Effect of NAMPT on the proliferation and apoptosis in odontoblast-like MDPC-23 cell.

This study aimed to evaluate the physiological role of NAMPT associated with MDPC-23 odontoblast cell proliferation. Cell viability was measured using the (DAPI) staining, caspase activation analysis and immunoblotting were performed. Visfatin promoted MDPC-23 odontoblast cell growth in a dose-dependent manner. Furthermore, the up-regulation of Visfatin promoted odontogenic differentiation and accelerated mineralization through an increase in representative odontoblastic biomarkers in MDPC-23 cells. However, FK-866 cell growth in a dose-dependent manner induced nuclear condensation and fragmentation. FK-866-treated cells showed H&E staining and increased apoptosis compared to control cells. The expression of anti-apoptotic factors components of the mitochondria-dependent intrinsic apoptotic pathway significantly decreased following FK-866 treatment. The expression of pro-apoptotic increased upon FK-866 treatment. In addition, FK-866 activated caspase-3 and PARP to induce cell death. In addition, after treating FK-866 for 72 h, the 3/7 activity of MDPC-23 cells increased in a concentration-dependent manner, and the IHC results also confirmed that Caspase-3 increased in a concentration-dependent. Therefore, the presence or absence of NAMPT expression in dentin cells was closely related to cell proliferation and formation of extracellular substrates.

Metformin Attenuates Manganese-Induced Oxidative Stress in N27-A Dopaminergic Neuronal Cells.

Metformin is an anti-diabetic drug that exerts protective effects against neurodegenerative diseases. In this study, we investigated the protective effects of metformin against manganese (Mn)-induced cytotoxicity associated with Parkinson's disease-like symptoms in N27-A dopaminergic (DA) cells. Metformin (0.1-1 mM) suppressed Mn (0.4 mM)-induced cell death in a concentration-dependent manner. Metformin pretreatment effectively suppressed the Mn-mediated increase in the levels of oxidative stress markers, such as reactive oxygen species (ROS) and thiobarbituric acid reactive substances. Moreover, metformin restored the levels of the antioxidants, superoxide dismutase, intracellular glutathione, and glutathione peroxidase, which were reduced by Mn. Metformin (0.5 mM) significantly attenuated the decrease in sirtuin-1 (SIRT1) and peroxisome proliferator activated receptor gamma coactivator-1 alpha levels, which were increased by Mn (0.4 mM). In addition, metformin inhibited the expression of microRNA-34a, which directly targeted SIRT1. Metformin also inhibited the loss of Mn-induced mitochondrial membrane potential (ΔΨm) and activation of the apoptosis marker, caspase-3. Furthermore, metformin-mediated inhibition of ROS generation and caspase-3 activation, recovery of ΔΨm, and restoration of cell viability were partially reversed by the SIRT1 inhibitor, Ex527. These results suggest that metformin may protects against Mn-induced DA neuronal cell death mediated by oxidative stress and mitochondrial dysfunction possibly via the regulation of SIRT1 pathway.

Adjuvant Chemotherapy after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma with Variant Histology: A Systematic Review and Meta-Analysis of Survival Outcomes.

INTRODUCTION: The objective of this study was to determine effects of adjuvant chemotherapy (AC) on survival outcomes compared to surgery alone without AC for upper tract urothelial carcinoma (UTUC) patients with variant histology (VH). METHODS: We conducted a systematic review and meta-analysis of studies investigating AC for UTUC in Medline, Embase, the Cochrane Library up to January 2023. Population, intervention, comparator, and outcome were UTUC patients with VH, radical nephroureterectomy with AC, radical nephroureterectomy only, and oncological survival, respectively. RESULTS: Four retrospective studies were included. Regarding overall survival (OS), the pooled hazard ratio was 0.61 (95% confidence interval: 0.42-0.87; p = 0.007) across two studies. Regarding cancer-specific survival (CSS), the pooled hazard ratio was 0.46 (95% confidence interval: 0.25-0.84; p = 0.01) across three studies. All included studies had a high quality based on the Newcastle-Ottawa Scale. Certainty of evidence for OS was low. Certainty of evidence for CSS was moderate due to a strong association (hazard ratio <0.5). Publication bias was not significant for any studies. CONCLUSION: In UTUC patients with VH, administration of AC after surgery might have better survival outcomes than surgery alone. Our study provides evidence for decision-making of clinicians who treat UTUC patients with VH.

Burnout, job satisfaction, and turnover intention among primary care nurse practitioners with their own patient panels.

BACKGROUND: Nurse practitioners (NPs) can enhance NP care and improve access to care by autonomously managing their patient panels. Yet, its impact on workforce outcomes such as burnout, job satisfaction, and turnover intention remains unexplored. PURPOSE: To estimate the impact of NP panel management on workforce outcomes. METHODS: Structural equation modeling was conducted using survey data from 1,244 primary care NPs. NP panel management was categorized into co-managing patients with other providers, both co-managing and autonomously managing, and fully autonomous management. DISCUSSION: Fully autonomous management led to more burnout than co-managing (B = 0.089, bias-corrected 95% bootstrap confidence interval [0.028, 0.151]). Work hours partially (27%) mediated this relationship. This findings indicate that greater autonomy in panel management among NPs may lead to increased burnout, partially due to longer work hours. CONCLUSION: Interventions to reduce work hours could help NPs deliver quality care without burnout.

Urolithiasis in Kidney Transplant Patients: A Multicenter KSER Research Series.

Background and Objectives: Urolithiasis occurrence is uncommon in kidney transplantation patients, though it has serious implications, including acute kidney injury in the transplanted kidney. This study investigates the leading causes of urolithiasis in kidney transplantation patients, the diagnostic process, and the outcomes of multimodal management. Materials and Methods: Data collection spanned from January 1997 to December 2021, involving kidney transplantation patients with urolithiasis from the database of the Korean Society of Endourology and Robotics (KSER) research committee. Analysis encompassed factors triggering urolithiasis, the diagnostic process, stone attributes, treatment methods, and outcomes. Results: Our analysis included 58 kidney transplantation patients with urolithiasis from eight medical centers. Of these patients, 37 were male and 4 had previous urolithiasis diagnoses. The mean age was 59.09 ± 10.70 years, with a mean duration from kidney transplantation to diagnosis of 76.26 ± 183.14 months. The most frequent method of stone detection was through asymptomatic routine check-ups (54.7%). Among the 58 patients, 51 underwent stone treatment. Notably, 95.3% of patients with ureter stones received treatment, a significantly higher rate than the 66.7% of patients with renal stones (p = 0.010). Success rates showed no significant differences between renal (70%) and ureter stone (78.0%) groups (p = 0.881). Conclusions: Urolithiasis in transplanted kidneys constitutes an acute condition requiring emergency intervention. Endo-urological interventions are effective for kidney transplantation patients with urolithiasis. To ensure prevention and early detection, diligent follow-up and routine imaging tests are necessary.

Ursodeoxycholic acid alleviates atopic dermatitis-associated inflammatory responses in HaCaT and RBL-2H3 cells and DNCB/DFE-treated mice.

AIMS: Ursodeoxycholic acid (UDCA) is a hydrophilic dihydroxy bile acid used for cholestatic liver disease and exhibits antioxidant, antitumor, and anti-inflammatory effects. However, its potential effects on atopic dermatitis (AD) have not been elucidated. This study aimed to evaluate the efficacy of UDCA in inhibiting the inflammatory response and alleviating lesions in AD-like mice. MAIN METHODS: To investigate the efficacy of UDCA in AD-like inflammatory responses, tumor necrosis factor-alpha (TNF-α)- and interferon-gamma (IFN-γ)-stimulated HaCaT cells and anti-dinitrophenyl immunoglobulin E (DNP-IgE)- and human serum albumin (HSA)-stimulated RBL-2H3 cells were used to investigate the levels of inflammatory factors and their mechanisms. AD-like lesions were induced by applying DNCB/DFE to mice. The effect of UDCA administration in AD-like mice was analyzed by assessing organ weight, serum IgE and inflammatory cytokine levels, and histopathological changes using immunohistochemical and immunofluorescent staining. KEY FINDINGS: In HaCaT cells, UDCA significantly diminished TARC, MDC, MCP-1, and IL-6 expression by inhibiting the phosphorylation of nuclear NF-κB and cytoplasmic IκB, and also increased the levels of skin barrier protein. In RBL-2H3 cells, UDCA reduced ß-hexosaminidase and IL-4 levels. In AD-like mice, UDCA suppressed organ hypertrophy, ear edema, SCORAD index, DFE-specific IgE levels, inflammatory cytokine levels, skin hypertrophy, mast cell invasion, skin barrier loss, and thymic stromal lymphopoietin-positive areas. SIGNIFICANCE: UDCA suppressed the expression of pro-inflammatory cytokines by keratinocytes and mast cells. It also alleviated atopy by suppressing symptoms without organ toxicity in AD-like mice. UDCA may be an effective and safe treatment for AD.

A dual role of the conserved PEX19 helix in safeguarding peroxisomal membrane proteins.

Accurate localization of membrane proteins is essential for proper cellular functioning and the integrity of cellular membranes. Post-translational targeting of peroxisomal membrane proteins (PMPs) is mediated by the cytosolic chaperone PEX19 and its membrane receptor PEX3. However, the molecular mechanisms underlying PMP targeting are poorly understood. Here, using biochemical and mass spectrometry analysis, we find that a conserved PEX19 helix, αd, is critical to prevent improper exposure of the PEX26 transmembrane domain (TMD) to cytosolic chaperones. Furthermore, the αd helix of PEX19 interacts with the cytosolic domain of the PEX3 receptor, thereby triggering PEX26 release at the correct destination membrane. The peroxisome-deficient PEX3-G138E mutant completely abolishes this secondary interaction, leading to lack of PEX3-induced PEX26 release from PEX19. These findings elucidate a dual molecular mechanism that is essential to membrane protein protection and destination-specific release by a molecular chaperone.

Impact of family history of prostate cancer on disease progression for prostatic cancer patients undergoing active surveillance: A systematic review and meta-analysis.

PURPOSE: To evaluate how a family history of prostate cancer influences the progression of the disease in individuals with prostate cancer undergoing active surveillance. MATERIALS AND METHODS: We conducted a thorough literature search in PubMed/MEDLINE, Embase, and Cochrane Library up to June 2023. This systematic review was registered in PROSPERO (CRD42023441853). The study evaluated the effects of family history of prostate cancer (intervention) on disease progression (outcome) in prostate cancer patients undergoing active surveillance (population) and compared them to those without a family history (comparators). For time to disease progression outcomes, the extracted data were synthesized using the inverse variance method on the log hazard ratios scale. RESULTS: A total of eight studies were incorporated into this systematic review and meta-analysis. The combined hazard ratio for unadjusted disease progression was 1.06 (95% confidential interval [CI] 0.66-1.69; p=0.82). The combined hazard ratio for adjusted disease progression was 1.31 (95% CI 1.16-1.48; p<0.0001). All the enlisted studies demonstrated high quality based on the Newcastle-Ottawa scale. The certainty of evidence for univariate and multivariate analysis of disease progression was very low and low, respectively. Publication bias for all studies was not significant. CONCLUSIONS: For individuals with prostate cancer opting for active surveillance, a family history of prostate cancer may serve as an independent risk factor associated with an elevated risk of disease progression. Clinicians should be counseled about the increased risk of disease progression in patients with a family history of prostate cancer undergoing active surveillance.

Impact of heavy alcohol consumption on cortical bone mechanical properties in male rhesus macaques.

Chronic heavy alcohol consumption may influence the skeleton by suppressing intracortical bone remodeling which may impact the quality of bone and its mechanical properties. However, this aspect has not been thoroughly assessed in either humans or animal models whose cortical bone microstructure resembles the microstructure of human cortical bone. The current study is the first to investigate the effects of chronic heavy alcohol consumption on various mechanical properties of bone in a non-human primate model with intracortical remodeling. Male rhesus macaques (5.3 years old at the initiation of treatment) were induced to drink alcohol and then given the choice to voluntarily self-administer water or ethanol (4 % w/v) for approximately 14 months, followed by three abstinence phases (lasting 34, 41, and 39-46 days) with approximately 3 months of ethanol access in between. During the initial 14 months of open-access, monkeys in the alcohol group consumed an average of 2.9 ± 0.8 g/kg/d ethanol (mean ± SD) resulting in a blood ethanol concentration of 89 ± 47 mg/dl in longitudinal samples taken at 7 h after the daily sessions began. To understand the impact of alcohol consumption on material properties, various mechanical tests were conducted on the distal tibia diaphysis of 2-5 monkeys per test group, including dynamic mechanical analysis (DMA) testing, nano-indentation, microhardness testing, compression testing, and fracture resistance curve (R-curve) testing. Additionally, compositional analyses were performed using Fourier-transform infrared (FTIR) spectroscopy. Significant differences in microhardness, compressive stress-strain response, and composition were not observed with alcohol consumption, and only minor differences were detected in hardness and elastic modulus of the matrix and osteons from nanoindentation. Furthermore, the R-curves of both groups overlapped, with similar crack initiation toughness, despite a significant decrease in crack growth toughness (p = 0.032) with alcohol consumption. However, storage modulus (p = 0.029) and loss factor (p = 0.015) from DMA testing were significantly increased in the alcohol group compared to the control group, while loss modulus remained unchanged. These results indicate that heavy alcohol consumption may have only a minor influence on the material properties and the composition of cortical bone in young adult male rhesus macaques.

Androgen Deprivation Therapy and Newly Developed Neovascular Age-Related Macular Degeneration Risk in Patients with Prostate Cancer.

Background/Objectives: to evaluate the association between androgen deprivation therapy (ADT) and newly developed neovascular age-related macular degeneration (AMD) in patients with prostate cancer. Methods: We identified 228,803 men from the nationwide claims database in the Republic of Korea diagnosed with prostate cancer between 1 August 2009 and 31 December 2018 and followed until April 2021. Cases were defined as those newly diagnosed with neovascular AMD during follow-up. Cases were matched with controls based on age, index date, and follow-up duration, at a case-to-control ratio of 1:4. Adjusted odds ratios (aORs) of incident neovascular AMD associated with ADT were estimated using conditional logistic regression. Results: The main analysis included 1700 cases and 6800 controls, with a median follow-up of 3.42 years. ADT was associated with a reduced risk of incident neovascular AMD in patients with prostate cancer (aOR = 0.840; 95% confidence interval [CI], 0.743-0.951; p = 0.0058) in the multivariable analysis. A cumulative ADT duration less than 1 year was associated with a reduced risk of neovascular AMD (aOR = 0.727; 95% CI, 0.610-0.866; p = 0.0004); however, no association was observed when the duration of ADT was between 1 and 2 years (aOR = 0.862; 95% CI, 0.693-1.074; p = 0.1854) or more than 2 years (aOR = 1.009; 95% CI, 0.830-1.226; p = 0.9304). Conclusions: In patients with prostate cancer, medical castration for less than a year is associated with a reduced risk of incident neovascular AMD. These results suggest that androgens are involved in the pathogenesis of neovascular AMD.

Dependence of Positive Bias Stress Instability on Threshold Voltage and Its Origin in Solution-Processed Aluminum-Doped Indium Oxide Thin-Film Transistors.

The initial electrical characteristics and bias stabilities of thin-film transistors (TFTs) are vital factors regarding the practical use of electronic devices. In this study, the dependence of positive bias stress (PBS) instability on an initial threshold voltage (VTH) and its origin were analyzed by understanding the roles of slow and fast traps in solution-processed oxide TFTs. To control the initial VTH of oxide TFTs, the indium oxide (InOx) semiconductor was doped with aluminum (Al), which functioned as a carrier suppressor. The concentration of oxygen vacancies decreased as the Al doping concentration increased, causing a positive VTH shift in the InOx TFTs. The VTH shift (∆VTH) caused by PBS increased exponentially when VTH was increased, and a distinct tendency was observed as the gate bias stress increased due to a high vertical electric field in the oxide dielectric. In addition, the recovery behavior was analyzed to reveal the influence of fast and slow traps on ∆VTH by PBS. Results revealed that the effect of the slow trap increased as the VTH moved in the positive direction; this occured because the main electron trap location moved away from the interface as the Fermi level approached the conduction band minimum. Understanding the correlation between VTH and PBS instability can contribute to optimizing the fabrication of oxide TFT-based circuits for electronic applications.

Comparison of Finasteride and Dutasteride on Risk of Prostate Cancer in Patients with Benign Prostatic Hyperplasia: A Pooled Analysis of 15 Real-world Databases.

PURPOSE: Finasteride and dutasteride are used to treat benign prostatic hyperplasia (BPH) and reduce the risk of developing prostate cancer. Finasteride blocks only the type 2 form of 5-alpha-reductase, whereas dutasteride blocks both type 1 and 2 forms of the enzyme. Previous studies suggest the possibility that dutasteride may be superior to finasteride in preventing prostate cancer. We directly compared the effects of finasteride and dutasteride on the risk of prostate cancer in patients with BPH using a pooled analysis of 15 real-world databases. MATERIALS AND METHODS: We conducted a multicenter, cohort study of new-users of finasteride and dutasteride. We include patients who were prescribed 5 mg finasteride or dutasteride for the first time to treat BPH and had at least 180 days of prescription. We excluded patients with a history of prostate cancer or a prostate-specific antigen level ≥ 4 ng/mL before the study drug prescription. Cox regression analysis was performed to examine the hazard ratio (HR) for prostate cancer after propensity score (PS) matching. RESULTS: A total of 8,284 patients of new-users of finasteride and 8,670 patients of new-users of dutasteride were included across the 15 databases. In the overall population, compared to dutasteride, finasteride was associated with a lower risk of prostate cancer in both on-treatment and intent-to-treat time-at-risk periods. After 1:1 PS matching, 4,897 patients using finasteride and 4,897 patients using dutasteride were enrolled in the present study. No significant differences were observed for risk of prostate cancer between finasteride and dutasteride both on-treatment (HR=0.66, 95% confidence interval [CI]: 0.44-1.00; p=0.051) and intent-to-treat time-at-risk periods (HR=0.87, 95% CI: 0.67-1.14; p=0.310). CONCLUSIONS: Using real-world databases, the present study demonstrated that dutasteride was not associated with a lower risk of prostate cancer than finasteride in patients with BPH.

Mitigating grain growth in fully stabilized zirconia via a two-step sintering strategy for esthetic dental restorations.

Overall, 8-mol% yttria-stabilized zirconia (8YSZ), unlike 3YSZ, is optically transparent and stable against low-temperature degradation but has insufficient mechanical properties due to its large grain size. The influence of the grain size of 8YSZ on mechanical properties was investigated to develop an 8YSZ suitable for dental restoration. Modulation of the grain size and relative density was achieved via a two-step sintering (TSS) process, and the corresponding kinetic window was established. The conditions of TSS employed herein yielded a relative density of more than 99% while maintaining a small grain size of 0.75 µm. On the other hand, the highest biaxial strength and the highest total transmittance attained were 833 MPa and 34.6% (1-mm-thick, 39.1% for a 0.5-mm thick sample) in the TSS 8YSZ with a grain size of 1.25 µm. These results suggest that strength has improved only when grain size reduction and increased relative density are achieved at the same time. The results demonstrate that the ceramic processing method has a significant effect on the mechanical and optical properties of 8YSZ needed for dental restoration and provide a new insight that contrasts previous studies focused on the starting material.

Methylsulfonylmethane ameliorates metabolic-associated fatty liver disease by restoring autophagy flux via AMPK/mTOR/ULK1 signaling pathway.

Introduction: Metabolism-associated fatty liver disease (MAFLD) is a global health concern because of its association with obesity, insulin resistance, and other metabolic abnormalities. Methylsulfonylmethane (MSM), an organic sulfur compound found in various plants and animals, exerts antioxidant and anti-inflammatory effects. Here, we aimed to assess the anti-obesity activity and autophagy-related mechanisms of Methylsulfonylmethane. Method: Human hepatoma (HepG2) cells treated with palmitic acid (PA) were used to examine the effects of MSM on autophagic clearance. To evaluate the anti-obesity effect of MSM, male C57/BL6 mice were fed a high-fat diet (HFD; 60% calories) and administered an oral dose of MSM (200 or 400 mg/kg/day). Moreover, we investigated the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin complex 1 (mTORC1)/UNC-51-like autophagy-activating kinase 1 (ULK1) signaling pathway to further determine the underlying action mechanism of MSM. Results: Methylsulfonylmethane treatment significantly mitigated PA-induced protein aggregation in human hepatoma HepG2 cells. Additionally, Methylsulfonylmethane treatment reversed the PA-induced impairment of autophagic flux. Methylsulfonylmethane also enhanced the insulin sensitivity and significantly suppressed the HFD-induced obesity and hepatic steatosis in mice. Western blotting revealed that Methylsulfonylmethane improved ubiquitinated protein clearance in HFD-induced fatty liver. Remarkably, Methylsulfonylmethane promoted the activation of AMPK and ULK1 and inhibited mTOR activity. Conclusion: Our study suggests that MSM ameliorates hepatic steatosis by enhancing the autophagic flux via an AMPK/mTOR/ULK1-dependent signaling pathway. These findings highlight the therapeutic potential of MSM for obesity-related MAFLD treatment.