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Irritable bowel syndrome (IBS), a common gastrointestinal disorder worldwide, is characterized by chronic abdominal pain, bloating, and disordered defecation. IBS is associated with several factors, including visceral hypersensitivity, gut motility, and gut-brain interaction disorders. Because currently available pharmacological treatments cannot adequately improve symptoms and may cause adverse effects, the use of herbal therapies for managing IBS is increasing. Lysimachia vulgaris var. davurica (LV) is a medicinal plant used in traditional medicine to treat diarrhea. However, information on whether LV can effectively improve diarrhea-predominant IBS (IBS-D) remains limited. In this study, using an experimental mouse model of IBS-D, we elucidated the effects of the LV extract. The methanol extract of LV decreased fecal pellet output in the restraint stress- or 5-hydroxytryptamine (5-HT)-induced IBS mouse model and inhibited 5-HT-mediated [Ca 2+ ] i increase in a dose-dependent manner. Furthermore, we developed and validated a high-performance liquid chromatography method using two marker compounds, namely, chlorogenic acid and rutin, for quality control analysis. Our study results suggest the feasibility of the methanol extract of LV for developing therapeutic agents to treat IBS-D by acting as a 5-HT 3 receptor antagonist.

Bifidobacteria are probiotic microorganisms commonly found in the gastrointestinal tract, some of which are known to utilize linear arabino-oligosaccharides (AOS) as prebiotic carbohydrates. In general, the synergistic actions of exo-type α-l-arabinofuranosidases (ABFs) and endo-α-1,5-l-arabinanases (ABNs) are required for efficient arabinan degradation. In this study, the putative gene cluster for arabinan degradation was discovered in the genome of Bifidobacterium longum subsp. suis . It consists of a variety of genes encoding exo- and endo-hydrolases, sugar-binding proteins, ABC-binding cassettes, and transcriptional regulators. Among them, two endo-ABNs GH43 (BflsABN43A and BflsABN43B), two exo-ABFs GH43 (BflsABF43A and BflsABF43B), and an exo-ABF GH51 (BflsABF51) were predicted to be the key hydrolases for arabinan degradation. These hydrolase genes were functionally expressed in Escherichia coli , and their enzymatic properties were characterized. Their synergism in arabinan degradation has been proposed from the detailed modes of action. Extracellular endo-BflsABN43A hydrolyzes sugar beet and debranched arabinans into the short-chain branched and linear AOS. Intracellularly, AOS can be further degraded into l-arabinose via the cooperative actions of endo-BflsABN43B, exo-BflsABF43A with debranching activity, α-1,5-linkage-specific exo-BflsABF43B, and exo-BflsABF51 with dual activities. The resulting l-arabinose is expected to be metabolized into energy through the pentose phosphate pathway by three enzymes expressed from the ara operon of bifidobacteria. It is anticipated that uncovering arabinan utilization gene clusters and their detailed functions in the genomes of diverse microorganisms will facilitate the development of customized synbiotics.

The mTOR signaling pathway integrates signaling inputs from nutrients, including glucose and amino acids, which are precisely regulated by transporters depending on nutrient levels. The L-type amino acid transporter 1 (LAT1) affects the activity of mTORC1 through upstream regulators that sense intracellular amino acid levels. While mTORC1 activation by LAT1 has been thoroughly investigated in cultured cells, the effects of LAT1 expression on the activity of mTORC2 has scarcely been studied. Here, we provide evidence that LAT1 recruits and activates mTORC2 on the lysosome for PMA-induced cell migration. LAT1 is translocated to the lysosomes in cells treated with PMA in a dose- and time-dependent manner. Lysosomal LAT1 interacted with mTORC2 through a direct interaction with Rictor, leading to the lysosomal localization of mTORC2. Furthermore, the depletion of LAT1 reduced PMA-induced cell migration in a wound-healing assay. Consistent with these results, the LAT1 N3KR mutant, which is defective in PMA-induced endocytosis and lysosomal localization, did not induce mTORC2 recruitment to the lysosome, with the activation of mTORC2 determined via Akt phosphorylation or the LAT1-mediated promotion of cell migration. Taken together, lysosomal LAT1 recruits and activates the mTORC2 complex and downstream Akt for PMA-mediated cell migration. These results provide insights into the development of therapeutic drugs targeting the LAT1 amino acid transporter to block metastasis, as well as disease progression in various types of cancer.

This study examines the impacts of copper and boron in parts per million (ppm) on the microstructure and mechanical properties of spheroidal graphite cast iron (SCI). Boron's inclusion increases the ferrite content whereas copper augments the stability of pearlite. The interaction between the two significantly influences the ferrite content. Differential scanning calorimetry (DSC) analysis indicates that boron alters the enthalpy change of the α + Fe3C → γ conversion and the α → γ conversion. Scanning electron microscope (SEM) analysis confirms the locations of copper and boron. Mechanical property assessments using a universal testing machine show that the inclusion of boron and copper decreases the tensile strength and yield strength of SCI, but simultaneously enhances elongation. Additionally, in SCI production, the utilization of copper-bearing scrap and trace amounts of boron-containing scrap metal, especially in the casting of ferritic nodular cast iron, offers potential for resource recycling. This highlights the importance of resource conservation and recycling in advancing sustainable manufacturing practices. These findings provide critical insights into the effects of boron and copper on SCI's behavior, contributing to the design and development of high-performance SCI materials.

Zinc (Zn), a heavy metal, is an essential element in fish; however, exposure to high concentrations causes oxidative stress. Water hardness reduces oxidative stress reactions caused by heavy metals. To confirm the effect of water hardness on oxidative stress caused by Zn, goldfish were exposed to various Zn concentrations (1.0, 2.0, and 5.0 mg/L) and water hardness (soft (S), hard (H), and very hard (V)). The activity of superoxide dismutase (SOD) and catalase (CAT) in plasma increased with 1.0, 2.0, and 5.0 mg/L of Zn, and decreased with H and V water hardness. The levels of H 2 O 2 and lipid peroxide (LPO) increased with Zn above 1.0 mg/L and decreased with H and V of water hardness. Caspase-9 mRNA expression in the liver increased after 7 and 14 days of Zn exposure and decreased with H and V water hardness. It was confirmed that DNA damage was less dependent on H and V water hardness. Based on the results of this study, at least 1.0 mg/L Zn causes oxidative stress in goldfish, and a high level of apoptosis occurs when exposed for more than 7 days. It appears that the oxidative stress generated by Zn can be alleviated by water hardness of at least 270 mg/L CaCO 3 . This study provides information on the relationship between the antioxidant response caused by heavy metals and water hardness in fish.

Cell-assisted lipotransfer (CAL), defined as co-transplantation of aspirated fat with enrichment of adipose-derived stem cells (ASCs), is a novel technique for cosmetic and reconstructive surgery to overcome the low survival rate of traditional fat grafting. However, clinically approved techniques for increasing the potency of ASCs in CAL have not been developed yet. As a more clinically applicable method, we used mechanical stress to reinforce the potency of ASCs. Mechanical stress was applied to the inguinal fat pad by needling . Morphological and cellular changes in adipose tissues were examined by flow cytometric analysis 1, 3, 5, and 7 days after the procedure. The proliferation and adipogenesis potencies of ASCs were evaluated. CAL with ASCs treated with mechanical stress or sham control were performed, and engraftment was determined at 4 weeks post-operation. Flow cytometry analysis revealed that mechanical stress significantly increased the number as well as the frequency of ASC proliferation in fat. Proliferation assays and adipocyte-specific marker gene analysis revealed that mechanical stress promoted proliferation potential but did not affect the differentiation capacity of ASCs. Moreover, CAL with cells derived from mechanical stress-treated fat increased the engraftment. Our results indicate that mechanical stress may be a simple method for improving the efficacy of CAL by enhancing the proliferation potency of ASCs.

Growth factors are mostly secreted proteins that play key roles in an organism's biophysical processes through binding to specific receptors on the cell surface. The mollusk-like growth factor ( MLGF ) is a novel cell signaling protein in the adenosine deaminase-related growth factor (ADGF) subfamily. In this study, the MLGF gene was cloned and characterized from the digestive gland tissue of Pacific abalone and designated as Hdh-MLGF . The transcribed full-length sequence of Hdh-MLGF was 1829 bp long with a 1566 bp open reading frame (ORF) encoding 521 amino acids. The deduced amino acid sequence contained a putative signal peptide and two conserved adenosine deaminase domains responsible for regulating molecular function. Fluorescence in situ hybridization localized Hdh-MLGF in the submucosa layer of digestive tubules in the digestive gland. The mRNA expression analysis indicated that Hdh-MLGF expression was restricted to the digestive gland in the adult Pacific abalone. However, Hdh-MLGF mRNA expressions were observed in all stages of embryonic and larval development, suggesting Hdh-MLGF might be involved in the Pacific abalone embryonic and larval development. This is the first study describing Hdh-MLGF and its involvement in the Pacific abalone embryonic and larval development.

Despite substantially elevated risk of serious adverse events (SAEs) from targeted therapy in combination with chemotherapy, comprehensive pharmacovigilance research is limited. This study aims to systematically assess SAE risks of commonly prescribed targeted agents (bevacizumab, cetuximab, and panitumumab) in patients with rat sarcoma viral oncogene homolog (RAS) wild-type metastatic colon cancer. Keyword searches of Cochrane Library, Clinical Key and MEDLINE were conducted per PRISMA-NMA guidelines. Frequentist network meta-analysis was performed with eight randomized controlled trials to compare relative risk (RR) of 21 SAE profiles. The risks of hematological, gastrointestinal, neurological SAE were insignificant among targeted agents (p > 0.05). The risk of serious hypertension was substantially elevated in bevacizumab-based chemotherapy (p < 0.05), whereas panitumumab-based chemotherapy had markedly elevated risk of serious thromboembolism (RR 3.65; 95% CI 1.30−10.26). Although both cetuximab and panitumumab demonstrated increased risk of serious dermatological and renal toxicities, panitumumab-based chemotherapy has relatively higher risk of skin toxicity (RR 15.22; 95% CI 7.17−32.35), mucositis (RR 3.18; 95% CI 1.52−6.65), hypomagnesemia (RR 20.10; 95% CI 5.92−68.21), and dehydration (RR 2.81; 95% CI 1.03−7.67) than cetuximab-based chemotherapy. Thus, further studies on risk stratification and SAE management are warranted for safe administration of targeted agents.

The white-rot fungi Ceriporia lacerata is used in bioremediation, such as lignocellulose degradation, in nature. Submerged cultures and extracts of C. lacerata mycelia (CLM) have been reported to contain various active ingredients, including β-glucan and extracellular polysaccharides, and to exert anti-diabetogenic properties in mice and cell lines. However, the immunostimulatory effects have not yet been reported. This study aimed to identify the immunomodulatory effects, and underlying mechanisms thereof, of submerged cultures of CLM using RAW264.7 macrophages and cyclophosphamide (CTX)-induced immunosuppression in mice. Compared to CTX-induced immunosuppressed mice, the spleen and thymus indexes in mice orally administered CLM were significantly increased; body weight loss was alleviated; and natural killer (NK) cytotoxicity, lymphocyte proliferation, and cytokine (tumor necrosis factor [TNF]-α, interferon [IFN]-γ, and interleukin [IL]-2) production were elevated in the serum. In RAW264.7 macrophages, treatment with CLM induced phagocytic activity, increased the production of nitric oxide (NO), and promoted mRNA expression of the immunomodulatory cytokines TNF-α, IFN-γ, IL-1β, IL-6, IL-10, and IL-12. In addition, CLM increased the inducible NO synthase (iNOS) concentration in macrophages, similar to lipopolysaccharide (LPS) stimulation. Mechanistic studies showed that CLM induced the activation of the NF-κB, PI3k/Akt, ERK1/2, and JNK1/2 pathways. Moreover, the phosphorylation of NF-κB and IκB induced by CLM in RAW264.7 cells was suppressed by specific MAPKs and PI3K inhibitors. Further experiments with a TLR4 inhibitor demonstrated that the production of TNF-α, IL-1β, and IL-6 induced by CLM was decreased after TLR4 was blocked. Overall, CLM protected against CTX-induced adverse reactions by enhancing humoral and cellular immune functions, and has potential as an immunomodulatory agent.

Background and Objectives : This study sought to investigate the natural course, the chronicity and recurrence rate, and the risk factors of chronic and recurrent herpes zoster ophthalmicus (HZO). We also evaluated the effects of long-term treatment for HZO. Materials and Methods : Patients diagnosed and treated for HZO were included in the retrospective medical chart review. Multivariable-adjusted logistic and Cox regression models were used to show risk factors for chronic and recurrent HZO along with hazard ratios (HRs) and 95% confidence intervals (CIs). Results : Among a total 130 of HZO patients, 31 patients (23.85%) had chronic disease and 19 patients (14.62%) had recurrent disease. The rate of chronic disease was higher in HZO with conjunctivitis, epithelial keratitis, and stromal keratitis. The recurrence rate increased in patients with chronic HZO (HR: 34.4, 95% CI: 3.6-324.6), epithelial keratitis (HR: 5.5, 95% CI: 1.3-30.0), stromal keratitis (HR: 18.8, 95% CI: 3.0-120.8), and increased intraocular pressure (IOP) (HR: 7.3, 95% CI: 1.6-33.2). Length of systemic antiviral therapy and anti-inflammatory eyedrop treatment were not associated with recurrent HZO ( p = 0.847 and p = 0.660, respectively). The most common ocular manifestation for recurrent HZO was stromal keratitis. Conclusions : This study demonstrated a considerable frequency of chronic and recurrent HZO. Chronic HZO in the form of epithelial or stromal keratitis with increased IOP provoked a significant rise in the risk of recurrence.

Due to the limited supply of vessels and nerves, acute or chronic tendon injuries often result in significant and persistent complications, such as pain and sprains, as well as the loss of joint functions. Among these complications, tendon adhesions within the surrounding soft tissue have been shown to significantly impair the range of motion. In this study, to elucidate the effects of a hyaluronic acid (HA) injection at the site of tenorrhaphy on tendon adhesion formation, we used a full transection model of a rat's Achilles tendon to investigate the anti-adhesive function of HA. Our initial findings showed that significantly lower adhesion scores were observed in the HA-treated experimental group than in the normal saline-treated control group, as determined by macroscopic and histological evaluations. Hematoxylin and eosin, as well as picrosirius red staining, showed denser and irregular collagen fibers, with the larger number of infiltrating inflammatory cells in the control group indicating severe adhesion formation. Furthermore, we observed that the expression of tendon adhesion markers in operated tendon tissue, such as collagen type I, transforming growth factor-β1, and plasminogen activator inhibitor-1, was suppressed at both the gene and protein levels following HA treatment. These results suggest that HA injections could reduce tendon adhesion formation by significantly ameliorating inflammatory-associated reactions.

Interleukin 33 (IL-33) is an IL-1 family cytokine that plays a central role in immune system by regulating and initiating inflammatory responses. The binding of IL-33 to the suppressor of tumorigenicity 2 (ST2) receptor induces mitogen-activated protein kinases (MAPK) and nuclear factor κB (NF-κB) pathways, thereby leading to inflammatory cytokines production in type 2 helper T cells and type 2 innate lymphoid cells. To develop an antibody specific to IL-33 with a defined epitope, we characterized a single-chain antibody variable fragments (scFvs) clone specific to IL-33, C2&#95;2E12, which was selected from a human synthetic library of scFvs using phage display. Affinity ( K d ) of C2&#95;2E12 was determined to be 38 nM using enzyme-linked immunosorbent assay. C2&#95;2E12 did not show cross-reactivity toward other interleukin cytokines, including closely related IL-1 family cytokines and unrelated proteins. Mutational scanning analysis revealed that the epitope of IL-33 consisted of residues 149-158 with key residues being L150 and K151 of IL-33. Structural modeling suggested that L150 and K151 residues are important for the interaction of IL-33 with C2&#95;2E12, implicating that C2&#95;2E12 could block the binding of ST2 to IL-33. Pull-down and in-cell assays supported that C2&#95;2E12 can inhibit the IL-33/ST2 signaling axis. These results suggest that the scFv clone characterized here can function as a neutralizing antibody.

This study investigated the mechanical properties of steel in flanges, with the goal of obtaining high strength and high toughness. Quenching was applied alone or in combination with tempering at one of nine combinations of three temperatures T TEM and durations t TEM . Cooling rates at various flange locations during quenching were first estimated using finite element method simulation, and the three locations were selected for mechanical testing in terms of cooling rate. Microstructures of specimens were observed at each condition. Tensile test and hardness test were performed at room temperature, and a Charpy impact test was performed at -46 °C. All specimens had a multiphase microstructure composed of matrix and secondary phases, which decomposed under the various tempering conditions. Decrease in cooling rate (CR) during quenching caused reduction in hardness and strength but did not affect low-temperature toughness significantly. After tempering, hardness and strength were reduced and low-temperature toughness was increased. Microstructures and mechanical properties under the various tempering conditions and CRs during quenching were discussed. This work was based on the properties directly obtained from flanges under industrial processes and is thus expected to be useful for practical applications.

Currently available COVID-19 antibody tests using enzyme immunoassay (EIA) or immunochromatographic assay have variable sensitivity and specificity. Here, we developed and evaluated a novel microsphere-based antibody assay (MBA) for detecting immunoglobulin G (IgG) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein (NP) and spike protein receptor binding domain (RBD). The seropositive cutoff value was set using a cohort of 294 anonymous serum specimens collected in 2018. The specificity was assessed using serum specimens collected from organ donors or influenza patients before 2020. Seropositive rate was determined among COVID-19 patients. Time-to-seropositivity and signal-to-cutoff (S/CO) ratio were compared between MBA and EIA. MBA had a specificity of 100% (93/93; 95% confidence interval (CI), 96-100%) for anti-NP IgG, 98.9% (92/93; 95% CI 94.2-100%) for anti-RBD IgG. The MBA seropositive rate for convalescent COVID-19 patients was 89.8% (35/39) for anti-NP IgG and 79.5% (31/39) for anti-RBD IgG. The time-to-seropositivity was shorter with MBA than EIA. MBA could better differentiate between COVID-19 patients and negative controls with higher S/CO ratio for COVID-19 patients, lower S/CO ratio with negative controls and fewer specimens in the equivocal range. MBA is robust, simple and is suitable for clinical microbiology laboratory for the accurate determination of anti-SARS-CoV-2 antibodies for diagnosis, serosurveillance, and vaccine trials.

The root bark of Morus has long been appreciated as an antiphlogistic, diuretic and expectorant drug in Chinese herbal medicine, albeit with barely known targets and mechanisms of action. In the 1970s, the development of analytic chemistry allowed for the discovery of morusin as one of 7 different isoprene flavonoid derivatives in the root bark of Morus . However, the remarkable antioxidant capacity of morusin with the unexpected potential for health benefits over the other flavonoid derivatives has recently sparked scientific interest in the biochemical identification of target proteins and signaling pathways and further clinical relevance. In this review, we discuss recent advances in the understanding of the functional roles of morusin in multiple biological processes such as inflammation, apoptosis, metabolism and autophagy. We also highlight recent in vivo and in vitro evidence on the clinical potential of morusin treatment for multiple human pathologies including inflammatory diseases, neurological disorders, diabetes, cancer and the underlying mechanisms.

Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms. Morusin-mediated induction of stress granules requires activation of protein kinase R (PKR) and subsequent eIF2α phosphorylation. Notably, genetic inactivation of stress granule formation mediated by G3BP1 knockout sensitized cancer cells to morusin treatment. This protective function against morusin-mediated cell death can be attributed at least in part to the sequestration of receptors for activated C kinase-1 (RACK1) within the stress granules, which reduces caspase-3 activation. Collectively, our study provides biochemical evidence for the role of stress granules in suppressing the antitumor capacity of morusin, proposing that morusin treatment, together with pharmacological inhibition of stress granules, could be an efficient strategy for targeting cancer.

Dendropanax morbifera H. Levis a medicinal plant native to South Korea, East Asia, and South America. Among some 75 species, one species grows in Korea. In previous studies, D. morbifera extracts with anti-oxidant, anti-inflammatory, anti-complementary and anti-cancer activities were reported. The present study aims to investigate optimization of extraction and evaluation of anti-hyperuricemic effects of D. morbifera leaf and the phytochemicals contained therein. Ethanol and hexane extract were found to display the best xanthine oxidase inhibition among six types of solvent and water extract. The antioxidant effect of the ethanol extract was superior to that of the hexane extract. The DPPH radical scavenging effect of the ethanol and hexane extracts were 81.52 ± 1.57% and 2.69 ± 0.16. The reducing power of the ethanol and hexane extracts were 9.71 ± 0.15 and 0.89 ± 0.01 mg/g equivalent of gallic acid. Total phenols of the ethanol and hexane extracts were 6.53 ± 0.16 and 0.63 ± 0.001 mg/g equivalent of gallic acid. In addition, we compared the two marker compounds from D. morbifera , chlorogenic acid and rutin, which were determined in the ethanol extract at 0.80 ± 0.03% and 0.52 ± 0.01%, respectively. We found that the ethanol extracts showed better xanthine oxidase inhibition than hexane extracts. Especially, ethanol extracts showed higher antioxidant activity than hexane extracts. Based on these results, we selected the ethanol extract as an effective xanthine oxidase inhibitor and confirmed whether ethanol extracts showed xanthine oxidase inhibition in animal experiments. The in vivo mouse study demonstrated that ethanol extract of D. morbifera leaf at the dose of 300 mg/kg could inhibit blood/hepatic xanthine oxidase activity and this result shows that the xanthine oxidase inhibitory activity in vitro is reproduced in vivo. The present study showed that ethanol extract was optimal xanthine oxidase inhibitor which can be applied to prevent diseases related to hyperuricemia.

New skin substitutes for burn medicine or reconstructive surgery pose an important issue in plastic surgery. Matriderm® is a clinically approved three-dimensional bovine collagen-elastin matrix which is already used as a dermal substitute of full thickness burn wounds. The drawback of an avital matrix is the limited integration in full thickness skin defects, depending on the defect size. To further optimize this process, Matriderm® has also been studied as a matrix for tissue engineering of skin albeit long-term cultivation of the matrix with cells has been difficult. Cells have generally been seeded onto the matrix with high cell loss and minimal time-consuming migration. Here we developed a cell seeded skin equivalent after microtransfer of cells directly into the matrix. First, cells were cultured, and microinjected into Matriderm®. Then, cell viability in the matrix was determined by histology in vitro. As a next step, the skin substitute was applied in vivo into a full thickness rodent wound model. The wound coverage and healing was observed over a period of two weeks followed by histological examination assessing cell viability, proliferation and integration into the host. Viable and proliferating cells could be found throughout the entire matrix. The presented skin substitute resembles healthy skin in morphology and integrity. Based on this study, future investigations are planned to examine behaviour of epidermal stem cells injected into a collagen-elastin matrix under the aspects of establishment of stem cell niches and differentiation.

Several new acyclic ammonium-TFSI ionic liquids with an allyl substituent(s) were synthesized and their physicochemical and electrochemical properties were characterized. [AAMM]Am-TFSI (3) with two allyl groups showed the widest electrochemical stability window (5.9 V) among the ammonium-based ILs reported to date because of the increment of both the anodic and cathodic limits. The charge-discharge performance of a LiCoO(2)-based half-cell containing [AAMM]Am-TFSI as an electrolyte was better in cycleability (the capacity retention ratio: 99% after 20 cycles) than that of the cell with the corresponding partially saturated analogue, [AMMP]Am-TFSI (2) (the capacity retention ratio: 92% after 20 cycles).