Induction of apoptotic cell death in human bladder cancer cells by ethanol extract of Zanthoxylum schinifolium leaf,through ROS-dependent inactivation of the PI3K/Akt signaling pathway

BACKGROUND/OBJECTIVESZanthoxylum schinifolium is traditionally used as a spice for cooking in East Asian countries. This study was undertaken to evaluate the anti-proliferative potential of ethanol extracts of Z. schinifolium leaves (EEZS) against human bladder cancer T24 cells.MATERIALS/METHODSSubsequent to measuring the cytotoxicity of EEZS, the anti-cancer activity was measured by assessing apoptosis induction, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP). In addition, we determined the underlying mechanism of EEZS-induced apoptosis through various assays, including Western blot analysis.RESULTSEEZS treatment concentration-dependently inhibited T24 cell survival, which is associated with apoptosis induction. Exposure to EEZS induced the expression of Fas and Fas-ligand, activated caspases, and subsequently resulted to cleavage of poly (ADP-ribose) polymerase. EEZS also enhanced the expression of cytochrome c in the cytoplasm by suppressing MMP, following increase in the ratio of Bax:Bcl-2 expression and truncation of Bid. However, EEZS-mediated growth inhibition and apoptosis were significantly diminished by a pan-caspase inhibitor. Moreover, EEZS inhibited activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, and the apoptosis-inducing potential of EEZS was promoted in the presence of PI3K/Akt inhibitor. In addition, EEZS enhanced the production of ROS, whereas N-acetyl cysteine (NAC), a ROS scavenger, markedly suppressed growth inhibition and inactivation of the PI3K/Akt signaling pathway induced by EEZS. Furthermore, NAC significantly attenuated the EEZS-induced apoptosis and reduction of cell viability.CONCLUSIONSTaken together, our results indicate that exposure to EEZS exhibits anti-cancer activity in T24 bladder cancer cells through ROS-dependent induction of apoptosis and inactivation of the PI3K/Akt signaling pathway.     

Comparison of the effects of dexmedetomidine and propofol on hypothermia in patients under spinal anesthesia: a prospective,randomized, and controlled trial

Background: Redistribution hypothermia caused by vasodilation during anesthesia is the primary cause of perioperative hypothermia. Propofol exerts a dose-dependent vasodilatory effect, whereas dexmedetomidine induces peripheral vasoconstriction at high plasma concentrations. This study compared the effects of dexmedetomidine and propofol on core temperature in patients undergoing surgery under spinal anesthesia.Methods: This prospective study included 40 patients (aged 19-70 years) with American Society of Anesthesiologists Physical Status class I-III who underwent elective orthopedic lower-limb surgery under spinal anesthesia. Patients were randomly allocated to a dexmedetomidine or propofol group (n = 20 per group). After induction of spinal anesthesia, patients received dexmedetomidine (loading dose: 1 μg/kg over 10 min; maintenance dose: 0.2-0.7 μg/kg/h) or propofol (loading dose: 75 μg/kg over 10 min; maintenance dose: 12.5-75 μg/kg/min). The doses of sedatives were titrated to maintain moderate sedation. During the perioperative period, tympanic temperatures, thermal comfort score, and shivering grade were recorded.Results: Core temperature at the end of surgery did not differ significantly between the groups (36.4 ± 0.4 and 36.1 ± 0.7°C in the dexmedetomidine and propofol groups, respectively; P = 0.118). The lowest perioperative temperature, incidence and severity of perioperative hypothermia, thermal comfort score, and shivering grade did not differ significantly between the groups (all P > 0.05).Conclusions: In patients undergoing spinal anesthesia with moderate sedation, the effect of dexmedetomidine on patients'' core temperature was similar to that of propofol.     

Sodium Glucose Cotransporter-2 Inhibitors as an Add-on Therapy to Metformin Plus Dipeptidyl Peptidase-4 Inhibitor in Patients with Type 2 Diabetes

PurposeTo date, no study has compared the effects of adding sodium glucose cotransporter-2 (SGLT-2) inhibitors to the combination of metformin plus dipeptidyl peptidase-4 (DPP-4) inhibitors to the effects of adding other conventional anti-diabetic drugs (ADDs) to the dual therapy. We aimed to compare the effect of adding SGLT-2 inhibitors with that of adding sulfonylurea (SU) in type 2 diabetes (T2D) patients inadequately controlled with metformin plus DPP-4 inhibitors.Materials and MethodsThis study was designed to evaluate the non-inferiority of SGLT-2 inhibitor to SU as an add-on therapy to the dual combination of metformin plus DPP-4 inhibitors. A total of 292 T2D patients who started SU or SGLT-2 inhibitors as an add-on therapy to metformin plus DPP-4 inhibitors due to uncontrolled hyperglycemia, defined as glycated hemoglobin (HbA1c) ≥7%, were recruited. After propensity score matching, 90 pairs of patients remained, and 12-week changes in HbA1c levels were reviewed to assess glycemic effectiveness. Data from these patients were analyzed retrospectively.ResultsAfter 12 weeks of triple therapy, both groups showed significant changes in HbA1c levels, with a mean of -0.9% in each group. The inter-group difference was 0.01% [95% confidence interval (CI): -0.26–0.27], and the upper limit of the 95% CI was within the limit for non-inferiority (0.40%). There were no inter-group differences in the changes of liver enzyme levels and kidney function.ConclusionAdding SGLT-2 inhibitors is not inferior to adding SU as a third-line ADD to metformin plus DPP-4 inhibitor combination therapy.     

Clinical Characteristics and Risk Factors for Mortality in Critical Coronavirus Disease 2019 Patients 50 Years of Age or Younger During the Delta Wave: Comparison With Patients > 50 Years in Korea

BackgroundNumerous patients around the globe are dying from coronavirus disease 2019 (COVID-19). While age is a known risk factor, risk analysis in the young generation is lacking. The present study aimed to evaluate the clinical features and mortality risk factors in younger patients (≤ 50 years) with a critical case of COVID-19 in comparison with those among older patients (> 50 years) in Korea.MethodsWe analyzed the data of adult patients only in critical condition (requiring high flow nasal cannula oxygen therapy or higher respiratory support) hospitalized with PCR-confirmed COVID-19 at 11 hospitals in Korea from July 1, 2021 to November 30, 2021 when the delta variant was a dominant strain. Patients’ electronic medical records were reviewed to identify clinical characteristics.ResultsDuring the study period, 448 patients were enrolled. One hundred and forty-two were aged 50 years or younger (the younger group), while 306 were above 50 years of age (the older group). The most common pre-existing conditions in the younger group were diabetes mellitus and hypertension, and 69.7% of the patients had a body mass index (BMI) > 25 kg/m². Of 142 younger patients, 31 of 142 patients (21.8%, 19 women) did not have these pre-existing conditions. The overall case fatality rate among severity cases was 21.0%, and it differed according to age: 5.6% (n = 8/142) in the younger group, 28.1% in the older group, and 38% in the ≥ 65 years group. Age (odds ratio [OR], 7.902; 95% confidence interval [CI], 2.754–18.181), mechanical ventilation therapy (OR, 17.233; 95% CI, 8.439–35.192), highest creatinine > 1.5 mg/dL (OR, 17.631; 95% CI, 8.321–37.357), and combined blood stream infection (OR, 7.092; 95% CI, 1.061–18.181) were identified as independent predictors of mortality in total patients. Similar patterns were observed in age-specific analyses, but most results were statistically insignificant in multivariate analysis due to the low number of deaths in the younger group. The full vaccination rate was very low among study population (13.6%), and only three patients were fully vaccinated, with none of the patients who died having been fully vaccinated in the younger group. Seven of eight patients who died had a pre-existing condition or were obese (BMI > 25 kg/m²), and the one remaining patient died from a secondary infection.ConclusionAbout 22% of the patients in the young critical group did not have an underlying disease or obesity, but the rate of obesity (BMI > 25 kg/m²) was high, with a fatality rate of 5.6%. The full vaccination rate was extremely low compared to the general population of the same age group, showing that non-vaccination has a grave impact on the progression of COVID-19 to a critical condition. The findings of this study highlight the need for measures to prevent critical progression of COVID-19, such as vaccinations and targeting young adults especially having risk factors.     

Antimicrobial second skin using copper nanomesh

The functional support and advancement of our body while preserving inherent naturalness is one of the ultimate goals of bioengineering. Skin protection against infectious pathogens is an application that requires common and long-term wear without discomfort or distortion of the skin functions. However, no antimicrobial method has been introduced to prevent cross-infection while preserving intrinsic skin conditions. Here, we propose an antimicrobial skin protection platform copper nanomesh, which prevents cross-infectionmorphology, temperature change rate, and skin humidity. Copper nanomesh exhibited an inactivation rate of 99.99% for Escherichia coli bacteria and influenza virus A within 1 and 10 min, respectively. The thin and porous nanomesh allows for conformal coating on the fingertips, without significant interference with the rate of skin temperature change and humidity. Efficient cross-infection prevention and thermal transfer of copper nanomesh were demonstrated using direct on-hand experiments.

The functional support and advancement of our body while preserving the inherent naturalness is one of the ultimate goals of bioengineering (1–4). A functional layer is placed on the skin to complement the intrinsic biological and interactive functions (5, 6) and to add functions that do not yet exist (7–9). During use, the second skin layer should completely exploit its function and underlay skin functions without deforming the skin or interfering with the skin’s external interaction. Materials and structures need to be conformal and mechanically similar to the skin to minimize the distortion of natural sensations and movements. In addition, the air and heat transfer on the skin must be unimpeded to obtain a natural and comfortable wear fit (10).Body protection that requires common and long-term wear is an application in which both functionality and naturalness are important. As the outermost layer connecting our body to the environment, the skin is exposed to physical damage, hazardous chemicals, and infectious pathogens (11, 12). Therefore, we add a protective layer on the skin that blocks or filters out external contaminants. This entails the isolation and accumulation of biochemical compounds, which can lead to self-contamination and the subsequent cross-contamination/infection by interacting with other objects. In contrast to chemical contamination, which is not self-reproductive, the biological contamination of infectious microbes, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a considerable issue to be addressed.By containing an antimicrobial material on the surface of the skin protective layer, cross-infection can be prevented in the long term. Unlike temporary rinsing or disinfection, the use of antibacterial or antiviral substances such as chemical or natural disinfectants and metal nanomaterials inhibits the growth of microorganisms on the surface (13–17). These materials are embedded in a complete covering polymer layer, such as gloves (18, 19), to isolate and protect both the inner and outer surfaces from the infection. To add breathability to the textile especially for the mask (13, 20, 21), many antibacterial fibers have been developed based on these materials. Moreover, various skin-attachable platforms with antimicrobial properties have been developed for convenient usage in daily lives. Antimicrobial nanofibers with conformal attachment to the skin have been developed for drug delivery, wound healing (22, 23), and electrophysiology (24, 25). In addition, stretchable and antibacterial hydrogels have been developed to allow more natural skin movement in wound-healing applications (26–28).However, there has been no practical skin protective solution to prevent cross-infection while preserving intrinsic skin conditions such as surface morphology, thermal transfer, and skin humidity. The thickening of the additional skin layer frequently results in a significant modification of the surface morphology, heat transfer, and the corresponding sensation. Thin layers have limited performance in terms of antimicrobial duration and speed. The skin coverage of polymer or hydrogel film blocks the transfer of air, moisture, and heat. In addition, the antimicrobial performance is focused on the skin side rather than the external side that affects cross-infection. Voids owing to the stiffness of the film or fiber and morphological differences compared to the skin further limit conformality, heat transfer, and water/air permeability (29).Here, we propose an antimicrobial skin protection platform copper nanomesh, which prevents cross-infection while minimizing modification of intrinsic skin properties such as interfacial morphology, temperature change rate, and skin humidity. The thin thickness and porous structure of the nanomesh allow conformal attachment to the fingertips, regardless of the mechanical and structural variations of the fingerprints, nails, and interfaces. To impart antimicrobial properties, copper, one of the most well-known antimicrobial (nano)materials (30–33), was coated with maintaining the nanomesh structure (copper nanomesh, from here onward). The measured inactivation rates of copper nanomesh against Escherichia coli bacteria and influenza virus A (H1N1) were 99.99% within 1 min and 10 min, respectively. It was found that the nanomesh structure contributed to the acceleration of bacterial inactivation compared to the copper film. Furthermore, it exhibited high biocompatibility with the skin cells and stable antibacterial performance even after long-term use (more than 6 h), including water immersion (more than 1 h).In addition, we investigated the naturalness of the copper nanomesh compared to that of the copper film and conventional gloves. As confirmed using the artificial skin and fingerprint recognition, the proposed copper nanomesh exhibited a higher conformability compared to that of the copper film. The copper nanomesh showed a high hydrophobicity to block external contaminants in solution while having high gas permeability and maintaining the skin humidity in a safe range. Additionally, the insertion of copper nanomesh did not affect the temperature change rate, which is important to maintain the sensation and comfort fit of the skin. Finally, the copper nanomesh was compared to the glove by wearing on our hands and interacting with various real-life objects. Using the proposed copper nanomesh, we successfully achieved an effective prevention of cross-infection and less-hindered thermal recognition of objects.     

Friction Properties of Solid Lubricants with Different Multiwalled Carbon Nanotube Contents

Bushes are circular bearings that surround a shaft and help it rotate smoothly. In heavy equipment, bushes are coated with solid lubricants to reduce friction. Although the coating layer of the lubricant has a stable coefficient of friction (CoF), it is important that this should last for a long time. In this study, multiwalled carbon nanotubes (MWCNTs), which have a low CoF, were added to the lubricant to improve its performance. When 2.3 wt% MWCNTs were added to the polymer resin, the dynamic CoF (under a 29 N external load) decreased by 78% in relation to that of the resin without MWCNTs. As the MWCNT content increased, the roughness of the coating decreased, which reduced the CoF. Moreover, MWCNT addition increased the overall tensile strength owing to an increase in the bonding force between the resins. Under a high load of 20 tonnes (t), the MWCNT-based solid lubricant had a CoF of 0.05, lower than commercial MoS₂-based solid lubricants; this was maintained for more than 10,000 cycles in a bush and shaft test. With the MWCNT-based solid lubricant, a lubricating polymer film formed, even on worn bush surfaces. The CoF of the solid lubricant was reduced and the number of cycles with a constant CoF increased when MWCNTs were added owing to the formation of the lubricating polymer film.     

Development of cyclosporin A-loaded hyaluronic microsphere with enhanced oral bioavailability

To develop a hyaluronic microsphere with the improved oral bioavailability of poorly water-soluble cyclosporin A (CsA), the microspheres were prepared with varying ratios of sodium hyaluronate (HA)/sodium lauryl sulfate (SLS)/CsA using a spray-drying technique. The effects of HA and SLS on the dissolution and solubility of CsA in microspheres were investigated. The CsA-microsphere prepared with HA/SLS/CsA at the ratio of 4/2/1 gave the highest solubility and dissolution rate of CsA among those formulae tested. As solubility and dissolution rate of CsA were increased about 17- and 2-fold compared to CsA powder, respectively, this CsA-microsphere was selected as an optimal formula for oral delivery in rats. The CsA-microsphere and Sandimmun neoral sol gave significantly higher blood levels compared with CsA powder alone. Moreover, the AUC, T(max) and C(max) values of CsA in CsA-microsphere were not significantly different from those in Sandimmun neoral sol in rats, indicating that CsA-microsphere was bioequivalent to the commercial product in rats. Our results demonstrated that the CsA-microsphere prepared with HA and SLS, with improved bioavailability of CsA, might have been useful to deliver a poorly water-soluble CsA.