflammatory responses and evaluated its action in a lipopolysaccharide- (LPS-) induced ALI model. EELCT alleviated histological changes, immune cell infiltration, inflammatory mediator production, and protein-rich pulmonary edema during ALI. Collectively, our results may explain the traditional usage of C. terniflora in inflammatory diseases and suggest the promising potential of EELCT as therapeutic candidate for ALI.

Therapeutic Effects of Switching to Anagliptin from Other DPP-4 Inhibitors in T2DM Patients with Inadequate Glycemic Control: A Non-interventional, Single-Arm, Open-Label, Multicenter Observational Study.

INTRODUCTION: The effects of switching DPP-4 inhibitors in type 2 diabetes mellitus (T2DM) patients are being widely studied. However, information of which factors affect the therapeutic response is limited. We evaluated the difference in HbA1c lowering effect by comorbidity and other variables after switching to anagliptin in patients with T2DM inadequately controlled by other DPP-4 inhibitors. METHODS: In a multicenter, open-label, single-arm, prospective observational study, patients with T2DM, HbA1c ≥ 7.0% who have taken DPP-4 inhibitors other than anagliptin, either alone or in combination (DPP-4 inhibitors + metformin/sulfonylurea (SU)/thiazolidinedione (TZD)/insulin), for at least 8 weeks were enrolled. After the switch to anagliptin, HbA1c and available clinical characteristics were determined. RESULTS: The change in HbA1c levels from baseline to week 12 and 24 was - 0.40% and - 0.42% in all patients. However, comparing the subgroups without and with comorbidities, the change in HbA1c levels at weeks 12 and 24 was - 0.68% and - 0.89% vs. - 0.27% and 0.22%, respectively. In addition, the proportion of patients achieving HbA1c < 7% from baseline to week 12 and 24 was increased to 70% and 70% vs. 20% and 24%, respectively. Duration of T2DM and different subtype classes of DPP-4 inhibitor did not significantly contribute to the change in HbA1c. CONCLUSION: In patients with T2DM poorly controlled by other DPP-4 inhibitors, HbA1c levels were significantly decreased after switching to anagliptin. Given that the change in HbA1c was greater in patients without comorbidities than in patients with comorbidities, switching to anagliptin before adding other oral hypoglycemic agents (OHAs) may be an option in patients without comorbidities.

Discovery of Pharmaceutical Composition for Prevention and Treatment in Patient-Derived Metastatic Medullary Thyroid Carcinoma Model.

Medullary thyroid carcinoma (MTC) is a well-known neuroendocrine carcinoma, derived from C cells of the thyroid gland. Additionally, MTC is an uncommon aggressive carcinoma that metastasizes to lymph nodes, bones, lungs and liver. For MTC, the 10-year general survival ratio of patients with localized disease is about 95%, whereas that of patients with local phase disorder is around 75%. Only 20% of patients with distant metastasis to lung at diagnosis survive 10 years, which is notably lower than survival for well-differentiated thyroid carcinoma (WDTC). The management of MTC with distant metastasis to lung could be re-surgery or chemotherapy. In this research, we planned to assess the in vitro and in vivo combinational anticancer effect of a novel combination of low-dose cisplatin and sorafenib in patient-derived MTC. The patient-derived MTC cell lines YUMC-M1, M2, and M3 were isolated and treated with a combination of cisplatin and sorafenib or either agent alone. Cisplatin and sorafenib acted in combination to forward tumor restraint compared with each agent administered alone at a low dose. Therefore, a combination of cisplatin and sorafenib could be a new therapeutic approach for MTC.

Immobilization of Laccase Through Inorganic-Protein Hybrids Using Various Metal Ions.

In this study, the inorganic-protein hybrid strategy was employed for immobilization of laccase from Rhus vernicifera (Rvlac) using various metals calcium, cobalt, copper, and zinc (Zn). The efficient synthesis of hybrids for Rvlac immobilization was noted at 4 °C for incubation of 24 h. Among these hybrids, the maximum encapsulation yields (EY) of 90.1% and relative activity (RA) of 225% to free enzyme were recorded for Zn and Rvlac based inorganic-protein hybrids as Zn3(PO4)2-Rvlac. The upper optimum pH, and temperature values were observed of 4.0, and 45 °C after immobilization as compared to 3.5, and 40 °C for the free enzyme, respectively. After encapsulation, Rvlac showed a significant improvement up to 11.4-fold in pH and 5.7-fold in temperature the activity profiles. Free enzyme completely lost its activity at 60 °C after 2 h of incubation, whereas Zn3(PO4)2-Rvlac retained its residual activity of 56.7% under similar conditions. After ten cycles of reusability, Zn3(PO4)2-Rvlac possessed high residual activity of 90.8%. This study showed that the variation in the metal ions for immobilization of Rvlac as inorganic-protein hybrids significantly altered EY and RA. Also, Zn3(PO4)2-Rvlac proved more efficient as compared to free laccase that can be beneficially employed for biotechnological applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-022-01000-5.

53BP1-ACLY-SLBP-coordinated activation of replication-dependent histone biogenesis maintains genomic integrity.

p53-binding protein 1 (53BP1) regulates the DNA double-strand break (DSB) repair pathway and maintains genomic integrity. Here we found that 53BP1 functions as a molecular scaffold for the nucleoside diphosphate kinase-mediated phosphorylation of ATP-citrate lyase (ACLY) which enhances the ACLY activity. This functional association is critical for promoting global histone acetylation and subsequent transcriptome-wide alterations in gene expression. Specifically, expression of a replication-dependent histone biogenesis factor, stem-loop binding protein (SLBP), is dependent upon 53BP1-ACLY-controlled acetylation at the SLBP promoter. This chain of regulation events carried out by 53BP1, ACLY, and SLBP is crucial for both quantitative and qualitative histone biogenesis as well as for the preservation of genomic integrity. Collectively, our findings reveal a previously unknown role for 53BP1 in coordinating replication-dependent histone biogenesis and highlight a DNA repair-independent function in the maintenance of genomic stability through a regulatory network that includes ACLY and SLBP.

Effects of Teneligliptin on HbA1c levels, Continuous Glucose Monitoring-Derived Time in Range and Glycemic Variability in Elderly Patients with T2DM (TEDDY Study).

BACKGROUND: To evaluate the effects of teneligliptin on glycosylated hemoglobin (HbA1c) levels, continuous glucose monitoring (CGM)-derived time in range, and glycemic variability in elderly type 2 diabetes mellitus patients. METHODS: This randomized, double-blinded, placebo-controlled study was conducted in eight centers in Korea (clinical trial registration number: NCT03508323). Sixty-five participants aged ≥65 years, who were treatment-naïve or had been treated with stable doses of metformin, were randomized at a 1:1 ratio to receive 20 mg of teneligliptin (n=35) or placebo (n=30) for 12 weeks. The main endpoints were the changes in HbA1c levels from baseline to week 12, CGM metrics-derived time in range, and glycemic variability. RESULTS: After 12 weeks, a significant reduction (by 0.84%) in HbA1c levels was observed in the teneligliptin group compared to that in the placebo group (by 0.08%), with a between-group least squares mean difference of -0.76% (95% confidence interval [CI], -1.08 to -0.44). The coefficient of variation, standard deviation, and mean amplitude of glycemic excursion significantly decreased in participants treated with teneligliptin as compared to those in the placebo group. Teneligliptin treatment significantly decreased the time spent above 180 or 250 mg/dL, respectively, without increasing the time spent below 70 mg/dL. The mean percentage of time for which glucose levels remained in the 70 to 180 mg/dL time in range (TIR70-180) at week 12 was 82.0%±16.0% in the teneligliptin group, and placebo-adjusted change in TIR70-180 from baseline was 13.3% (95% CI, 6.0 to 20.6). CONCLUSION: Teneligliptin effectively reduced HbA1c levels, time spent above the target range, and glycemic variability, without increasing hypoglycemia in our study population.

Semantic Network Analysis Using Construction Accident Cases to Understand Workers' Unsafe Acts.

Unsafe acts by workers are a direct cause of accidents in the labor-intensive construction industry. Previous studies have reviewed past accidents and analyzed their causes to understand the nature of the human error involved. However, these studies focused their investigations on only a small number of construction accidents, even though a large number of them have been collected from various countries. Consequently, this study developed a semantic network analysis (SNA) model that uses approximately 60,000 construction accident cases to understand the nature of the human error that affects safety in the construction industry. A modified human factor analysis and classification system (HFACS) framework was used to classify major human error factors-that is, the causes of the accidents in each of the accident summaries in the accident case data-and an SNA analysis was conducted on all of the classified data to analyze correlations between the major factors that lead to unsafe acts. The results show that an overwhelming number of accidents occurred due to unintended acts such as perceptual errors (PERs) and skill-based errors (SBEs). Moreover, this study visualized the relationships between factors that affected unsafe acts based on actual construction accident case data, allowing for an intuitive understanding of the major keywords for each of the factors that lead to accidents.

Biotin and Zn2+ Increase Xylitol Production by Candida tropicalis.

In this study, the medium requirements to increase the production of xylitol by using Candida tropicalis (CT) have been investigated. The technique of single addition or omission of medium components was applied to determine the nutritional requirements. The addition of amino acids such as Asp, Glu, Gln, Asn, Thr, and Gly had no significant effect on CT growth. However, in the absence of other metal ions, there was a higher concentration of cell growth and xylitol production when only Zn2+ was present in the medium. The analysis of various vitamins unveiled that biotin and thiamine were the only vitamins required for the growth of CT. Surprisingly, when only biotin was present in the medium as a vitamin, there was less growth of CT than when the medium was complete, but the amount of xylitol released was significantly higher. Overall, this study will increase the xylitol production using the single omission or addtion technique.

Hyperdioxanes, dibenzo-1,4-dioxane derivatives from the roots of Hypericum ascyron.

Six dibenzo-1,4-dioxane derivatives (1-6) were isolated from the roots of a Hypericaceous plant Hypericum ascyron. Spectroscopic analyses revealed 2 and 4-6 to be new compounds. The partial racemic natures of 1-3 were concluded by chiral HPLC analyses, while 5 was confirmed to be a racemate. The absolute configurations 1-4 were deduced on the basis of ECD calculations. Biological activity evaluation of the dibenzo-1,4-dioxane derivatives along with two related compounds: hyperdioxanes A (7) and B (8), previously isolated from the same plant material by our group demonstrated that 7 exhibit an anti-HIV activity (IC50 5.3 µM, TI 7.2) while 8 showed an inhibitory effect on IL-1ß production (inhibition rate: 72.3% at 6.3 µM) from LPS-stimulated microglial cells.

Scaphium affine Ethanol Extract Induces Anoikis by Regulating the EGFR/Akt Pathway in HCT116 Colorectal Cancer Cells.

Scaphium affine ethanol extracts (SAE) is a species that has been shown to contain various physiological effects; however, its anticancer effects have yet to be revealed. We qualitatively evaluated ß-sitosterol in SAE through high-performance liquid chromatography (HPLC). The cytotoxicity in HCT116 and HT29 colorectal cancer cells and CCD841 normal colon cells was confirmed through WST-1 assays. Selective cytotoxicity was observed in colorectal cancer cells, with greater cytotoxicity demonstrated in the HCT116 cell line. As such, the HCT116 colorectal cell line was selected for subsequent experiments. After HCT116 cells were treated with SAE, it was confirmed that the apoptosis rate was increased in a SAE dose-dependent manner through Annexin V assay. SAE further showed dose-dependent suppression of invasion through invasion assays. Anoikis induction through the EGFR/Akt pathway in HCT116 colorectal cancer cells was confirmed by Western blotting. The tumor suppressive effects of SAE was assessed in vivo using a xenograft model of human HCT116 colorectal cancer cells. As a result, we confirmed that SAE decreased tumor size in a dose-dependent manner and that p-EGFR and cleaved-caspase 3 in tumors were also regulated in a dose-dependent manner. This study showed that SAE, by containing ß-sitosterol with proven anticancer effects, induces anoikis through the EGFR/Akt pathway in HCT116 colorectal cancer cells both in vitro and in vivo.

Rhus vernicifera Laccase Immobilization on Magnetic Nanoparticles to Improve Stability and Its Potential Application in Bisphenol A Degradation.

In the present study, Rhus vernicifera laccase (RvLac) was immobilized through covalent methods on the magnetic nanoparticles. Fe2O3 and Fe3O4 nanoparticles activated by 3-aminopropyltriethoxysilane followed with glutaraldehyde showed maximum immobilization yields and relative activity up to 81.4 and 84.3% at optimum incubation and pH of 18 h and 5.8, respectively. The maximum RvLac loading of 156 mg/g of support was recorded on Fe2O3 nanoparticles. A higher optimum pH and temperature of 4.0 and 45 °C were noted for immobilized enzyme compared to values of 3.5 and 40 °C for free form, respectively. Immobilized RvLac exhibited better relative activity profiles at various pH and temperature ranges. The immobilized enzyme showed up to 16-fold improvement in the thermal stability, when incubated at 60 °C, and retained up to 82.9% of residual activity after ten cycles of reuses. Immobilized RvLac exhibited up to 1.9-fold higher bisphenol A degradation efficiency potential over free enzyme. Previous reports have demonstrated the immobilization of RvLac on non-magnetic supports. This study has demonstrated that immobilization of RvLac on magnetic nanoparticles is very efficient especially for achieving high loading, better pH and temperature profiles, and thermal- and solvents-stability, high reusability, and higher degradation of bisphenol A.

Anti-Obesity Effect of an Ethanol Extract of Cheongchunchal In Vitro and In Vivo.

Cheongchunchal (CE) is a developed crop more highly enriched in cyanidin-3-O-glucoside chloride (anthocyanin) than conventional waxy corn. Anthocyanin has been proven to have anti-oxidant, anti-inflammatory, anti-obesity, and anti-cancer effects. In this study, using high-performance liquid chromatography (HPLC), Cheongchunchal was confirmed to contain 8.99 mg/g anthocyanin. The inhibitory effect of an ethanol extract of Cheongchunchal (CE) on adipocyte differentiation was demonstrated using Oil Red O staining and a triglyceride assay. By conducting Western blotting, we also confirmed the regulatory effect of CE on adipocyte differentiation factors by assessing changes in the levels of factors that play a significant role in the differentiation of 3T3-L1 preadipocytes. A C57BL/6N mouse model of obesity was induced with a high-fat diet, and CE (400, 600, and 800 mg/kg/day) or Garcinia (245 mg/kg/day) was orally administered to verify the anti-obesity effect of CE. As a result of CE administration, the food efficiency ratio (FER), weight gain, and weight of tissues decreased. Additionally, blood biochemical changes were observed. Furthermore, the inhibitory effect of CE on adipocytes was confirmed through morphological observation and the expression of adipocyte differentiation-related factors in the liver and fat tissues. Therefore, in this study, we verified the anti-obesity effects of anthocyanin-rich CE both in vitro and in vivo.

Agesasines A and B, Bromopyrrole Alkaloids from Marine Sponges Agelas spp.

Exploration for specialized metabolites of Okinawan marine sponges Agelas spp. resulted in the isolation of five new bromopyrrole alkaloids, agesasines A (1) and B (2), 9-hydroxydihydrodispacamide (3), 9-hydroxydihydrooroidin (4), and 9E-keramadine (5). Their structures were elucidated on the basis of spectroscopic analyses. Agesasines A (1) and B (2) were assigned as rare bromopyrrole alkaloids lacking an aminoimidazole moiety, while 3-5 were elucidated to be linear bromopyrrole alkaloids with either aminoimidazolone, aminoimidazole, or N-methylated aminoimidazole moieties.

Context-Dependent Requirement of Euchromatic Histone Methyltransferase Activity during Reprogramming to Pluripotency.

Methylation of histone 3 at lysine 9 (H3K9) constitutes a roadblock for cellular reprogramming. Interference with methyltransferases or activation of demethylases by the cofactor ascorbic acid (AA) facilitates the derivation of induced pluripotent stem cells (iPSCs), but possible interactions between specific methyltransferases and AA treatment remain insufficiently explored. We show that chemical inhibition of the methyltransferases EHMT1 and EHMT2 counteracts iPSC formation in an enhanced reprogramming system in the presence of AA, an effect that is dependent on EHMT1. EHMT inhibition during enhanced reprogramming is associated with rapid loss of H3K9 dimethylation, inefficient downregulation of somatic genes, and failed mesenchymal-to-epithelial transition. Furthermore, transient EHMT inhibition during reprogramming yields iPSCs that fail to efficiently give rise to viable mice upon blastocyst injection. Our observations establish novel functions of H3K9 methyltransferases and suggest that a functional balance between AA-stimulated enzymes and EHMTs supports efficient and less error-prone iPSC reprogramming to pluripotency.

Author Correction: The peptide AC 2 isolated from Bacillus-treated Trapa japonica fruit extract rescues DHT (dihydrotestosterone)-treated human dermal papilla cells and mediates mTORC1 signaling for autophagy and apoptosis suppression.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Characterization of Cellobiohydrolases from Schizophyllum commune KMJ820.

A novel cellobiohydrolase (CBH)-generating fungi have been isolated and categorized as Schizophyllum commune KMJ820 based on morphology and rDNA gene sequence. Cellulose powder was used as carbon source, the total enzyme activity was 11.51 U/ml is noted; which is among the highest amounts of CBH-generating microbes studied. CBH have been purified to homogenize, with pursual of serial chromatography using S. commune supernatants and two different CBHs were found; CBH 1 and 2. The filtered CBHs showed greater activity (V max = 51.4 and 20.8 U/mg) in contrast to CBHs from earlier studies. The MW (molecular weights) of S. commune CBH 1 and 2 were verified to be approximately 50 kDa and 150 kDa, respectively, by size exclusion chromatography. Even though CBHs have been evaluated from other sources, but S. commune CBH is prominent in comparison to other CBHs by its high enzyme activity.

Tyr320 is a molecular determinant of the catalytic activity of ß-glucosidase from Neosartorya fischeri.

ß-Glucosidases (BGL) are key members of the cellulase enzyme complex that determine efficiency of lignocellulosic biomass degradation, which have shown great functional importance to many biotechnological systems. A previous reported BGL from Neosartorya fischeri (NfBGL) showed much higher activity than other BGLs. Screening the important residues based on sequence alignment, analyzing a homology model, and subsequent alteration of individually screened residues by site-directed mutagenesis were carried out to investigate the molecular determinants of the enzyme's high catalytic efficiency. Tyr320, located in the wild-type NfBGL substrate-binding pocket was identified as crucial to the catalytic function of NfBGL. The replacement of Tyr320 with aromatic amino acids did not significantly alter the catalytic efficiency towards p-nitrophenyl ß-d-glucopyranoside (pNPG). However, mutants with charged and hydrophilic amino acids showed almost no activity towards pNPG. Computational studies suggested that an aromatic acid is required at position 320 in NfBGL to stabilize the enzyme-substrate complex formation. This knowledge on the mechanism of action of the molecular determinants can also help rational protein engineering of BGLs.

Linaburiosides A-D, acylated iridoid glucosides from Linaria buriatica.

Four previously undescribed acylated iridoid glucosides, linaburiosides A‒D, one undescribed iridoid, 7-deoxyiridolactonic acid, and one known acylated iridoid glucoside, iridolinarin C, were isolated from the aerial parts of a Mongolian traditional herbal medicine, Linaria buriatica. Linaburiosides A‒D had an acyl moiety corresponding to 7-deoxyiridolactonic acid. Detailed spectroscopic analyses of linaburiosides A‒D and 7-deoxyiridolactonic acid led to the assignment of their structures. The absolute configuration of 7-deoxyiridolactonic acid was elucidated by application of the PGME method; those of linaburiosides A‒D were assigned on the basis of chemical conversions, as well as application of the modified Mosher's method. The absolute configuration of iridolinarin C was also elucidated in this study. Anti-inflammatory and antiproliferative activities of isolated compounds and their derivatives were evaluated.

Solvent fractions of fermented Trapa japonica fruit extract stimulate collagen synthesis through TGF-ß1/GSK-3ß/ß-catenin pathway in human dermal fibroblasts.

BACKGROUND: The dermis, composed predominantly of dermal fibroblasts and extracellular matrix (ECM), consists of fibrous proteins such as collagen and elastin and is associated with wrinkle formation and dermal elasticity. As the major constituent of the dermal matrix, collagen strengthens the skin, enhances its elasticity and protects it from external factors, such as ultraviolet (UV) rays, skin inflammation, intracellular metabolites, and aging. AIMS: Economic growth and long-life expectancy have increased the interest in beauty, with extensive studies conducted to evaluate the anti-aging and health-promoting benefits of bioactive substances. METHODS: In this study, we used natural ingredients, Trapa japonica fruit is a hard, aquatic plant that grows in ponds or marshes and contains protein and starch. To develop the ingredients for comprehensive skin improvement, this study investigated the effects of the trapa japonica fruit extract on the improvement of skin cells. CONCLUSION: We investigated the role of the fermented hot-water trapa japonica fruit extract to isolate the active ingredients with antiwrinkle effects in vitro and ex vivo situation through human dermal fibroblast cell proliferation via activating TGF-ß1/GSK-3ß/ß-catenin pathway.

Comparison of the effects of gemigliptin and dapagliflozin on glycaemic variability in type 2 diabetes: A randomized, open-label, active-controlled, 12-week study (STABLE II study).

AIMS: The aim of this study was to compare the effect of gemigliptin, a dipeptidyl peptidase-4 inhibitor, and dapagliflozin, a sodium glucose co-transporter-2 inhibitor, on glycaemic variability in type 2 diabetes patients. MATERIALS AND METHODS: In this randomized, blinded end point, multicentre clinical trial, we enrolled 71 patients with type 2 diabetes who were inadequately controlled with metformin alone or were drug naïve. The participants were randomized to receive gemigliptin 50 mg (n = 35) or dapagliflozin 10 mg (n = 36) daily for 12 weeks. Glycaemic variability was estimated by mean amplitude of glycaemic excursions (MAGE), standard deviation (SD) and coefficient of variation (CV) using a 6-day continuous glucose monitoring system. The primary efficacy endpoint was change in MAGE after 12 weeks compared to baseline. RESULTS: Intergroup differences in baseline characteristics were not significant. The adjusted mean change (± standard error) in MAGE after 12 weeks in the gemigliptin and dapagliflozin groups was -27.2 ± 4.4 mg/dL and -7.9 ± 4.9 mg/dL, respectively. Between-group comparisons showed a significantly larger reduction in MAGE in the gemigliptin group (-19.2 mg/dL; 95% CI, -31.3 to -7.2; P = .002). Measures of SD and CV also showed a significantly larger reduction in the gemigliptin group. Average glycaemic control, estimated by HbA1c, fasting glucose and safety profiles, was comparable between the two groups. CONCLUSIONS: Compared to dapagliflozin, gemigliptin significantly improved glycaemic variability, with similar glucose-lowering efficacy and safety profiles in patients with type 2 diabetes who were inadequately controlled with metformin alone or were drug naïve.