8-Br-cGMP suppresses tumor progression through EGFR/PLC γ1 pathway in epithelial ovarian cancer.

BACKGROUND: Cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (PKG-I), a serine/threonine kinase, is important in tumor development. The present study determines that the cGMP/PKG I pathway is essential for promoting cell proliferation and survival in human ovarian cancer cells, whereas cGMP analog has been shown to lead to growth inhibition and apoptosis of various cancer cells. The role of cGMP/PKG I pathway in epithelial ovarian cancer (EOC), therefore, remains controversial. We investigated the effect of cGMP/PKG I pathway and the underlying mechanism in EOC. METHODS AND RESULTS: The results showed that exogenous 8-Bromoguanosine-3', 5'-cyclic monophosphate (8-Br-cGMP) (cGMP analog) could antagonize the effects by EGF, including suppressing proliferation, invasion and migration of EOC cells. In vivo, 8-Br-cGMP hampered the growth of the xenograft tumor. Additionally, the expressions of epidermal growth factor receptor (EGFR), matrix metallopeptidase 9 (MMP9), proliferating cell nuclear antigen and Ki67 in xenograft tumor were decreased after 8-Br-cGMP intervention. Further research demonstrated that 8-Br-cGMP decreased the phosphorylation of EGFR (Y992) and downstream proteins phospholipase Cγ1 (PLC γ1) (Y783), calmodulin kinase II (T286) and inhibited cytoplasmic Ca2+ release as well as PKC transferring to cell membrane. It's worth noting that the inhibition was 8-Br-cGMP dose-dependent and 8-Br-cGMP showed similar inhibitory effect on EOC cells compared with U-73122, a specific inhibitor of PLC γ1. CONCLUSIONS: The activation of endogenous PKG I by addition of exogenous 8-Br-cGMP could inhibit EOC development probably via EGFR/PLCγ1 signaling pathway. 8-Br-cGMP/PKG I provide a new insight and strategy for EOC treatment.

The characterization and comorbidities of heterozygous Bardet-Biedl syndrome carriers.

Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies, learning disabilities, hypogonadism, and genitourinary abnormalities. Nevertheless, previous studies on the phenotypic traits of BBS heterozygous carriers have generated inconclusive results. The aim of our study was to investigate the impact of BBS heterozygosity on carriers when compared to non-carriers within the Taiwanese population. Materials and Methods: This study follows a hospital-based case-control design. We employed the Taiwan Biobank version 2 (TWBv2) array to identify three specific loci associated with BBS (rs773862084, rs567573386, and rs199910690). In total, 716 patients were included in the case group, and they were compared to a control group of 2,864 patients who lacked BBS alleles. The control group was selected through gender and age matching at a ratio of 1:4. The association between BBS-related loci and comorbidity was assessed using logistic regression models. Results: We found that BBS heterozygous carriers exhibited a significant association with elevated BMI levels, especially the variant rs199910690 in MKS1 (p=0.0037). The prevalence of comorbidities in the carriers' group was not higher than that in the non-carriers' group. Besides, the average values of the biochemistry data showed no significant differences, except for creatinine level. Furthermore, we conducted a BMI-based analysis to identify specific risk factors for chronic kidney disease (CKD). Our findings revealed that individuals carrying the CA/AA genotype of the BBS2 rs773862084 variant or the CT/TT genotype of the MKS1 rs199910690 variant showed a reduced risk of developing CKD, irrespective of their BMI levels. When stratified by BMI level, obese males with the MKS1 rs199910690 variant and obese females with the BBS2 rs773862084 variant exhibited a negative association with CKD development. Conclusion: We found that aside from the association with overweight and obesity, heterozygous BBS mutations did not appear to increase the predisposition of individuals to comorbidities and metabolic diseases. To gain a more comprehensive understanding of the genetic susceptibility associated with Bardet-Biedl Syndrome (BBS), further research is warranted.

Medication use patterns in pregnant women with psoriasis: A nationwide study in Taiwan.

BACKGROUND: Psoriasis, an autoimmune skin condition, affects 2%-4% of the global population, with significant prevalence among women of childbearing age. Pregnancy presents challenges in managing psoriasis due to hormonal changes and treatment safety concerns. Understanding treatment patterns in pregnant women is crucial, given limited real-world evidence. OBJECTIVES: Explore the utilization patterns of medications among pregnant women diagnosed with psoriasis within a real-world data, utilizing data sourced from a nationwide database in Taiwan. METHODS: This nationwide study utilized Taiwan's National Health Insurance (NHI) database and Birth Certificate Application. It included registered pregnant women diagnosed with psoriasis from 2005 to 2014. Medication usage was tracked three years before conception to three years after delivery. Medications were categorized based on Anatomical Therapeutic Chemical (ATC) codes, and statistical analyses were conducted using SAS software. RESULTS: A total of 30,267 pregnant women with psoriasis were studied. 11,651 (38.49%) mothers had received at least one prescription during follow-up (exposed group), and >60% had never received medication (unexposed group). Demographics and comorbidities were similar between these two groups. Topical corticosteroids were the most prescribed treatment, followed by phototherapy, with systemic drugs and biologics less common. During the study period, 11,096 women with psoriasis had used topical corticosteroids, 3,376 had used non-steroidal topical agents, 218 had used systemic agents or biologics, and 519 had received treatment with phototherapy. Medication usage declined during pregnancy, reaching its lowest in the third trimester but rebounded postpartum. CONCLUSIONS: Psoriasis medications, systemic, biological, or topical, were largely discontinued during pregnancy, sometimes up to 2 years before and extending postpartum. Research is needed to understand its impact on maternal and child health.

Impact of 3D Printing Technology-Assisted Rehabilitation Cycles on Prognostic Motility in Surgically Treated Tibial Plateau Fractures: A Meta-Analysis.

Background: Tibial Plateau Fractures (TPF) present significant challenges in orthopedic surgery due to their complex anatomy and associated morbidity. Conventional surgical approaches are often limited by the difficulty in achieving anatomical reduction and stable fixation, leading to prolonged recovery times and increased risk of complications. Objective: This study aims to evaluate the impact of 3D printing technology-assisted interventions in the surgical management of Tibial Plateau Fractures (TPF). Methods: A comprehensive search of the PubMed database was conducted to identify relevant studies investigating the application of 3D printing technology in TPF surgery. Eligible studies were selected based on predefined inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.3 software to assess various outcome measures, including operative time, intraoperative bleeding, fracture healing duration, and incidence of adverse effects across the selected literature. Results: 10 studies met the inclusion criteria and were included in the final analysis. Meta-analysis results indicate that patients undergoing TPF surgery with 3D printing technology assistance experienced significantly shorter operative times and fracture healing durations compared to those undergoing conventional surgery (P < .05). Moreover, they exhibited reduced intraoperative bleeding and a markedly lower occurrence of adverse effects during the treatment process (P < .05). Conclusions: The findings suggest that the integration of 3D printing technology into TPF surgical procedures can effectively mitigate surgical trauma and expedite fracture healing. Additionally, it offers a higher level of safety, thereby providing patients with a more reliable recovery trajectory and prognosis. This finding highlights the promising potential of 3D printing technology in advancing clinical orthopedics. Further research in this area is warranted to realize its clinical benefits fully.

Association between neighborhood availability of physical activity facilities and cognitive performance in older adults.

The existing evidence on the contextual influence of the availability of local facilities for physical activity on the cognitive health of elderly residents is sparse. This study examined the association between neighborhood physical activity facilities and cognitive health in older individuals. A cohort study of community-dwelling older adults was performed using baseline data and follow-up data from the Taiwan Biobank. Cognitive health was measured in 32,396 individuals aged 60-70 years using the Mini-Mental State Examination (MMSE) with follow-up information on 8025 participants. The district was used as the proxy for local neighborhood. To determine neighborhood physical activity facilities, school campuses, parks, activity centers, gyms, swimming pools, and stadiums were included. Multilevel linear regression models were applied to examine the associations of neighborhood physical activity facilities with baseline MMSE and MMSE decline during follow-up, with adjustment for individual factors and neighborhood socioeconomic characteristics. Multilevel analyses revealed that there was a neighborhood-level effect on cognitive health among older adults. After adjusting for compositional and neighborhood socioeconomic characteristics, baseline MMSE was higher in individuals living in the middle- (beta = 0.12, p-value = 0.140) and high-density facility (beta = 0.22, p-value = 0.025) groups than in the low-density group (p-value for trend-test = 0.031). MMSE decline during follow-up was slower in the middle- (beta = 0.15, p-value = 0.114) and high-density facility (beta = 0.27, p-value = 0.052) groups than in the low-density group (p-value for trend-test = 0.032). Greater neighborhood availability of physical activity facilities was associated with better cognitive health among older residents. These findings have implications for designing communities and developing strategies to support cognitive health of an aging population.

Fractal complexity alternations in paroxysmal atrial fibrillation patients with and without recurrence after pulmonary vein isolation.

BACKGROUND: Pulmonary vein isolation (PVI) is a cornerstone therapy for paroxysmal atrial fibrillation (PAF). The variations in nonlinear heart rate variability (HRV) between patients with and without recurrences remain unclear. We aimed to characterize the nonlinear HRV before and after PVI in patients with and without recurrence. METHODS: Twenty-five drug-refractory PAF patients (56.0 ± 9.1 years old, 20 males) who received PVI were enrolled. Holter electrocardiography were performed before, 1-3, and 6-12 months after PVI. After 8.2 ± 2.5 months of follow-ups after PVI, patients were divided into two groups: the recurrence (n = 8) and non-recurrence (n = 17) groups. Linear and nonlinear HRV variables were analyzed, including the Poincaré Plot analysis and the Detrended Fluctuation Analysis (DFA). RESULTS: The non-recurrence group, but not the recurrence group, had decreased high-frequency component (HF), the root mean square of successive RR interval differences (RMSSD), and the Poincaré Plot index SD1 1-3 months after PVI and increased DFAslope2 6-12 months after PVI. The non-recurrence group's LF/HF ratio and DFAslope1 decreased significantly 1-3 and 6-12 months after PVI, respectively, whereas there was no significant change in the recurrence group after PVI. CONCLUSIONS: Significantly reduced vagal tone 1-3 months after PVI, increased long-term fractal complexity 6-12 months after PVI, and decreased sympathetic tone as well as short-term fractal complexity 1-3 and 6-12 months after PVI led to a better AF-free survival after PVI. These findings suggest that neuromodulation and heart rate dynamics play crucial roles in AF recurrence following PVI.

Daytime napping and Alzheimer's dementia: A potential bidirectional relationship.

INTRODUCTION: Daytime napping is frequently seen in older adults. The longitudinal relationship between daytime napping and cognitive aging is unknown. METHODS: Using data from 1401 participants of the Rush Memory and Aging Project, we examined the longitudinal change of daytime napping inferred objectively by actigraphy, and the association with incident Alzheimer's dementia during up to 14-year follow-up. RESULTS: Older adults tended to nap longer and more frequently with aging, while the progression of Alzheimer's dementia accelerates this change by more than doubling the annual increases in nap duration/frequency. Longer and more frequent daytime naps were associated with higher risk of Alzheimer's dementia. Interestingly, more excessive (longer or more frequent) daytime napping was correlated with worse cognition a year later, and conversely, worse cognition was correlated with more excessive naps a year later. DISCUSSION: Excessive daytime napping and Alzheimer's dementia may possess a bidirectional relationship or share common pathophysiological mechanisms.

Precise Synthesis of Chiral Z-Allylamides by Cobalt-Catalyzed Asymmetric Sequential Hydrogenations.

Asymmetric sequential hydrogenations of conjugated enynes have been developed using a Ph-BPE-CoI catalyst for the precise synthesis of chiral Z-allylamides in high activity (up to 1000 substrate/catalyst (S/C)) and with excellent enantioselectivity (up to >99 % enantiomeric excess (ee)). Mechanism experiments and theoretical calculations support a cationic CoI /CoIII redox catalytic cycle. The catalytic activity difference between cobalt complexes of Ph-BPE and QuinoxP* was explained by the process decomposition of rate-determining step in the second hydrogenation.

Nonlinear Heart Rate Dynamics Before and After Paroxysmal Atrial Fibrillation Events.

Background: Heart rate complexity, derived from nonlinear heart rate variability (HRV), has been shown to help predict the outcomes of various diseases. Changes in heart rate complexity before and after paroxysmal atrial fibrillation (PAF) events are unclear. Objectives: To evaluate changes in heart rate complexity through nonlinear HRV before and after PAF events. Methods: We enrolled 65 patients (72 ± 12.34 years old, 31 females) with 99 PAF events who received 24-hour Holter recording, and analyzed nonlinear HRV variables including Poincaré plot analysis, sample entropy (SampEn), and multiscale entropy (MSE). HRV analyses were applied to a 20-minute window before the onset and after the termination of PAF events. HRV parameters were evaluated and compared based on eight different 5-minute time segments, as we divided each 20-minute window into four segments of 5 minutes each. Results: SampEn and MSE1~5 significantly decreased before the onset of PAF events, whereas SampEn, MSE1~5 and MSE6~20 significantly increased after the termination of PAF events. SD1 and SD2, which are nonlinear HRV parameters calculated via Poincaré plot analysis, did not significantly change before the PAF events, however they both decreased significantly after termination. Conclusions: Heart rate complexity significantly decreased before the initiation and increased after the termination of PAF events, which indicates the crucial role of nonlinear heart rate dynamics in the initiation and termination of PAF.

TNF-α - mediated peripheral and central inflammation are associated with increased incidence of PND in acute postoperative pain.

BACKGROUND: Acute postoperative pain plays an important role in the perioperative neurocognitive disorders (PND). The pathogenesis of PND is still unknown, but it is generally believed that peripheral and central nervous system inflammation play an important role, and acute postoperative pain is also thought to aggravate postoperative inflammatory response. The aim of the present study is to explore the effect of acute postoperative pain on peripheral and central nervous system inflammation and related cognitive impairment behaviour in elderly rats after surgery. METHODS: Rats were assigned into four groups: control, surgery for internal fixation for tibial fracture, surgery with analgesia using intraperitoneal morphine, and morphine without surgery. Pain was assessed by the Subjective Pain Scale. The spatial memory of rats was assessed by the Morris water maze (delayed matching task) from the second day to the seventh day after surgery (POD2-POD7). In part of the rats, the pro-inflammatory cytokines TNF-α in plasma, the medial prefrontal cortex (mPFC), and the hippocampus were determined by ELISA on the POD2. The activation of microglia and the expression of c-Fos in the hippocampal CA1 regions and mPFC were detected by the immunohistochemical method on the POD2. RESULTS: Acute postoperative pain and spatial memory impairment occurred after operation, and postoperative analgesia could significantly improve the both parameters. Additionally, on the POD2, the levels of TNF-α in plasma, hippocampus and mPFC were significantly increased, while the activation of microglia cells and the expression c-Fos in the hippocampal CA1 regions and mPFC were significantly increased. And postoperative analgesia with morphine significantly inhibited the above reactions. CONCLUSION: Our data suggest that acute postoperative pain increases the incidence of perioperative neurocognitive disorders. Peripheral and central nervous system inflammation may be involved in this cognitive impairment. And reducing the intensity of acute postoperative pain may be one of the main preventive strategies for PND.

Arecoline enhances miR-21 to promote buccal mucosal fibroblasts activation.

BACKGROUND/PURPOSE: Oral submucous fibrosis (OSF) is an irreversible fibrosis disease and a potentially malignant disorder in the oral cavity. Various studies have shown that miR-21 was implicated in the fibrogenesis and carcinogenesis, but its functional role in the development of OSF has not been investigated. METHODS: The expression levels of miR-21 in arecoline-stimulated normal buccal mucosal fibroblasts (BMFs) and OSF specimens were determined by qRT-PCR. Exogenous administration of TGF-ß and its inhibitor (SB431542) were utilized to examine the involvement of TGF-ß signaling in miR-21 alteration. Collagen gel contraction, transwell migration, and invasion assays were used to assess the myofibroblast activities. The relationship between α-SMA and miR-21 was calculated using the Pearson correlation coefficient. RESULTS: MiR-21 expression was induced in BMFs by arecoline treatment in a dose-dependent manner. Our results showed that this upregulation was mediated by TGF-ß signaling. Subsequently, we demonstrated that the administration of the miR-21 inhibitor suppressed the arecoline-induced myofibroblast characteristics, including a higher collagen gel contractility and cell motility, in normal BMFs. Furthermore, inhibition of miR-21 was sufficient to attenuate the myofibroblast features in fibrotic BMFs. Besides, we showed that the expression of miR-21 was aberrantly upregulated in the OSF tissues and there was a positive correlation between miR-21 and myofibroblast marker, α-SMA. CONCLUSION: MiR-21 overexpression in OSF may be due to the stimulation of areca nut, which was mediated by the TGF-ß pathway. Our data suggested that the repression of miR-21 was a promising direction to palliate the development and progression of OSF.

Complex dynamics of skin sympathetic nerve activities as a prognostic predictor for critically ill patients.

BACKGROUND: The skin sympathetic nerve activity (SKNA) is a new method to measure sympathetic nerve activity by using conventional ECG electrodes. We developed a novel approach to analyze the complexity of SKNA time series under different time scales and showed its prognostic significance in patients receiving critical care. METHODS: This study measured SKNA in patients admitted to an intensive care unit (ICU). Each recording is 10-minute long with 10000Hz sampling rate. Multi-scale fluctuation analysis (MSFA) was developed to quantify the variation within each time scale after removing the linear trend. The prognostic value of SKNA was combined with traditional prognostics scoring system to improve the predictive values. RESULTS: 155 patients were recruited. After 30 and 90 days, 30 and 48 patients expired. MSFA was significantly higher in survival group than mortality group for 30-day (0.487 ± 0.185 vs 0.401 ± 0.045, p = 0.018) and 90-day (0.499 ± 0.196 vs 0.414 ± 0.061, p = 0.001) follow-up. Sequential Organ Failure Assessment (SOFA) score was significantly lower in the survival group compared to the expired group for 30-day and 90-day (4.1 ± 2.9 vs. 5.5 ± 4.1, p = 0.032 and 3.9 ± 3.0 vs. 5.4 ± 3.5, p = 0.012). The Kaplan-Meier survival analysis showed MSFA lower than 0.401 (log-rank test:4.96, p = 0.03) or with SOFA score lower than 5 (log-rank test:5.49, p = 0.019) have a significantly higher mortality rate. A multivariate Cox regression model showed that the MSFA is an independent predictor for 30-day mortality (HR = 2.35, 1.08-5.09, p = 0.031) and 90-day mortality (HR = 1.96, 1.08-3.58, p = 0.027). CONCLUSION: MSFA was a significant prognostic predictor for critically ill patients. MSFA adding to SOFA score could help improve risk prediction.

Long-Term Effect of Device-Guided Slow Breathing on Blood Pressure Regulation and Chronic Inflammation in Patients with Essential Hypertension Using a Wearable ECG Device.

BACKGROUND: Hypertension is related to autonomic nervous system (ANS) dysfunction, atherosclerosis and chronic inflammation. The stimulation of baroreflex regulation by slow-breathing exercise may improve the interplay among these systems. The objective of this study was to investigate the effect of device-guided slow breathing on ANS, cardiovascular system and chronic inflammation in hypertensive patients. METHODS: We prospectively collected 36 essential hypertension patients who were requested to practice slow-breathing exercise 5 times per day for 3 months. The breathing exercise was guided by a cellphone app with a wearable electrocardiography device and a rhythm of 6 cycles per minute. Cardiovascular indicators including heart rate variability (HRV), blood pressure, pulse wave velocity and baroreflex indexes were sampled 3 times: at the first visit, and 1 month and 3 months after the intervention. The levels of blood inflammatory biomarkers, including tumor necrosis factor-alpha (TNF-α), interleukin-6, interleukin-1 receptor antagonist and C-reactive protein were also collected at all 3 visits. The longitudinal differences in these variables and their correlations were tested. RESULTS: There was a significant decrease in blood pressure after 1 month of exercise. A significantly continuous decrease in TNF-α was also observed. The baroreflex indexes were significantly increased in the acute intervention of slow-breathing but not in the longitudinal effect. The HRV variables did not show differences with time. There were positive correlations between sympathetic index and TNF-α and galectin-3. CONCLUSIONS: The effect of slow-breathing exercise on blood pressure and chronic inflammation was significant. HRV indexes may also be used to assess chronic inflammation.

In-Situ Intermolecular Interaction in Composite Polymer Electrolyte for Ultralong Life Quasi-Solid-State Lithium Metal Batteries.

Solid-state lithium metal batteries built with composite polymer electrolytes using cubic garnets as active fillers are particularly attractive owing to their high energy density, easy manufacturing and inherent safety. However, the uncontrollable formation of intractable contaminant on garnet surface usually aggravates poor interfacial contact with polymer matrix and deteriorates Li+ pathways. Here we report a rational designed intermolecular interaction in composite electrolytes that utilizing contaminants as reaction initiator to generate Li+ conducting ether oligomers, which further emerge as molecular cross-linkers between inorganic fillers and polymer matrix, creating dense and homogeneous interfacial Li+ immigration channels in the composite electrolytes. The delicate design results in a remarkable ionic conductivity of 1.43×10-3  S cm-1 and an unprecedented 1000 cycles with 90 % capacity retention at room temperature is achieved for the assembled solid-state batteries.

The effect of Sirt1 deficiency on Ca2+ and Na+ regulation in mouse ventricular myocytes.

This study addressed the hypothesis that cardiac Sirtuin 1 (Sirt1) deficiency alters cardiomyocyte Ca2+ and Na+ regulation, leading to cardiac dysfunction and arrhythmogenesis. We used mice with cardiac-specific Sirt1 knockout (Sirt1-/- ). Sirt1flox/flox mice were served as control. Sirt1-/- mice showed impaired cardiac ejection fraction with increased ventricular spontaneous activity and burst firing compared with those in control mice. The arrhythmic events were suppressed by KN93 and ranolazine. Reduction in Ca2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca2+ stores, and increased SR Ca2+ leak were shown in the Sirt1-/- mice. Electrophysiological measurements were performed using patch-clamp method. While L-type Ca2+ current (ICa, L ) was smaller in Sirt1-/- myocytes, reverse-mode Na+ /Ca2+ exchanger (NCX) current was larger compared with those in control myocytes. Late Na+ current (INa, L ) was enhanced in the Sirt1-/- mice, alongside with elevated cytosolic Na+ level. Increased cytosolic and mitochondrial reactive oxygen species (ROS) were shown in Sirt1-/- mice. Sirt1-/- cardiomyocytes showed down-regulation of L-type Ca2+ channel α1c subunit (Cav1.2) and sarcoplasmic/endoplasmic reticulum Ca2+  ATPase 2a (SERCA2a), but up-regulation of Ca2+ /calmodulin-dependent protein kinase II and NCX. In conclusions, these findings suggest that deficiency of Sirt1 impairs the regulation of intracellular Ca2+ and Na+ in cardiomyocytes, thereby provoking cardiac dysfunction and arrhythmogenesis.

Hinokitiol ablates myofibroblast activation in precancerous oral submucous fibrosis by targeting Snail.

Oral submucous fibrosis (OSF) is a precancerous condition with symptoms of limited mouth opening and areca nut chewing habit has been implicated in its pathogenesis. Hinokitiol, a natural tropolone derived from Chamacyparis taiwanensis, has been reported to improve oral lichen planus and inhibit various cancer cells. Here, we showed that hinokitiol reduced the myofibroblast activities in fBMFs and prevented the arecoline-induced transdifferentiation. Treatment of hinokitiol dose-dependently downregulated the myofibroblast markers as well as various EMT transcriptional factors. In particular, we identified that Snail was able to bind to the E-box in the α-SMA promoter. Our data suggested that exposure of fBMFs to hinokitiol mitigated the hallmarks of myofibroblasts, while overexpression of Snail eliminated the effect of hinokitiol. These findings revealed that the inhibitory effect of hinokitiol on myofibroblasts was mediated by repression of α-SMA via regulation of Snail and showed the anti-fibrotic potential of hinokitiol in the treatment of OSF.

Glabridin inhibits the activation of myofibroblasts in human fibrotic buccal mucosal fibroblasts through TGF-ß/smad signaling.

Oral submucous fibrosis (OSF) has been recognized as one of the oral potentially malignant disorders. Areca nut chewing is implicated in this pathological fibrosis, and it causes chronic inflammation and persistent activation of myofibroblasts. As yet, existing treatments only provide temporary symptomatic relief and there is a lack of an effective intervention to cure OSF. Therefore, development of approaches to ameliorate myofibroblast activities becomes a crucial objective to prevent the malignant progression of OSF. In this study, we examined the inhibitory effect of glabridin, an isoflavane extracted from licorice root, on the myofibroblast characteristics in human fibrotic buccal mucosal fibroblasts (fBMFs). Our results showed that myofibroblast activities, including collagen gel contractility, migration, invasion and wound healing abilities were reduced after exposure of glabridin in a dose-dependent manner. Most importantly, we demonstrated that the arecoline-induced myofiroblast activities were abolished by glabridin treatment. Additionally, the expression of the myofibroblast marker α-smooth muscle actin and other fibrogenic marker, type I collagen, in fBMFs were dose-dependently downregulated. Moreover, we showed that the production of TGF-ß was suppressed by glabridin in fBMFs and the protein expression of phospho-Smad2 was decreased as well. In summary, our data suggested that glabridin repressed the myofibroblast features in fBMFs via TGF-ß/Smad2 signaling pathway. Glabridin also prevented the arecoline-increased myofibroblast activities, and could serve as a natural anti-fibrosis compound for OSF.

LncRNA GAS5-AS1 inhibits myofibroblasts activities in oral submucous fibrosis.

BACKGROUND/PURPOSE: Emerging research findings suggest that long non-coding RNAs (lncRNAs) are key regulators to fibrosis formation. Nevertheless, the role of lncRNA GAS5-AS1 in the progression of precancerous oral submucous fibrosis (OSF) remains to be elucidated. METHODS: Quantitative real-time PCR were used to examine the expression of GAS5-AS1 in OSF tissues. The activities of myofibroblasts, including collagen contractility and cell migration, as well as the marker α-smooth muscle actin (SMA) were assessed following overexpression of GAS5-AS1. Also, we analyzed the expression of Smad activity in order to gain insight into the downstream regulator. RESULTS: The level of GAS5-AS1 was found significantly downregulated in the OSF tissues and fibrotic buccal mucosal fibroblasts (fBMFs). Ectopic expression of GAS5-AS1 significantly reduced the abilities of collagen gel contraction and migration in fBMFs or arecoline-treated BMFs. Moreover, we have shown that overexpression of GAS5-AS1 inhibited the expression of p-Smad and the marker of myofibroblasts. CONCLUSION: We showed the reduced expression of GAS5-AS1 in OSF tissues and demonstrated its effect on the myofibroblast activities and the level of p-Smad and α-SMA, indicating its potential contribution in OSF pathogenesis.

Transient-Ligand-Enabled ortho-Arylation of Five-Membered Heterocycles: Facile Access to Mechanochromic Materials.

Reported herein is the first example of a direct arylation of heteroarenes by a transient-ligand-directed strategy without the need to construct and deconstruct the directing group. A wide range of heteroarenes undergoes the coupling with diverse aryl iodides to assemble a large library of highly selective and functionalized 3-arylthiophene-2-carbaldehydes. This route provides an opportunity to rapidly access new mechanofluorochromic materials. Moreover, a novel strategy for mechanochromic luminogens with chromism trends of red- and blue-shifts has been disclosed for the first time by facile functional-group modifications to a common structural core.