Transient Receptor Potential Ankyrin 1 (TRPA1), which is expressed in the airways, has causative and exacerbating roles in respiratory diseases. TRPA1 is known as a target of sick building ...syndrome-related air pollutants, such as formaldehyde. Thus, an in vitro TRPA1 activation assay would be useful for predicting the potential risk of air pollution. In this study, we used human TRPA1 (hTRPA1)- and mouse TRPA1 (mTRPA1)-expressing cell lines to measure TRPA1 activation by the emerging indoor air pollutants 2-ethyl-1-hexanol (2-EH), a mixture of 2,2,4-trimethyl-1,3-pentanediol 1- and 3-monoisobutyrate (Texanol), and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB). The results indicated that 2-EH activated both hTRPA1 and mTRPA1 in a concentration-dependent manner, whereas TXIB did not activate hTRPA1 or mTRPA1. Texanol also activated hTRPA1 in a concentration-dependent manner. In contrast, a bell-shaped concentration-dependent curve was observed for mouse TRPA1 activation by Texanol, indicating inhibitory effects at a higher concentration range, which was also reported for menthol, a typical TRPA1 modulator. To further elucidate the mechanism underlying the species difference in TRPA1 activation by Texanol, V875G and G878V mutations were introduced into hTRPA1 and mTRPA1, respectively, which were reported to be key mutations for the inhibitory effect of menthol. These mutations switched the inhibitory effects of Texanol; thus, hTRPA1/V875G, but not mTRPA1/G878V, was inhibited at higher concentrations of Texanol. These results indicate that Texanol shares an interaction site with menthol. Overall, these findings suggest that careful interpretation is necessary when extrapolating rodent TRPA1-dependent toxicological effects to humans, especially with respect to the risk assessment of indoor air pollutants.
Manganese (Mn) poisoning may result in a neurological disorder called manganism. Although the neurotoxic mechanism of Mn is unclear, oxidative stress may be involved based on the interactions between ...neurotransmitter catecholamines and metals such as iron. Here, we propose a novel mechanism in which Mn oxidizes catecholamines and inhibits cellular transcription. Mn accelerated the oxidation of adrenaline (Ad) and produced adrenochrome (AdC) more effectively than iron. Furthermore, the oxidation of DNA bases increased when Ad, Mn, and iron were present. However, despite the absence of iron, cell viability decreased in the presence of AdC or Ad with Mn, which suggests there is another mechanism independent of oxidative DNA damage. AdC or preincubated Ad with Mn reduced mRNA synthesis in T7 RNA polymerase-driven transcription. RNA synthesis decreased in AdC-treated cells dose-dependently. These results show that Mn disrupts neuronal function via catecholamine oxidation-mediated transcriptional inhibition.
Abstract
Background
The relationship between spinopelvic alignment and functional disability after total hip arthroplasty (THA) has not been fully elucidated despite the growing recognition of its ...importance on patient-reported outcome measures. Therefore, our aim was to assess the effect of global sagittal spinal deformity on post-operative disability.
Methods
This analysis was based on 208 cases of THA, with functional disability measured at a follow-up of 2 years. The Hip Disability and Osteoarthritis Outcome Score-Joint Replacement (HOOS-JR), ranging from a scale of 0 (complete joint disability) to 100 (perfect joint health), was used to divide eligible patients into two groups, namely
with
and
without
disability, using a score of 70 as the cut-off. The following factors were compared between the two groups using multivariate analysis: age, sex, body height, body mass index, spinopelvic parameters, and surgeon experience. To identify the cut-off value of the parameters for predicting disability (HOOS-JR < 70/100), we used the receiver-operating characteristic curve.
Results
The disability (30 hips) and control (178 hips) groups showed a significant difference in pre-operative body height (
p
= 0.020), T1 pelvic angle divided by pelvic incidence (T1PA/PI;
p
= 0.018), PI minus lumbar lordosis (
p
= 0.027), post-operative HOOS-JR (
p
= 0.010), patient satisfaction (
p
= 0.033), and the modified Harris Hip Score (
p
= 0.038). On multivariate analysis, the following factors were associated with persistent disability: T1PA/PI > 0.2 (odds ratio OR, 2.11; 95% confidence interval CI, 1.19–4.14;
p
< 0.001) and height < 148 cm equivalent to legal standards as short stature (OR, 1.26; 95% CI, 1.09–1.48;
p
= 0.011). The cut-off value of pre-operative T1PA/PI was > 0.19, with a sensitivity of 95% and specificity of 85%. Post-operative satisfaction (
p
< 0.001), HOOS-JR (
p
= 0.023), and EuroQol 5-Dimension (
p
= 0.041) differed between the two groups when the pre-operative cut-off value was chosen as 0.2.
Conclusions
A T1PA/PI > 0.2 was associated with greater disability after THA. Clinicians should be aware that patient-related factors, including global spinal deformities, particularly in patients with a short stature, can influence THA outcomes at 2 years postoperatively.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ten-eleven translocation (TET) proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5fC and 5caC can be excised and ...repaired by the base excision repair (BER) pathway, implicating 5mC oxidation in active DNA demethylation. Genome-wide DNA methylation is erased in the transition from metastable states to the ground state of embryonic stem cells (ESCs) and in migrating primordial germ cells (PGCs), although some resistant regions become demethylated only in gonadal PGCs. Understanding the mechanisms underlying global hypomethylation in naive ESCs and developing PGCs will be useful for realizing cellular pluripotency and totipotency. In this study, we found that PRDM14, the PR domain-containing transcriptional regulator, accelerates the TET-BER cycle, resulting in the promotion of active DNA demethylation in ESCs. Induction of Prdm14 expression transiently elevated 5hmC, followed by the reduction of 5mC at pluripotency-associated genes, germline-specific genes and imprinted loci, but not across the entire genome, which resembles the second wave of DNA demethylation observed in gonadal PGCs. PRDM14 physically interacts with TET1 and TET2 and enhances the recruitment of TET1 and TET2 at target loci. Knockdown of TET1 and TET2 impaired transcriptional regulation and DNA demethylation by PRDM14. The repression of the BER pathway by administration of pharmacological inhibitors of APE1 and PARP1 and the knockdown of thymine DNA glycosylase (TDG) also impaired DNA demethylation by PRDM14. Furthermore, DNA demethylation induced by PRDM14 takes place normally in the presence of aphidicolin, which is an inhibitor of G1/S progression. Together, our analysis provides mechanistic insight into DNA demethylation in naive pluripotent stem cells and developing PGCs.
Purpose: Treatment of meniscal injury is important for osteoarthritis (OA) prevention. Meniscus cells are divided between inner and outer cells, which have different characteristics and vascularity. ...We evaluated the effects of hyaluronic acid (HA) on the proliferation and migration of human inner and outer meniscus cells, and investigated the underlying healing mechanisms.
Materials and Methods: Lateral menisci from 18 patients who underwent total knee arthroplasty were used. Meniscus cells were harvested from the outer and inner menisci and evaluated using migration and proliferation assays after treatment with HA or chondroitin sulfate (CS). The effects of HA on prostaglandin E2 (PGE2)-induced apoptosis and gene expression were evaluated.
Results: Cell migration and proliferation were increased by HA in a concentration-dependent manner, in both inner and outer meniscus cells. PGE2-induced apoptosis and caspase-3/7 activity were suppressed by HA in both inner and outer meniscus cells, and these effects were blocked by an anti-CD44 antibody. COL2A1 and ACAN mRNA levels were upregulated following HA treatment of inner meniscus cells. MMP13 mRNA was downregulated following CS stimulation of both inner and outer meniscus cells. These results suggest that CS treatment suppresses the inflammatory reaction rather than providing meniscal restoration. The phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways were activated by HA in both types of meniscus cells; these effects were blocked by treatment with an anti-CD44 antibody.
Conclusions: HA promoted human meniscus regeneration by inhibiting apoptosis, promoting cell migration, and accelerating cell proliferation, potentially through the PI3K/MAPK pathway via the CD44 receptor.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Tamoxifen (TAM) has been prescribed worldwide to patients with and women at high-risk of breast cancer. However, long-term use of TAM increases the incidence of endometrial cancer. The carcinogenic ...mechanisms of TAM have been extensively investigated. TAM is hydroxylated and sulfonated at α-carbon to form α-hydroxytamoxifen-
-sulfonate. This metabolite readily reacts with genomic DNA, particularly with 2'-deoxyguanosine, leading to DNA replication error. TAM also exerts estrogenic activity at endometrial tissue to induce endometrial hyperplasia. Therefore, our efforts focused on the development of novel and safer anti-estrogens to diminish carcinogenic potential of TAM based on chemical modifications. In this review, we describe a crucial idea of our drug design and introduce our compounds SS1020 and SS5020, possessing high effectiveness, and no genotoxic and estrogenic activities.
The inner avascular zone of the meniscus has limited healing capacity as the area is poorly vascularized. Although peptide hydrogels have been reported to regenerate bone and cartilage, their effect ...on meniscus regeneration remains unknown. We tested whether the self‐assembling peptide hydrogel scaffold KI24RGDS stays in the meniscal lesion and facilitates meniscal repair and regeneration in an induced rabbit meniscal defect model. Full‐thickness (2.0 mm diameter) cylindrical defects were introduced into the inner avascular zones of the anterior portions of the medial menisci of rabbit knees (n = 40). Right knee defects were left empty (control group) while the left knee defects were transplanted with peptide hydrogel (KI24RGDS group). Macroscopic meniscus scores were significantly higher in the KI24RGDS group than in the control group at 2, 4, and 8 weeks after surgery. Histological examinations including quantitative and qualitative scores indicated that compared with the control group, the reparative tissue in the meniscus was significantly enhanced in the KI24RGDS group at 2, 4, 8, and 12 weeks after surgery. Immunohistochemical staining showed that the reparative tissue induced by KI24RGDS at 12 weeks postimplantation was positive for Type I and II collagen. KI24RGDS is highly biocompatible and biodegradable, with strong stiffness, and a three dimensional structure mimicking native extracellular matrix and RGDS sequences that enhance cell adhesion and proliferation. This in vivo study demonstrated that KI24RGDS remained in the meniscal lesion and facilitated the repair and regeneration in a rabbit meniscal defect model.
Causes of spontaneous osteonecrosis of the knee (SONK) have not been clearly elucidated. This study investigated the relationship between medial meniscal extrusion and SONK.
We reviewed 108 SONK ...knees and determined their Aglietti stage. Meniscal extrusion is defined when it extends beyond the medial margin of tibial plateau and osteophytes are excluded for determining the margin. Both absolute extrusion (AE) and relative percentage of extrusion (RPE) were measured, and meniscal tear patterns were evaluated in the early stages of SONK (I and II).
All knees had meniscal extrusion. Stage I was detected in 39 knees; II, in 23; III, in 16; IV, in 18; and V, in 12. The mean AE and RPE were 4.2 mm and 42% in stage I, 5.0 mm and 52% in stage II, 6.8 mm and 71% in stage III, 7.0 mm and 69% in stage IV, and 7.8 mm and 80% in stage V, respectively. The knees in the early stages showed less AE and RPE than those in late stages IV (p < 0.05) and V (p < 0.01). Additionally, the level of AE (ρ = 0.63, p < 0.0001) and RPE (ρ = 0.58, p < 0.0001) correlated with the SONK stage. Of knees with early-stage SONK, 12 knees had no tear, 26 had horizontal tears, 1 had longitudinal tear, 6 had degenerative tears, 2 had radial tears, 1 had complex tear, and 14 had root tears. Neither AE nor RPE differed significantly among tear patterns.
Meniscal extrusion was recognized even in early stages, with a significant correlation between the SONK stage and extrusion. Although the most frequent tear pattern in early-stage SONK was horizontal tear, 12 knees had meniscal extrusion with no tears. Therefore, meniscal extrusion, which indicates meniscal dysfunction, may be a cause of SONK and be related with the developmental stage of SONK.
Purpose:
Medial opening-wedge high tibial osteotomy (OWHTO) induces a lower patellar position, and the subsequent degree of patellar movement may not be predicted preoperatively. The purpose of this ...study was to clarify the relationship between preoperative and postoperative patellar height based on the correction angle of OWHTO and to create a formula to predict the appearance of patella baja following OWHTO.
Materials and Methods:
Seventy-five knees with varus knee osteoarthritis treated with OWHTO were included in this study. The Caton–Deschamps index was used to evaluate patellar height preoperatively and postoperatively, and the cut-off value for preoperative parameters was determined by a receiver operating characteristic curve to determine the risk ratio for postoperative patella baja.
Results:
The Caton–Deschamps index significantly decreased from 0.93 to 0.77 after OWHTO (p < 0.01). The OWHTO correction angle negatively correlated with the delta Caton–Deschamps index (r = −0.44, p < 0.01), and a 1.7% decrease in the Caton–Deschamps index was shown with a 1° correction angle. Receiver operating characteristic curve analysis revealed that a Caton–Deschamps index of 0.8 was the cutoff for OWHTO; knees with a preoperative Caton–Deschamps index of < 0.8 tended to develop patella baja after OWHTO, with a risk ratio of 9.5 (95% confidence interval 4.3–20.7).
Conclusions:
OWHTO can induce patella baja, and a 1.7% decrease in the Caton–Deschamps index was shown with a 1°-correction angle. A preoperative Caton–Deschamps index < 0.8 should be considered a risk factor for postoperative patella baja.
Level of Evidence:
Retrospective study, Level IV
Abstract Background In posterior-stabilized (PS) total knee arthroplasty (TKA), various post-cam designs can be used. A larger cam of the femoral component may tighten the extension gap. Few studies ...have investigated the relationship between capsular release around the intercondylar notch and the extension gap. The aim of this study was to assess the effect of capsular release around the intercondylar notch on the extension gap. Methods Forty-eight patients (54 knees) who underwent PS rotating-platform TKA (PFC Sigma RP-F) were enrolled retrospectively. We measured the extension gap with and without a femoral trial using a knee balancer, applying a joint distraction force of 44 lb. When an intraoperative flexion contracture of > 5° persisted, we performed a capsular release approximately 10 mm cranial to the intercondylar notch. After full knee extension was achieved, the extension gap was measured again. Results Thirty knees required capsular release. With a trial, the medial and lateral differences between the extension gaps before and after capsular release were 1.7 mm ( p < 0.0001) and 2.3 mm ( p < 0.0001), respectively. Without a trial, the gaps were enlarged by 0.4 mm ( p = 0.0452) and 0.6 mm ( p = 0.0215), respectively. Twenty-four knees did not require release. No significant differences were noted in the range of motion at one-year follow-up between the two cohorts. Conclusions With PS rotating-platform TKA, capsular release around the intercondylar notch is found to increase the extension gap and may prevent postoperative flexion contracture. Level of Evidence Level III, retrospective comparative study.
PDF
