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Ultraviolet-B (UVB) radiation-induced photoaging of the skin is characterized by amplified expression of matrix metalloproteinase-1 (MMP-1) and reduced collagen fibers, both of which contribute to skin wrinkle formation. Edible natural products can protect against skin photoaging. Here, we investigate the protective effect of Dolichos lablab Linne (DLL) water extract against UVB radiation-prompted skin damage and attempt to uncover its fundamental mechanisms in human keratinocytes (HaCaT) and HR-1 hairless mouse. We found DLL extract rescued the reduction in cell viability associated with UVB exposure without any associated cytotoxic effects. It also protected against skin photoaging by inhibiting mitogen-activating protein kinase (MAPK) signaling, thereby preventing the UVB-associated increase in MMP-1 and -9 expression. DLL extract also increased the expression of both superoxide dismutase 1 (SOD1) and catalase (CAT). We identified chikusetsusaponin IVa, soyasaponin Bb, and sandosaponin A as bioactive components of DLL. Although we have not yet identified the mechanisms by which these compounds reduce the effects of photoaging, we have demonstrated that chikusetsusaponin IVa, soyasaponin Bb, and sandosaponin A reduce MMP-1, MMP-9, p–c-Fos, and p–c-Jun expression, while also avoiding any cytotoxicity. We found oral administration of DLL extract effectively alleviated dorsal epidermal thickening and skin dehydration in HR-1 hairless mouse visible to UVB. DLL extract also prevents UVB-induced activation of the MAPK/AP-1 signaling pathway, thereby reducing the expression of MMPs in dorsal mouse skin. Our results indicate that chikusetsusaponin IVa, soyasaponin Bb, and sandosaponin A are bioavailable components of DLL extract that can reduce UVB-induced skin damage via MMPs by deactivating the MAPK/AP-1 signaling pathway. These findings suggest DLL extract can be used as a skin anti-photoaging agent.

The leaves of Thunb. are a source of traditional herbal medicines found in East Asia. The present study aimed to evaluate the mechanisms underlying the antidepressant-like effects of water extract of Thunb. leaves (VBLW) in a mouse model of chronic restraint stress (CRS) and to identify the possible molecular mechanisms of the neuroprotective effects. The CRS-exposed mice were orally administered VBLW (100 and 200 mg/kg) daily for 21 days consecutively. The behavioral effects of VBLW were assessed through the forced swim test (FST) and the open field test (OFT). The levels of serum corticosterone (CORT), corticotropin releasing hormone (CRH), and adrenocorticotropin hormone (ACTH), brain monoamines, such as serotonin, dopamine, and norepinephrine, and serotonin turnover by tryptophan hydroxylase 2 (TPH2), serotonin reuptake (SERT), and monoamine oxidase A (MAO-A) were evaluated, in addition to the extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt) signaling pathway. CRS-exposed mice treated with VBLW (100 and 200 mg/kg) showed significantly reduced immobility time and increased swimming and climbing times in the FST, and increased locomotor activity in the OFT. Moreover, CRS mice treated with VBLW exhibited significantly decreased CORT and ACTH, but enhanced brain monoamine neurotransmitters. In addition, CRS mice treated with VBLW had dramatically decreased protein levels of MAO-A and SERT, but increased TPH2 protein levels in the hippocampus and the PFC. Similarly, VBLW significantly upregulated the ERKs/Akt signaling pathway in the hippocampus and the PFC. Furthermore, VBLW showed neuroprotective effects via increased CREB phosphorylation in CORT-induced cell injury that were mediated through the ERK/Akt/mTOR signaling pathways. These results suggested that the antidepressant-like effects of VBLW might be mediated by the regulation of the HPA axis, glucocorticoids, and serotonin turnover, such as TPH2, SERT, and MAO-A, as well as the concentration of monoamine neurotransmitters, and the activities of ERK and Akt phosphorylation, which were possibly associated with neuroprotective effects.

Inflammation is emerging as a key contributor to many vascular diseases and furthermore plays a major role in autoimmune diseases, arthritis, allergic reactions, and cancer. Lipopolysaccharide (LPS), which is a component constituting the outer membrane of Gram-negative bacteria, is commonly used for an inflammatory stimuli to mimic inflammatory diseases. Nuclear factor-kappa B (NF-κB) is a transcription factor and regulates gene expression particularly related to the inflammatory process. (Lardizabalaceae) is widely used as a traditional herbal medicine for rheumatism and osteoporosis and as an analgesic, sedative, and diuretic in Korea, Japan, and China. The purpose of this study was to investigate the anti-inflammatory activity of YRA-1909, the leaf aqueous extract of using LPS-activated rat peritoneal macrophages and rodent inflammation models. YRA-1909 inhibited the LPS-induced nitric oxide (NO) and proinflammatory cytokine production in rat peritoneal macrophages without causing cytotoxicity and reduced inducible NO synthase and prostaglandin E levels without affecting the cyclooxygenase-2 expression. YRA-1909 also prevented the LPS-stimulated Akt and NF-κB phosphorylation and reduced the carrageenan-induced hind paw edema, xylene-induced ear edema, acetic acid-induced vascular permeation, and cotton pellet-induced granuloma formation in a dose-dependent manner in mice and rats. leaf extract YRA-1909 had anti-inflammatory activity and that involves modulation of Akt/NF-κB signaling. Thus, YRA-1909 is safe and effective for the treatment of inflammation.

To provide consistent pain relief and improve convenient sustained release (SR), a fixed-dose combination tramadol/acetaminophen tablet was formulated. This study aimed to evaluate the pharmacokinetic profiles of an SR 75-mg tramadol/650-mg acetaminophen formulation after a single dose compared with an immediate release (IR) 37.5-mg tramadol/325-mg acetaminophen formulation after 2 doses and at steady state and to assess the effect of food on the pharmacokinetic SR formulation profile after a single dose. Two clinical trials were conducted: (1) an open-label, randomized, 3-period, 3-treatment, crossover study to assess the pharmacokinetic SR (one 75-mg tramadol/650-mg acetaminophen combination tablet) formulation profiles after a single dose and IR (one 37.5-mg tramadol/325-mg acetaminophen combination tablet q6h for 2 doses) formulation profiles after 2 doses and the effect of food intake on healthy male subjects and (2) an open, randomized, 2-period, 2-treatment multiple dose crossover study to evaluate the steady-state pharmacokinetic SR and IR formulation profiles. Safety assessments were performed. Forty-three subjects completed each study protocol. The SR combination tramadol/acetaminophen formulation was clinically and statistically equivalent to the IR combination formulation in the fasting state. When tramadol and acetaminophen tablets were administered with food, the time to peak plasma concentrations and the tramadol/acetaminophen absorption were unaffected. There was no serious adverse event reported. The SR combination tramadol/acetaminophen tablet exhibited similar exposure and absorption rates compared with those of the IR formulation of tramadol, O-desmethyltramadol, and acetaminophen. The SR formulation may be more convenient for patients and has the potential to enhance compliance and pain control. ClinicalTrials.gov identifier: NCT01880125

We investigated the in vitro transport characteristics of catalposide in HEK293 cells overexpressing organic anion transporter 1 (OAT1), OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, organic cation transporter 1 (OCT1), OCT2, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). The transport mechanism of catalposide was investigated in HEK293 and LLC-PK1 cells overexpressing the relevant transporters. The uptake of catalposide was 319-, 13.6-, and 9.3-fold greater in HEK293 cells overexpressing OAT3, OATP1B1, and OATP1B3 transporters, respectively, than in HEK293 control cells. The increased uptake of catalposide via the OAT3, OATP1B1, and OATP1B3 transporters was decreased to basal levels in the presence of representative inhibitors such as probenecid, furosemide, and cimetidine (for OAT3) and cyclosporin A, gemfibrozil, and rifampin (for OATP1B1 and OATP1B3). The concentration-dependent OAT3-mediated uptake of catalposide revealed the following kinetic parameters: Michaelis constant (K m) =41.5 μM, maximum uptake rate (V max) =46.2 pmol/minute, and intrinsic clearance (CL int) =1.11 μL/minute. OATP1B1- and OATP1B3-mediated catalposide uptake also showed concentration dependency, with low CL int values of 0.035 and 0.034 μL/minute, respectively. However, the OCT1, OCT2, OAT1, P-gp, and BCRP transporters were apparently not involved in the uptake of catalposide into cells. In addition, catalposide inhibited the transport activities of OAT3, OATP1B1, and OATP1B3 with half-maximal inhibitory concentration values of 83, 200, and 235 μM, respectively. However, catalposide did not significantly inhibit the transport activities of OCT1, OCT2, OAT1, P-gp, or BCRP. In conclusion, OAT3, OATP1B1, and OATP1B3 are major transporters that may regulate the pharmacokinetic properties and may cause herb-drug interactions of catalposide, although their clinical relevance awaits further evaluation.

Stauntonia hexaphylla leaf extract (YRA-1909), which is widely used for the antirheumatic properties, has been under phase 2 clinical trials in patients with rheumatoid arthritis since April 2017. Liquid chromatography-tandem mass spectrometric method while using liquid–liquid extraction with ethyl acetate was validated for the simultaneous determination of the major active components of YRA-1909, including chlorogenic acid (CGA), neochlorogenic acid (NCGA), cryptochlorogenic acid (CCGA), and their metabolites (i.e., caffeic acid (CA), caffeic acid 3-O-glucuronide (CA-3-G), caffeic acid 4-O-glucuronide (CA-4-G), and ferulic acid (FA)) in rat plasma and applied to a pharmacokinetic study of YRA-1909 in rats. Seven analytes were separated on Halo C18 while using gradient elution of formic acid and methanol, and then quantified in selected reaction monitoring mode whle using negative electrospray ionization. Following oral administration of YRA-1909 at doses of 25, 50, and 100 mg/kg to male Sprague-Dawley rats, CGA, NCGA, and CCGA were rapidly absorbed and metabolized to CA, CA-3-G, and CA-4-G. The area under the plasma concentration-time curve (AUClast) of CGA, NCGA, CCGA, and three metabolites linearly increased as the YRA-1909 dose increased. Other pharmacokinetic parameters were comparable among three doses studied. AUClast values for CA, CA-3-G, and CA-4-G exceeded those for CGA, NCGA, and CCGA.

Verproside, a catalpol derivative iridoid glycoside isolated from Pseudolysimachion rotundum var. subintegrum, is a biologically active compound with anti-inflammatory, antinociceptic, antioxidant, and anti-asthmatic properties. Twenty-one metabolites were identified in bile and urine samples obtained after intravenous administration of verproside in rats using liquid chromatography-quadrupole Orbitrap mass spectrometry. Verproside was metabolized by O-methylation, glucuronidation, sulfation, and hydrolysis to verproside glucuronides (M1 and M2), verproside sulfates (M3 and M4), picroside II (M5), M5 glucuronide (M7), M5 sulfate (M9), isovanilloylcatalpol (M6), M6 glucuronide (M8), M6 sulfate (M10), 3,4-dihydroxybenzoic acid (M11), M11 glucuronide (M12), M11 sulfates (M13 and M14), 3-methyoxy-4-hydroxybenzoic acid (M15), M15 glucuronides (M17 and M18), M15 sulfate (M20), 3-hydroxy-4-methoxybenzoic acid (M16), M16 glucuronide (M19), and M16 sulfate (M21). Incubation of verproside with rat hepatocytes resulted in thirteen metabolites (M1–M11, M13, and M14). Verproside sulfate, M4 was a major metabolite in rat hepatocytes. After intravenous administration of verproside, the drug was recovered in bile (0.77% of dose) and urine (4.48% of dose), and O-methylation of verproside to picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation was identified as major metabolic pathways compared to glucuronidation and sulfation of verproside in rats.

Verproside, an active iridoid glycoside component of Veronica species, such as Pseudolysimachion rotundum var. subintegrum and Veronica anagallis-aquatica, possesses anti-asthma, anti-inflammatory, anti-nociceptive, antioxidant, and cytostatic activities. Verproside is metabolized into nine metabolites in human hepatocytes: verproside glucuronides (M1, M2) via glucuronidation, verproside sulfate (M3) via sulfation, picroside II (M4) and isovanilloylcatalpol (M5) via O-methylation, M4 glucuronide (M6) and M4 sulfate (M8) via further glucuronidation and sulfation of M4, and M5 glucuronide (M7) and M5 sulfate (M9) via further glucuronidation and sulfation of M5. Drug-metabolizing enzymes responsible for verproside metabolism, including sulfotransferase (SULT) and UDP-glucuronosyltransferase (UGT), were characterized. The formation of verproside glucuronides (M1, M2), isovanilloylcatalpol glucuronide (M7), and picroside II glucuronide (M6) was catalyzed by commonly expressed UGT1A1 and UGT1A9 and gastrointestinal-specific UGT1A7, UGT1A8, and UGT1A10, consistent with the higher intrinsic clearance values for the formation of M1, M2, M6, and M7 in human intestinal microsomes compared with those in liver microsomes. The formation of verproside sulfate (M3) and M5 sulfate (M9) from verproside and isovanilloylcatalpol (M5), respectively, was catalyzed by SULT1A1. Metabolism of picroside II (M4) into M4 sulfate (M8) was catalyzed by SULT1A1, SULT1E1, SULT1A2, SULT1A3, and SULT1C4. Based on these results, the pharmacokinetics of verproside may be affected by the co-administration of relevant UGT and SULT inhibitors or inducers.

Ground settlement occurs because of the surrounding ground behavior during tunnel excavation. A high chance of its occurrence could cause the collapse of buildings; therefore, the accurate prediction and assessment of ground settlement are necessary when structures are concentrated in urban regions. This study leverages Geographic Information Systems (GIS) and 3D modeling to evaluate the effects of tunnel excavation on the ground settlement and damage of buildings along the Mandeok–Centum underground highway in Busan. It integrates the field topography with building data to simulate and visualize construction-induced interactions. Numerical analysis is used to assess the effects of the terrain elevation, building presence, excavation sequences, and lag distance between the twin tunnels on the settlement. The results indicate that high terrain elevation, dense building layouts, and shorter distances between tunnels increase settlement. Furthermore, this study deduces that bidirectional excavation causes a rapid increase in settlement compared with parallel excavation, which is evident from the variations in the inflection points during the excavation process. Finally, this study estimates the damage to buildings and ground settlements and visualizes risk maps using GIS, emphasizing the practicality of 3D modeling based on GIS.

There has been an increasing awareness of sarcopenia, which is characterized by a concomitant decrease in skeletal muscle mass and quality due to aging. Resistance exercise is considered more effective than aerobic exercise in terms of therapeutic exercise. To confirm the effect of long-term aerobic exercise in preventing sarcopenia, we evaluated the skeletal muscle mass, quality, and angiogenic capacity of super-aged mice that had undergone lifelong spontaneous exercise (LSE) through various experiments. Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition, ex vivo experiments showed that the angiogenic capacity was maintained at a high level. However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed. In conclusion, LSE appears to maintain the potential of angiogenesis and slow the aging process to maintain skeletal muscle mass and quality. Aerobic exercise may thus be effective for the prevention of sarcopenia.