Interaction between fatty acid oxidation and ethanol metabolism in liver.

Fatty acid oxidation (FAO) releases the energy stored in fat to maintain basic biological processes. Dehydrogenation is a major way to oxidize fatty acids, which needs NAD+ to accept the released H+ from fatty acids and form NADH, which increases the ratio of NADH/NAD+ and consequently inhibits FAO leading to the deposition of fat in the liver, which is termed fatty liver or steatosis. Consumption of alcohol (ethanol) initiates simple steatosis that progresses to alcoholic steatohepatitis, which constitutes a spectrum of liver disorders called alcohol-associated liver disease (ALD). ALD is linked to ethanol metabolism. Ethanol is metabolized by alcohol dehydrogenase (ADH), microsomal ethanol oxidation system (MEOS), mainly cytochrome P450 2E1 (CYP2E1), and catalase. ADH also requires NAD+ to accept the released H+ from ethanol. Thus, ethanol metabolism by ADH leads to increased ratio of NADH/NAD+, which inhibits FAO and induces steatosis. CYP2E1 directly consumes reducing equivalent NADPH to oxidize ethanol, which generates reactive oxygen species (ROS) that lead to cellular injury. Catalase is mainly present in peroxisomes, where very long-chain fatty acids and branched-chain fatty acids are oxidized, and the resultant short-chain fatty acids will be further oxidized in mitochondria. Peroxisomal FAO generates hydrogen peroxide (H2O2), which is locally decomposed by catalase. When ethanol is present, catalase uses H2O2 to oxidize ethanol. In this review, we introduce FAO (including α-, ß-, and ω-oxidation) and ethanol metabolism (by ADH, CYP2E1, and catalase) followed by the interaction between FAO and ethanol metabolism in the liver and its pathophysiological significance.

Therapeutic implication of human placental extract to prevent liver cirrhosis in rats with metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is always accompanied with hepatic fibrosis that could potentially progress to liver cirrhosis and hepatocellular carcinoma. Employing a rat model, we evaluated the role of human placental extract (HPE) to arrest the progression of hepatic fibrosis to cirrhosis in patients with MASH. SHRSP5/Dmcr rats were fed with a high-fat and high-cholesterol diet for 4 weeks and evaluated for the development of steatosis. The animals were divided into control and treated groups and received either saline or HPE (3.6 ml/kg body weight) subcutaneously thrice a week. A set of animals were killed at the end of 6th, 8th, and 12th weeks from the beginning of the experiment. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hepatic malondialdehyde (MDA), and glutathione content were measured. Immunohistochemical staining was performed for α-smooth muscle actin (α-SMA), 4-hydroxy-2-nonenal (4-HNE), collagen type I, and type III. Control rats depicted progression of liver fibrosis at 6 weeks, advanced fibrosis and bridging at 8 weeks, and cirrhosis at 12 weeks, which were significantly decreased in HPE-treated animals. Treatment with HPE maintained normal levels of MDA and glutathione in the liver. There was marked decrease in the staining intensity of α-SMA, 4-HNE, and collagen type I and type III in HPE treated rats compared with control animals. The results of the present study indicated that HPE treatment mediates immunotropic, anti-inflammatory, and antioxidant responses and attenuates hepatic fibrosis and early cirrhosis. HPE depicts therapeutic potential to arrest the progression of MASH towards cirrhosis.

Longitudinal assessment of dental erosion-abrasion by cross-polarization optical coherence tomography in vitro.

This study tested a novel in vitro dental erosion-abrasion model and the performance of cross-polarization optical coherence tomography (CP-OCT) in longitudinally monitoring the simulated lesions. Thirty human enamel specimens were prepared and randomized to receive three dental erosion-abrasion (EA) protocols: severe (s-EA, lemon juice/pH:2.5/4.25%w/v citric acid), moderate (m-EA, grapefruit juice/pH:3.5/1.03%w/v citric acid) and no-EA (water, control). EA challenge was performed by exposing the specimens to acidic solutions 4x/day and to brushing 2x/day with 1:3 fluoridated toothpaste slurry, for 14 days. Enamel thickness measurements were obtained using CP-OCT at baseline (D0), 7 (D7) and 14 days (D14) and micro-computed tomography (micro-CT) at D14. Enamel surface loss was measured with both CP-OCT and optical profilometry at D0, D7 and D14. Data was analyzed with repeated-measures ANOVA and Pearson's correlation (r) (α = 0.05). CP-OCT enamel thickness decreased over time in the s-EA group (D0 >D7 > D14, p < 0.001) and m-EA group (D0 > D14, p = 0.019) but did not change in the no-EA group (p = 0.30). Overall, CP-OCT and micro-CT results at D14 correlated moderately (r = 0.73). CP-OCT surface loss was highest for s-EA (p <0.001) but did not differ between moderate and no-EA (p = 0.25). Enamel surface loss with profilometry increased with severity (no-EA>m-EA>s-EA, p < 0.001). D14 surface loss was higher than D7 for both methods except for the no-EA group with profilometry. CP-OCT and profilometry had moderate overall correlation (r = 0.70). Our results revealed that the currently proposed in vitro dental erosion-abrasion model is valid and could simulate lesions of different severities over time. CP-OCT was a suitable method for monitoring the EA lesions.

Eosinophilic Fasciitis Possibly Provoked by Exercise.

A 26-year-old woman was referred to dermatology for evaluation of "lumpy skin" for 4 months. She experienced Achilles tendon pain and muscle tightness, occurring before the skin lesions had appeared. The lesions began on her arms and progressed to her legs over 1 month.

Tension pyopneumothorax caused by Burkholderia cenocepacia: a rare case report in an immunocompetent individual.

Tension pyopneumothorax is a medical emergency that occurs when air and pus build up in the pleural space. This case report describes a 47-year-old diabetic female who presented with tension pyopneumothorax due to Burkholderia cenocepacia. The patient was successfully treated with a 24-French tube thoracostomy and antibiotics. To the best of our knowledge, this is the first case of tension pyopneumothorax caused by Burkholderia cenocepacia to be reported.

Immediate and 90-Day Clinical Outcome of Patients with Acute Stroke Treated with the NeVa-Vesalio Mechanical Thrombectomy Device: A Retrospective Case Series.

OBJECTIVE: The NeVa stent retriever is a newly designed mechanical thrombectomy device for the treatment of acute ischemic stroke caused by large vessel occlusion. We investigate the procedural characteristics and patients' clinical outcomes at discharge and at 90 days of follow-up. METHODS: We retrospectively reviewed a cohort of 75 patients (median age, 74 years) treated with the NeVa device for acute large vessel occlusion stroke. Per pass modified Treatment in Cerebral Infarction (mTICI) scores, procedural complications, and clinical outcome parameters including the National Institutes of Health Stroke Scale (NIHSS) score, modified Rankin Scale (mRS) score, and mortality were analyzed, based on patients' electronic medical records. RESULTS: Complete first pass effect was observed in 24 patients (32%). Vasospasm, repeated re-thrombosis, failure to advance the NeVa device through the microcatheter, and symptomatic intracranial hemorrhage were observed in 2, 1, 1, and 2 patient(s) respectively. The rate of complete (mTICI 2c-3) reperfusion was achieved in 61 patients (81.33%), with a median number of 2 passes (1-3). Median NIHSS score on admission, after 24 hours, and after 5-10 days or at discharge was 19 (15-23), 11 (4-19), and 3 (2-13.5), respectively. The number of patients with a functional mRS score (0-2) at 90 days follow-up was 29 (39%). CONCLUSIONS: Endovascular stroke management with use of the NeVa-Vesalio stent retriever may be associated with a 90-day functional mRS score in nearly 40% of treated patients.

Inferior scapula avulsion fracture: an unusual presentation of winged scapula.

Inferior scapula avulsion fractures are rare injuries, with few cases reported and only a small number managed operatively discussed in the literature. We report the case of a man in his 40s who fell from a height and presented with right-sided scapular winging and point tenderness at the inferior pole of his right scapula with no neurological deficit. Radiographs and CT diagnosed avulsion fracture of the inferior scapula. The patient underwent surgical fixation and, following a course of physiotherapy, successfully recovered with no residual winging and full range of movement.

Parkinson's disease relevant pathological features are manifested in male Pink1/Parkin deficient rats.

Animal disease models are important for neuroscience experimentation and in the study of neurodegenerative disorders. The major neurodegenerative disorder leading to motor impairments is Parkinson's disease (PD). The identification of hereditary forms of PD uncovered gene mutations and variants, such as loss-of-function mutations in PTEN-induced putative kinase 1 (Pink1) and the E3 ubiquitin ligase Parkin, two proteins involved in mitochondrial quality control, that could be harnessed to create animal models. However, to date, such models have not reproducibly recapitulated major aspects of the disease. Here, we describe the generation and phenotypic characterization of a combined Pink1/Parkin double knockout (dKO) rat, which reproducibly exhibits PD-relevant abnormalities, particularly in male animals. Motor dysfunction in Pink1/Parkin dKO rats was characterized by gait abnormalities and decreased rearing frequency, the latter of which was responsive to levodopa treatment. Pink1/Parkin dKO rats exhibited elevated plasma levels of neurofilament light chain and significant loss of tyrosine hydroxylase expression in the substantia nigra pars compacta (SNpc). Glial cell activation was also observed in the SNpc. Pink1/Parkin dKO rats showed elevated plasma and reduced cerebrospinal levels of alpha-synuclein as well as the presence of alpha-synuclein aggregates in the striatum. Further, the profile of circulating lymphocytes was altered, as elevated CD3+CD4+ T cells and reduced CD3+CD8+ T cells in Pink1/Parkin dKO rats were found. This coincided with mitochondrial dysfunction and infiltration of CD3+ T cells in the striatum. Altogether, the Pink1/Parkin dKO rats exhibited phenotypes similar to what is seen with PD patients, thus highlighting the suitability of this model for mechanistic studies of the role of Pink1 and Parkin in PD pathogenesis and as therapeutic targets.

Synovial Chondromatosis Ankle - A Case Report.

Introduction: Many loose bodies are present in the joint due to the uncommon benign neoplastic disorder known as synovial chondromatosis, which causes the production of intra-articular nodular cartilaginous lesions from the synovium. Synovial chondromatosis of the ankle joint is an uncommon condition. Here, we present a case of synovial chondromatosis of the ankle joint treated by surgical excision. Case Report: A 42-year-old woman who had been experiencing discomfort and edema in her left ankle for 8 years and had gotten worse during the previous 2 years visited our outpatient department. Clinical and radiological examination revealed synovial chondromatosis of the left ankle joint. Conclusion: Synovial chondromatosis of the ankle is an uncommon synovial neoplasm in an unlikely anatomic location. The diagnosis should be considered when evaluating monoarticular synovitis.

Healing pattern of subfoveal retinal pigment epithelium rip and aperture in central serous chorioretinopathy.

This report describes a rare case of spontaneous Grade-4 retinal pigment epithelium (RPE) rip of serous pigment epithelial detachment (PED) in central serous chorioretinopathy (CSC) and RPE aperture in the fellow eye, with favorable long-term outcomes. A 38-year-old man presented with defective vision (20/30) in the left eye (LE) due to bullous CSC associated with a large extramacular RPE rip located temporally and inferior exudative retinal detachment. Optical coherence tomography (OCT) confirmed a subfoveal serous PED with RPE aperture, subretinal fluid (SRF) and fibrinous exudation, and a large extramacular RPE rip temporally. The right eye (RE) had an asymptomatic large serous PED. The LE was treated with low-fluence photodynamic therapy, which resulted in the closure of RPE aperture and complete resolution of PED and SRF. Six-month later, the patient presented with sudden defective vision (20/120) in the RE secondary to a large fovea-involving (Grade-4) RPE rip with SRF as confirmed on OCT. Fluorescein angiography showed two extrafoveal active point leaks, which were treated with focal photocoagulation. He was also started on oral eplerenone. On subsequent serial follow-ups over 1 year, OCT showed SRF resolution and patchy reorganization of the subfoveal RPE-photoreceptor complex with good visual outcome (20/30).

Patient-reported outcome measures in congenital heart surgery: a systematic review.

BACKGROUND: Patient-reported outcome measures are commonly used to evaluate the effectiveness of treatments. CHD remains the most common congenital malformation. There has been a gradual shift in evaluating the outcome of surgery for CHD from mortality to morbidity and now to self-reported outcomes. AIMS: We aimed to review studies assessing patient-reported outcome measures as a useful marker of outcome for patients, both children and adults, who underwent surgery for CHD. METHODS: A systematic database search was conducted of original articles that explored the application of patient-reported outcome measures in the CHD surgical setting in PubMed and SCOPUS from inception to February 2022. RESULTS: Our search yielded 1511 papers, of which six studies were included in this review after screening abstract and full-text, with a total sample size of 5734 patients. The main areas of discussion were the utility of patient-reported outcome measures, determinants of patient-reported outcome measures, and the need for a congenital cardiac surgery-specific patient-reported outcome measure for paediatric patients and their parents/guardians and adult patients. CONCLUSION: This systematic review reports the use of patient-reported outcome measures to be a useful indicator to gain insight into the patients' perspective to provide holistic and patient-centred management. However, further studies are required to assess the utility of patient-reported outcome measures in a congenital cardiac surgical setting.

Robotic Arm-Assisted versus Manual Total Knee Arthroplasty: A Propensity Score-Matched Analysis.

The purpose of this study was to compare (1) operative time, (2) in-hospital pain scores, (3) opioid medication use, (4) length of stay (LOS), (5) discharge disposition at 90-day postoperative, (6) range of motion (ROM), (7) number of physical therapy (PT) visits, (8) emergency department (ED) visits, (9) readmissions, (10) reoperations, (11) complications, and (12) 1-year patient-reported outcome measures (PROMs) in propensity matched patient cohorts who underwent robotic arm-assisted (RA) versus manual total knee arthroplasty (TKA). Using a prospectively collected institutional database, patients who underwent RA- and manual TKA were the nearest neighbor propensity score matched 3:1 (255 manual TKA:85 RA-TKA), accounting for various preoperative characteristics. Data were compared using analysis of variance (ANOVA), Kruskal-Wallis, Pearson's Chi-squared, and Fisher's exact tests, when appropriate. Postoperative pain scores, opioid use, ED visits, readmissions, and 1-year PROMs were similar between the cohorts. Manual TKA patients achieved higher maximum flexion ROM (120.3 ± 9.9 versus 117.8 ± 10.2, p = 0.043) with no statistical differences in other ROM parameters. Manual TKA had shorter operative time (105 vs.113 minutes, p < 0.001), and fewer PT visits (median [interquartile range] = 10.0 [8.0-13.0] vs. 11.5 [9.5-15.5] visits, p = 0.014). RA-TKA had shorter LOS (0.48 ± 0.59 vs.1.2 ± 0.59 days, p < 0.001) and higher proportion of home discharges (p < 0.001). RA-TKA and manual TKA had similar postoperative complications and 1-year PROMs. Although RA-TKA patients had longer operative times, they had shorter LOS and higher propensity for home discharge. In an era of value-based care models and the steady shift to outpatient TKA, these trends need to be explored further. Long-term and randomized controlled studies may help determine potential added value of RA-TKA versus manual TKA. This study reflects level of evidence III.

Longitudinal assessment of dental erosion-abrasion by cross-polarization optical coherence tomography in vitro

Abstract: This study tested a novel in vitro dental erosion-abrasion model and the performance of cross-polarization optical coherence tomography (CP-OCT) in longitudinally monitoring the simulated lesions. Thirty human enamel specimens were prepared and randomized to receive three dental erosion-abrasion (EA) protocols: severe (s-EA, lemon juice/pH:2.5/4.25%w/v citric acid), moderate (m-EA, grapefruit juice/pH:3.5/1.03%w/v citric acid) and no-EA (water, control). EA challenge was performed by exposing the specimens to acidic solutions 4x/day and to brushing 2x/day with 1:3 fluoridated toothpaste slurry, for 14 days. Enamel thickness measurements were obtained using CP-OCT at baseline (D0), 7 (D7) and 14 days (D14) and micro-computed tomography (micro-CT) at D14. Enamel surface loss was measured with both CP-OCT and optical profilometry at D0, D7 and D14. Data was analyzed with repeated-measures ANOVA and Pearson's correlation (r) (α = 0.05). CP-OCT enamel thickness decreased over time in the s-EA group (D0 >D7 > D14, p < 0.001) and m-EA group (D0 > D14, p = 0.019) but did not change in the no-EA group (p = 0.30). Overall, CP-OCT and micro-CT results at D14 correlated moderately (r = 0.73). CP-OCT surface loss was highest for s-EA (p <0.001) but did not differ between moderate and no-EA (p = 0.25). Enamel surface loss with profilometry increased with severity (no-EA>m-EA>s-EA, p < 0.001). D14 surface loss was higher than D7 for both methods except for the no-EA group with profilometry. CP-OCT and profilometry had moderate overall correlation (r = 0.70). Our results revealed that the currently proposed in vitro dental erosion-abrasion model is valid and could simulate lesions of different severities over time. CP-OCT was a suitable method for monitoring the EA lesions.

Surgical implantation of human adipose derived stem cells attenuates experimentally induced hepatic fibrosis in rats.

BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent stromal cells and could exert hepatoprotective effects against acute liver injury, steatohepatitis, and fibrogenesis. Here, we evaluated the effects of human adipose derived stem cells (hADSCs) to attenuate experimentally induced hepatic fibrosis and early cirrhosis in rats. METHODS: Hepatic fibrosis was induced by intraperitoneal injections of CCl4 (0.1 ml/100 g body weight) twice a week for 8 weeks. hADSCs were isolated and cultured on polyethylene discs coated with hydroxyapatite and 2 cm diameter disc was surgically implanted on the right lateral lobe of the liver. Discs implanted without hADSCs served as control. The animals were injected again with CCl4 once a week for another 8 weeks. All the animals were sacrificed at the end of 16th week. RESULTS: Serial administrations of CCl4 resulted in well developed fibrosis and early cirrhosis at 8th week which maintained until the 16th week. Animals treated with hADSC discs depicted over 50% decrease of collagen with significant increase in serum albumin and total protein levels. Immunohistochemical staining for TGF-ß1, α-smooth muscle actin, and collagen type I and type III demonstrated marked decrease compared to the animals without hADSC treatment. CONCLUSIONS: Treatment with hADSCs improved liver functions, markedly reduced hepatic fibrosis and early cirrhosis. Various pleiotropic and paracrine factors secreted from the hADSCs seem to serve as reparative functions in the attenuation of liver cirrhosis. The data demonstrated that treatment with hADSCs can be successfully used as a potent therapeutic method to prevent progression of hepatic fibrosis and related adverse events.

Non-Biological and Biological Risk Indicators for Tooth Wear Outcomes in Adults.

This study was undertaken to estimate the prevalence and severity of tooth wear (TW), as well as to assess non-biological and biological risk indicators for TW outcomes in adults. A cross-sectional study, adhering to the reporting STROBE guidelines, was conducted and had a convenience sample of adults ≥18 years of age who had at least one bilateral posterior molar contact. A total of 570 participants, seeking consultation at the University Hospital in Brussels, Belgium, were allocated to three age groups: 18-34 years (n = 232), 35-54 years (n = 256), and ≥55 years old (n = 79). Participants answered a self-applied questionnaire regarding sociodemographics, oral hygiene, and lifestyle behavior. The questionnaire was tested-retested (intraclass correlation coefficient = 0.71). Inter-examiner reliability for clinical examinations was k = 0.76-0.80. The prevalence of TW was 75% (95% CI: 71.7-78.9). Out of these patients, 42% (95% CI: 38.0-46.3) had as the primary etiological factor the process of dental erosion, while 22% (95% CI: 18.9-25.9) and 11% (95% CI: 8.6-13.9) had the processes of dental attrition and dental abrasion, respectively. The severity of TW according to BEWE highest score was mild in 31%, moderate in 28%, and severe in 17% of participants. The hierarchical logistic regression model for the association between risk indicators and TW irrespective of the etiology was significant for age (>35-54 years: OR = 2.35 and ≥55 years: OR = 3.89; p < 0.001), gender (>male: OR = 2.03; p < 0.001), toothpaste (>sensitive teeth: OR = 2.34; p = 0.005), occlusal splint (>yes: OR = 1.62; p = 0.03), and acidic beverages (≥once per day: OR = 1.62; p = 0.044). Consumption of acidic beverages was not associated with TW having as the primary etiological factor the process of dental attrition or dental abrasion, while it was significantly associated with the process of dental erosion (>once per week: OR = 1.69; p = 0.043 and ≥once per day: OR = 1.73; p = 0.016). Medical conditions were equally associated with the latter (OR = 3.11; p < 0.001). These findings could contribute to improving the effectiveness and sustainability of awareness in contemporary adult populations. In conclusion, the prevalence and severity of TW in adults were substantial. Medical conditions and consumption of acidic beverages were risk indicators for TW having as the primary etiological factor the process of dental erosion, although associations were moderate and weak, respectively.

Role of oral acetazolamide in refractory glaucomatous deep cup-related maculopathy.

A 39-year-old man, a known case of primary open-angle glaucoma on treatment, presented with defective central vision in the left eye. On examination, his intraocular pressure (IOP) was 26 mmHg in the right eye and 30 mmHg in the left eye with best-corrected visual acuity of 6/12 in each eye. Fundus examination showed glaucomatous optic neuropathy in both eyes and macular thickening in the left eye. Optical coherence tomography of the left eye showed macular detachment with peripapillary retinoschisis and a hyporeflective tract connecting schitic retina and the deep cup in the absence of an optic disc pit. A diagnosis of glaucomatous deep cup maculopathy (DCM) was made in the left eye, which persisted despite well-controlled IOP and peripapillary laser photocoagulation. The addition of oral acetazolamide (250 mg twice daily) to his regimen resulted in prompt resolution of maculopathy. Glaucomatous DCM is relatively rare, and its primary management is adequate IOP control with antiglaucoma medications. Including oral acetazolamide in the antiglaucoma regimen can help in faster resolution of maculopathy due to its additional effect on retinal pigment epithelial pump induction and stabilization of the pressure gradient.

Tooth wear and oral-health-related quality of life in dentate adults.

OBJECTIVES: This study estimated the extent to which tooth wear, adjusted for (oral) health risk indicators, impacts adversely on the Oral-Health-Related Quality of Life (OHRQoL) of dentate adults. METHODS: A cross-sectional study was conducted and had a convenience sample of 570 adults ≥18 years old with at least one bilateral molar occlusal contact. Participants answered a self-applied questionnaire (ICC=0.71) consisting of four domains: socio-demographics, oral care attendance, (oral) health conditions and lifestyle, complaints and oral-health-related quality of life (OHIP-14). Tooth wear was clinically assessed using the Basic Erosive Wear Examination index by two examiners, whose inter-examiner reliability were k=0.76-0.80. RESULTS: The outcome was a high score on the OHRQoL (median split ≥ 7). The prevalence of tooth wear was 75.0%. Only 30.2% of adults reported impacts on at least 1 performance parameter affected 'fairly often' or 'very often'. The hierarchical logistic regression showed that participants 35-54 years old (OR=2.1), who were ever prevented from regular oral health care due to costs of care (OR=3.6), who ingested acidic beverages ≥ daily (OR=1.7), who had tooth sensitivity (OR= 2.9) and those having the impression that their teeth have changed appearance (OR= 5.9) were significantly more likely to report lower OHRQoL than their counterparts. The severity of tooth wear was not significant when considering moderate and severe cases together. CONCLUSIONS: Although the prevalence of tooth wear was high, its severity and impact on OHRQoL were limited. However, distal and proximal indicators for tooth wear were mediators for impaired OHRQoL and treatment needs. CLINICAL SIGNIFICANCE: Prevalence and severity of tooth wear had limited impact on OHRQoL in adults. Distal and proximal indicators for tooth wear were mediators for impaired OHRQoL. The understanding of these relationships offers an opportunity to assess in depth the treatment needs and quality of life of patients affected by tooth wear.

Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis.

Pulmonary hypertension in sickle cell disease is an independent predictor of mortality, yet the pathogenesis of pulmonary vascular disease in chronic hemolytic disorders remains incompletely understood and treatment options are limited primarily to supportive care. The release of extracellular hemoglobin has been implicated in the development of pulmonary hypertension, and in this study we explored the direct effects of hemin, the oxidized moiety of heme, on the pulmonary artery endothelium. We found that low dose hemin exposure leads to significantly increased endothelial cell proliferation, migration, and cytokine release as markers of endothelial dysfunction. Protein expression changes in our pulmonary artery endothelial cells showed upregulation of mesenchymal markers after hemin treatment in conjunction with a decrease in endothelial markers. Endothelial to mesenchymal transition (EndoMT) resulting from hemin exposure was further confirmed by showing upregulation of the transcription factors SNAI1 and SLUG, known to regulate EndoMT. Lastly, given the endothelial dysfunction and phenotypic transition observed, the endothelial cytoskeleton was considered a potential novel target. Inhibiting myosin light chain kinase, to prevent phosphorylation of myosin light chain and cytoskeletal contraction, attenuated hemin-induced endothelial hyper-proliferation, migration, and cytokine release. The findings in this study implicate hemin as a key inducer of endothelial dysfunction through EndoMT, which may play an important role in pulmonary vascular remodeling during the development of pulmonary hypertension in chronic hemolytic states.

Epigallocatechin-3-gallate inhibits osteopontin expression and prevents experimentally induced hepatic fibrosis.

Osteopontin (OPN) is a matricellular cytokine and a stress-induced profibrogenic molecule that promotes activation of stellate cells during the pathogenesis of hepatic fibrosis. We studied the protective effects of epigallocatechin-3-gallate (EGCG) to suppress oxidative stress, inhibit OPN expression, and prevent experimentally induced hepatic fibrosis. Liver injury was induced with intraperitoneal injections of N-nitrosodimethylamine (NDMA) in a dose of 1 mg/100 g body weight on 3 consecutive days of a week for 28 days. A group of rats received 0.2 mg EGCG/100 g body weight orally everyday during the study. The animals were sacrificed on day 28th from the beginning of exposure. Serum levels of AST, ALT, OPN, malondialdehyde, collagen type IV, and hyaluronic acid were measured. Immunohistochemistry and/or real-time PCR were performed for α-SMA, 4-HNE, OPN, collagen type I, and type III. Serial administrations of NDMA produced well developed fibrosis and early cirrhosis in rat liver. Treatment with EGCG significantly reduced serum/plasma levels of AST, ALT, OPN, malondialdehyde, collagen type IV, and hyaluronic acid and prevented deposition of collagen fibers in the hepatic tissue. Protein and/or mRNA levels demonstrated marked decrease in the expression of α-SMA, 4-HNE, OPN, collagen type I, and type III. Treatment with EGCG prevented excessive generation of reactive oxygen species, suppressed oxidative stress, significantly reduced serum and hepatic OPN levels, and markedly attenuated hepatic fibrosis. The results indicated that EGCG could be used as a potent therapeutic agent to prevent hepatic fibrogenesis and related adverse events.