Prevalence of Overweight/Obesity Associated With Anemia Among Female Medical Students at Umm Al-Qura University in Makkah, Saudi Arabia: A Cross-Sectional Study.

Introduction The obesity epidemic has been linked to a wide range of health and nutritional problems, including anemia, which is often caused by impaired iron metabolism. The World Health Organization considers anemia and obesity to be global health issues among adolescent girls and women experiencing menstruation. This study aims to examine the association between iron deficiency anemia and obesity/overweight among female medical students. Methodology This cross-sectional descriptive study conducted as an online self-administered questionnaire. Furthermore, blood samples were collected from 206 students to evaluate the complete blood count, iron and lipid profile. Results The convenience sampling technique was used and a total of 206 students were enrolled in the study. The average body mass index (BMI) was 22.51 ± 3.25, with 83.5% (n = 172) falling within the normal weight range, 12.6% (n = 26) as overweight, and 3.9% (n = 8) as obese. Anemia was present in 16.0% (n = 33) of the participants overall. Higher prevalence of anemia was observed among overweight participants with 10 out of 26 (38.5%) subjects compared to obese with two out of eight (25.0%) and normal weight 21 out of 172 (12.2%); this difference was highly significant (P = 0.005). Individuals with anemia exhibited a significant association with those experiencing a diet full of unhealthy fats and carbohydrates (P = 0.05) and a diet containing all essential nutrients (P = 0.01). There is no statistically significant correlation between anemia prevalence and participants' response to the presence of signs of anemia, physical activity or other dietary habits. Obese participants had a significantly higher mean value of triglycerides (129.5 ± 20.5) compared to normal weight and overweight participants (74.5 ± 12.02 and 51.2 ± 15.04), respectively (P = 0.001). Conclusion A dependable assembly exists between obesity and overweight in cases of iron deficient anemia. The prevalence of iron deficiency anemia was substantially higher among overweight/obese females, highlighting that overweight/obesity signifies both quantitative and qualitative malnutrition. A high BMI was associated with elevated triglycerides, typically considered indicators of obesity. This association may suggest compromised iron homeostasis.

Mechanistic insights into the potential role of dietary polyphenols and their nanoformulation in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aß biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.

Knowledge, attitude, and practices toward dengue fever among the public: a cross-sectional study in the Western region of Saudi Arabia.

Background: Dengue fever (DF) is a primary viral disease transmitted to humans by mosquitoes, imposing a significant economic and health burden in numerous regions globally. There is a lack of studies addressing the importance of health education regarding DF in Saudi Arabia. Therefore, this study aimed to assess predictors influencing knowledge, attitude, and practices of the Western region public in Saudi Arabia related to DF. Methods: This cross-sectional study was conducted as an online self-administered questionnaire collected from July 2023 until August 2023, included 695 participants from the Western region residents aged ≥18 years. Data collected involved sociodemographics, participants' knowledge, attitude, and practices toward DF. We presented the descriptive data as mean ± standard deviations (SD) and medians [interquartile range (IQR)] for continuous variables, while categorical variables were presented as frequencies [percent (%)]. Results: Good participants' knowledge and attitude toward DF were observed among participants [median score 21.0 (interquartile range 16.0-24.0)] out of 35 and [median score 4.00 (interquartile range 3.00-5.00)] out of 5, respectively. Limited practices toward DF were observed among participants [median score 3.0 (interquartile range 0.00-5.00)] out of 8. Participants' knowledge and attitude were not correlated. Participants' education level and employment status predicted participant's knowledge of DF. Participants' age, monthly income, employment status and marital status predicted participants' attitude toward DF. Participants' age, marital status, education levels and income predicted participants' practices toward DF. Conclusion: Knowledge, attitude, and practices toward DF among adults in Saudi Arabia can be predicted by specific sociodemographic characteristics. Implementing interferences that focus on improving public practices toward DF is imperative.

Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders.

Neurodegenerative disorders, such as Alzheimer's disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A-N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3ß, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3ß (ΔG: -8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M-1), NMDA (ΔG: -9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M-1), and BACE-1 (ΔG: -9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M-1). It showed a 25-fold higher affinity with GSK-3ß, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3ß-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C.

Recurrent COVID-19 Infection in a Refractory/Classical Hodgkin's Lymphoma Patient Undergoing Autologous Stem Cell Transplantation: A Case Report.

Patients with challenging hematological malignancies like classic Hodgkin lymphoma (cHL) can be further complicated when affected by a concurrent coronavirus disease-2019 (COVID-19) infection and often face unique and complex management and outcomes. In this case report, we describe a refractory or relapsed classic Hodgkin lymphoma patient with a recurrent infection of COVID-19 three times preceding chemotherapy. A 52-year-old female presented to our hospital with a second incidence of COVID-19 and a complaint of fever, anorexia, night sweats, and abdominal lymphadenopathy, for which she was diagnosed with mixed cellularity classic Hodgkin lymphoma. Three weeks later, in consideration of her manifestation of lung disease, which was due to her past medical history of airway hypersensitivity and abnormal pulmonary function test along with testing positive for COVID-19, she was started with the first-line chemotherapy of the brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine chemotherapy regimen, commonly referred to as Bv-AVD, without bleomycin. After six cycles of chemotherapy, at the end of treatment, positron emission tomography/computed tomography (PET/CT) revealed the progression of nodes in the abdomen and the development of new lymphadenopathy in the chest and right supraclavicular region. Hence, it was considered refractory Hodgkin's lymphoma, and the patient was referred for salvage therapy. She was started on salvage chemotherapy with brentuximab/bendamustine (BvB). Follow-up evaluations after two cycles of BvB continued to show newer lesions in the right sub-diaphragmatic area, internal mammary, and supraclavicular lymph nodes. Therefore, the patient was switched to pembrolizumab immunotherapy, a PD-1 inhibitor. After four cycles of pembrolizumab monotherapy, PET/CT showed significant improvement with a complete molecular response (CMR). Then, she was admitted for high-dose therapy/autologous stem cell transplantation (HDT/ASCT) after collecting stem cells. PET/CT: three months post-ASCT, she continued to be in a CMR with a Deauville score of 1. The patient was continued on pembrolizumab maintenance for six months afterward. Currently, the patient is healthy and doing well. COVID-19 patients with hematological malignancies may experience compromised viral elimination and a prolonged period of viral infection, which may also worsen the symptoms and outcomes and entitle them to comprehensive and extended care.

Regulation of HDAC11 gene expression in early myogenic differentiation.

Histone acetylation and deacetylation affect the patterns of gene expression in cellular differentiation, playing pivotal roles in tissue development and maintenance. For example, the intrinsic histone acetyltransferase activity of transcriptional coactivator p300 is especially required for the expression of myogenic regulatory factors including Myf5 and MyoD, and consequently for skeletal myogenesis. On the other hand, histone deacetylases (HDACs) remove the acetyl group from histones, which is critical for gene repression in stem cell fate transition. Through integrative omic analyses, we found that while some HDACs were differentially expressed at the early stage of skeletal myoblast differentiation, Hdac11 gene expression was significantly enhanced by nuclear receptor signaling. In addition, p300 and MyoD control Hdac11 expression in milieu of normal and signal-enhanced myoblast differentiation. Thus, HDAC11 may be essential to differential gene expression at the onset of myoblast differentiation.

Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3ß, NMDA-Receptor, and BACE-1 for the Management of Alzheimer's Disease.

The complexity of Alzheimer's disease (AD) and several side effects of currently available medication inclined us to search for a novel natural cure by targeting multiple key regulatory proteins. We initially virtually screened the natural product-like compounds against GSK3ß, NMDA receptor, and BACE-1 and thereafter validated the best hit through molecular dynamics simulation (MDS). The results demonstrated that out of 2029 compounds, only 51 compounds exhibited better binding interactions than native ligands, with all three protein targets (NMDA, GSK3ß, and BACE) considered multitarget inhibitors. Among them, F1094-0201 is the most potent inhibitor against multiple targets with binding energy -11.7, -10.6, and -12 kcal/mol, respectively. ADME-T analysis results showed that F1094-0201 was found to be suitable for CNS drug-likeness in addition to their other drug-likeness properties. The MDS results of RMSD, RMSF, Rg, SASA, SSE and residue interactions indicated the formation of a strong and stable association in the complex of ligands (F1094-0201) and proteins. These findings confirm the F1094-0201's ability to remain inside target proteins' binding pockets while forming a stable complex of protein-ligand. The free energies (MM/GBSA) of BACE-F1094-0201, GSK3ß-F1094-0201, and NMDA-F1094-0201 complex formation were -73.78 ± 4.31 kcal mol-1, -72.77 ± 3.43 kcal mol-1, and -52.51 ± 2.85 kcal mol-1, respectively. Amongst the target proteins, F1094-0201 have a more stable association with BACE, followed by NMDA and GSK3ß. These attributes of F1094-0201 indicate it as a possible option for the management of pathophysiological pathways associated with AD.

Determination of Chemical Composition and Investigation of Biological Activities of Ocimum basilicum L.

This study aimed to determine the chemical composition of the essential oils (EOs) of Ocimum basilicum L., as well as to evaluate the antibacterial, antidiabetic, dermatoprotective, and anti-inflammatory properties, and the EOs and aqueous extracts of O. basilicum. The antibacterial activity was evaluated against bacterial strains, Gram-positive and Gram-negative, using the well diffusion and microdilution methods, whereas the antidiabetic activity was assessed in vitro using two enzymes involved in carbohydrate digestion, α-amylase and α-glucosidase. On the other hand, the dermatoprotective and anti-inflammatory activities were studied by testing tyrosinase and lipoxygenase inhibition activity, respectively. The results showed that the chemical composition of O. basilicum EO (OBEO) is dominated by methyl chavicol (86%) and trans-anethol (8%). OBEO exhibited significant antibacterial effects against Gram-negative and Gram-positive strains, demonstrated by considerable diameters of the inhibition zones and lower MIC and MBC values. In addition, OBEO exhibited significant inhibition of α-amylase (IC50 = 50.51 ± 0.32 µg/mL) and α-glucosidase (IC50 = 39.84 ± 1.2 µg/mL). Concerning the anti-inflammatory activity, OBEO significantly inhibited lipoxygenase activity (IC50 = 18.28 ± 0.03 µg/mL) compared to the aqueous extract (IC50 = 24.8 ± 0.01 µg/mL). Moreover, tyrosinase was considerably inhibited by OBEO (IC50 = 68.58 ± 0.03 µg/mL) compared to the aqueous extract (IC50 = 118.37 ± 0.05 µg/mL). The toxicological investigations revealed the safety of O. basilicum in acute and chronic toxicity. The finding of in silico analysis showed that methyl chavicol and trans-anethole (main compounds of OBEO) validate the pharmacokinetics of these compounds and decipher some antibacterial targets.

Chemical Profiling and Biological Activities of Pelargonium graveolens Essential Oils at Three Different Phenological Stages.

The aim of this work was the determination of Pelargonium graveolens (aerial parts) volatile compounds at three developmental stages and the evaluation of their antioxidant, antidiabetic, dermaprotective, anti-inflammatory, and antibacterial effects. The aerial parts of Pelargonium graveolens were collected at three stages, namely the vegetative, beginning, and full flowering. Pelargonium graveolens essential oils were extracted from the dried materials of these aerial parts by hydrodistillation. The volatiles were analyzed by Gas Chromatography-Mass Spectrometry GC-MS, and the antioxidant activity was assessed by DPPH, ABTS, H2O2, and FRAP assays. The in vitro antidiabetic effect was evaluated by the inhibition of α-amylase, α-glucosidase, and lipase enzymes, while the antibacterial activity was assessed against six bacterial strains using an agar well diffusion assay and a microdilution method. The main constituents were menthol, menthene, eremophilene, isoborneol, isogeraniol, α-pinene, linalyl acetate, and 3-carene, with quantitative differences at the three phenological stages. The essential oil at the full flowering stage showed the best antioxidant activity, with IC50 values of 83.26 ± 0.01, 116.42 ± 0.07, 132.25 ± 0.11, and 48.67 ± 0.04 µg/mL for DPPH, FRAP, ABTS, and H2O2 assays, respectively. This oil also exhibited significant effects against α-amylase (IC50 = 43.33 ± 0.01 µg/mL), α-glucosidase (IC50 = 19.04 ± 0.01 µg/mL), lipase (IC50 = 24.33 ± 0.05 µg/mL), 5-lipoxygenase (IC50 = 39.31 ± 0.01 µg/mL), and tyrosinase (IC50 = 124.49 ± 0.07 µg/mL). The essential oil extracted at the full flowering stage showed the best antibacterial effect against a panel of microorganisms with diameter inhibition zones ranging between 11.00 ± 0.17 mm and 17.30 ± 0.17 mm and MIC values from 0.25% to 2% v/v. Overall, the results presented here suggest that the full flowering stage is the best optimal harvest time of Pelargonium graveolens for food and pharmaceutical applications.

Singular and Combined Effects of Essential Oil and Honey of Eucalyptus Globulus on Anti-Inflammatory, Antioxidant, Dermatoprotective, and Antimicrobial Properties: In Vitro and In Vivo Findings.

Eucalyptus globulus is a plant widely used by the world population, including Morocco, in the treatment of several pathologies. The aim of this work is to evaluate the antioxidant, anti-inflammatory, dermatoprotective, and antimicrobial effects of essential oil and honey from E. globulus, as well as their combination. Chemical composition was determined by GC-MS analysis. The antioxidant activity was evaluated by three tests, namely, DPPH, reducing power, and the ß-carotene/linoleic acid assay. The anti-inflammatory activity was investigated in vitro (5-lipoxygenase inhibition) and in vivo (carrageenan-induced paw edema model), while the dermatoprotective activity was tested in vitro (tyrosinase inhibition). Moreover, the antibacterial activity was assessed using agar well diffusion and microdilution methods. The results showed that eucalyptol presents the main compound of the essential oil of E. globulus (90.14%). The mixture of essential oil with honey showed the best antioxidant effects for all the tests used (0.07 < IC50 < 0.19 mg/mL), while the essential oil was the most active against tyrosinase (IC50 = 38.21 ± 0.13 µg/mL) and 5-lipoxygenase (IC50 = 0.88 ± 0.01 µg/mL), which corroborated the in vivo test. Additionally, the essential oil showed the best bactericidal effects against all strains tested, with inhibition diameter values ranging from 12.8 to 21.6 mm. The findings of this work showed that the combination of the essential oil with honey showed important results in terms of biological activity, but the determination of the underlying mechanisms of action remains a major prospect to be determined.

Chemical Analysis and Investigation of Biological Effects of Salvia officinalis Essential Oils at Three Phenological Stages.

Salvia officinalis is a medicinal plant used to treat some diseases, including microbial infections and diabetes. Different studies showed the biological and pharmacological properties of this species. The aim of this study was the determination of the chemical compounds of S. officinalis essential oils and the investigation of their antimicrobial, antioxidant, antidiabetic, and anti-inflammatory properties. The chemical compounds of S. officinalis were determined by GC-MS analysis. The antioxidant activity was assessed by DPPH, ABTS, H2O2, and FRAP assays. The in vitro antidiabetic effect was evaluated by the inhibition of α-amylase, α-glucosidase, and lipase activities, and the anti-inflammatory effect was evaluated using the 5-lipoxygenase assay. Moreover, antibacterial activity was assessed against six bacterial strains using agar well diffusion assay and microdilution method. The main compounds in essential oils of S. officinalis at three phenological stages were naphthalenone, camphor, 1.8-cineole, and α-thujone. The full flowering stage essential oil showed the best antioxidant activity with different IC50 values according to the used tests. This oil also exhibited important inhibitory effects at the full flowering stage against α-amylase (IC50 = 69.23 ± 0.1 µg/mL), α-glucosidase (IC50 = 22.24 ± 0.07 µg/mL), and lipase (IC50 = 37.3 ± 0.03 µg/mL). The 5-lipoxygenase inhibitory effect was the best at the full flowering stage (IC50 = 9.24 ± 0.03 µg/mL). The results of the antibacterial evaluation revealed that, at three seasonal periods, S. officinalis essential oil demonstrated strong antibacterial activity. Although the full flowering stage had the best antibacterial activity, there were no significant differences between the three stages. Additionally, the essential oils showed bactericidal effects on Listeria monocytogenes, Staphylococcus aureus, Bacillus subtilis, Proteus mirabilis, Escherichia coli, and Salmonella typhimurium, respectively. The findings of this work showed remarkably that S. officinalis synthesizes essential oils according to different developmental stages. Moreover, it has exhibited interesting biological and pharmacological properties justifying its medicinal effects and suggesting it as a very important source of natural drugs.

Determination of Volatile Compounds of Mentha piperita and Lavandula multifida and Investigation of Their Antibacterial, Antioxidant, and Antidiabetic Properties.

Mentha piperita and Lavandula multifida are widely used in Moroccan traditional medicine for the treatment of diabetes and infectious diseases. The aims of this work were the determination of the chemical composition of Mentha piperita (MPEO) and Lavandula multifida (LMEO) essential oils and the evaluation of their antibacterial, antioxidant, and antidiabetic activities. The chemical composition was determined by GC-MS analysis. The antibacterial effects were evaluated against several bacterial strains using disc diffusion, MIC, and MBC methods. The antioxidant activity was evaluated in vitro using DPPH, H2O2, and xanthine oxidase, and the antidiabetic activity was estimated by the inhibitory effects of α-amylase, α-glucosidase, and lipase activities. GC-MS results showed that the main compounds of MPEO were menthone (29.24%), levomenthol (38.73%), and eucalyptol (6.75%). However, eucalyptol (28.11%), 2-bornanone (11.57%), endo-borneol (7.82%), and linalyl acetate (5.22%) are the major compounds of LMEO. The results exhibited important inhibitory effects against some bacterial strains with MIC = MBC = 0.39 mg/mL for MPEO against Staphylococcus aureus ATCC. However, LMEO exhibited remarkable antioxidant and antidiabetic activities compared to MPEO. Indeed, LMEO inhibited DPPH, H2O2, and xanthine oxidase with concentrations of 15.23, 21.52, and 8.89 µg/mL, respectively. Moreover, LMEO exhibited α-amylase and α-glucosidase at IC50 = 85.34 and IC50 = 59.36 µg/mL, respectively. The findings showed that both MPEO and LMEO exhibit promising biological properties. However, the application of these species or their main bioactive compounds requires further investigation.

Polychlorinated Biphenyls and Pulmonary Hypertension.

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that were banned because of their potential carcinogenicity. Population studies have shown that PCBs are associated with lung toxicity and hypertension. The objective of this study was to evaluate whether higher exposure to PCB congeners is associated with the risk of pulmonary hypertension. Serum levels of PCBs in 284 subjects with combined risk factors for pulmonary arterial hypertension (PAH) were compared to 4210 subjects with no risk for PAH using the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. The major findings from this study include significantly higher PCB levels in PAH subjects compared to non-PAH subjects; for example, the geometric mean (GM) of PCB74 was 15.91 (ng/g) (14.45-17.53) vs. 11.48 (ng/g) (10.84-12.16), respectively. Serum levels of PCB congeners showed an increasing trend in the age group 20-59 years as PCB180 GM was 19.45 (ng/g) in PAH vs. 12.75 (ng/g) in the control. A higher body burden of PCB153 followed by PCB138, PCB180, and PCB118 was observed. Estimated age, race, BMI, and gender-adjusted ORs for PCB congener levels in subjects with the combined risk factors for PAH compared to controls was significant; for example, PCB99 (OR: 1.5 (CI: 1.49-1.50). In summary, these findings indicate that exposure, as well as body burden estimated based on lipid adjustment of PCBs, were higher in people with risk factors for PAH, and PCB congeners accumulated with age. These findings should be interpreted with caution because of the use of cross-sectional self-reported data and a small sample size of subjects with combined risk factors for pulmonary arterial hypertension. Nonetheless, our finding emphasizes a need for a comprehensive environmental molecular epidemiologic study to determine the potential role of environmental exposures to PCBs in the development of pulmonary arterial hypertension.

Regulation of Dystroglycan Gene Expression in Early Myoblast Differentiation.

Dystroglycan, a component of the dystrophin-associated glycoprotein complex, connects the extracellular matrix and cytoskeleton to maintain muscle membrane integrity. As such, abnormalities of dystroglycan are linked to different types of muscular dystrophies. In an effort to develop therapeutic approaches to re-establish signal integration for muscle repair and homeostasis, we have previously determined that a clinically approved agonist of retinoid X receptor enhances myoblast differentiation through direct regulation of gene expression of the muscle master regulator MyoD. Using comprehensive omics and molecular analyses, we found that dystroglycan gene expression is responsive to retinoid X receptor-selective signaling in early myoblast differentiation. In addition, the dystroglycan gene is a MyoD target, and residue-specific histone acetylation coincides with the occupancy of histone acetyltransferase p300 at the MyoD binding sites. Consequently, the p300 function is important for rexinoid-augmented dystroglycan gene expression. Finally, dystroglycan plays a role in myoblast differentiation. Our study sheds new light on dystroglycan regulation and function in myoblast differentiation and presents a potential avenue for re-establishing signal integration of a specific chromatin state pharmacologically to overcome muscle pathology and identify additional myogenic interactions for therapeutic applications.

Dissecting myogenin-mediated retinoid X receptor signaling in myogenic differentiation.

Deciphering the molecular mechanisms underpinning myoblast differentiation is a critical step in developing the best strategy to promote muscle regeneration in patients suffering from muscle-related diseases. We have previously established that a rexinoid x receptor (RXR)-selective agonist, bexarotene, enhances the differentiation and fusion of myoblasts through a direct regulation of MyoD expression, coupled with an augmentation of myogenin protein. Here, we found that RXR signaling associates with the distribution of myogenin at poised enhancers and a distinct E-box motif. We also found an association of myogenin with rexinoid-responsive gene expression and identified an epigenetic signature related to histone acetyltransferase p300. Moreover, RXR signaling augments residue-specific histone acetylation at enhancers co-occupied by p300 and myogenin. Thus, genomic distribution of transcriptional regulators is an important designate for identifying novel targets as well as developing therapeutics that modulate epigenetic landscape in a selective manner to promote muscle regeneration.

Loci-specific histone acetylation profiles associated with transcriptional coactivator p300 during early myoblast differentiation.

Molecular regulation of stem cell differentiation is exerted through both genetic and epigenetic determinants over distal regulatory or enhancer regions. Understanding the mechanistic action of active or poised enhancers is therefore imperative for control of stem cell differentiation. Based on the genome-wide co-occurrence of different epigenetic marks in committed proliferating myoblasts, we have previously generated a 14-state chromatin state model to profile rexinoid-responsive histone acetylation in early myoblast differentiation. Here, we delineate the functional mode of transcription regulators during early myogenic differentiation using genome-wide chromatin state association. We define a role of transcriptional coactivator p300, when recruited by muscle master regulator MyoD, in the establishment and regulation of myogenic loci at the onset of myoblast differentiation. In addition, we reveal an enrichment of loci-specific histone acetylation at p300 associated active or poised enhancers, particularly when enlisted by MyoD. We provide novel molecular insights into the regulation of myogenic enhancers by p300 in concert with MyoD. Our studies present a valuable aptitude for driving condition-specific chromatin state or enhancers pharmacologically to treat muscle-related diseases and for the identification of additional myogenic targets and molecular interactions for therapeutic development. ABBREVIATIONS: MRF: Muscle regulatory factor; HAT: Histone acetyltransferase; CBP: CREB-binding protein; ES: Embryonic stem; ATCC: American type culture collection; DM: Differentiation medium; DMEM: Dulbecco's Modified Eagle Medium; GM: Growth medium; GO: Gene ontology; GREAT: Genomic regions enrichment of annotations tool; FPKM: Fragments per kilobase of transcript per million; GEO: Gene expression omnibus; MACS: Model-based analysis for ChIP-seq.

Insights into interplay between rexinoid signaling and myogenic regulatory factor-associated chromatin state in myogenic differentiation.

While skeletal myogenesis is tightly coordinated by myogenic regulatory factors including MyoD and myogenin, chromatin modifications have emerged as vital mechanisms of myogenic regulation. We have previously established that bexarotene, a clinically approved agonist of retinoid X receptor (RXR), promotes the specification and differentiation of skeletal muscle lineage. Here, we examine the genome-wide impact of rexinoids on myogenic differentiation through integral RNA-seq and ChIP-seq analyses. We found that bexarotene promotes myoblast differentiation through the coordination of exit from the cell cycle and the activation of muscle-related genes. We uncovered a new mechanism of rexinoid action which is mediated by the nuclear receptor and largely reconciled through a direct regulation of MyoD gene expression. In addition, we determined a rexinoid-responsive residue-specific histone acetylation at a distinct chromatin state associated to MyoD and myogenin. Thus, we provide novel molecular insights into the interplay between RXR signaling and chromatin states pertinent to myogenic programs in early myoblast differentiation.

Molecular Basis for the Regulation of Transcriptional Coactivator p300 in Myogenic Differentiation.

Skeletal myogenesis is a highly ordered process which specifically depends on the function of transcriptional coactivator p300. Previous studies have established that Akt/protein kinase B (PKB), a positive regulator of p300 in proliferating cells, is also important for proper skeletal muscle development. Nevertheless, it is not clear as to how the p300 is regulated by myogenic signaling events given that both p300 and Akt are involved in many cellular processes. Our studies revealed that the levels of p300 protein are temporally maintained in ligand-enhanced skeletal myocyte development. Interestingly, this maintenance of p300 protein is observed at the stage of myoblast differentiation, which coincides with an increase in Akt phosphorylation. Moreover, regulation of p300 during myoblast differentiation appears to be mediated by Akt signaling. Blunting of p300 impairs myogenic expression and myoblast differentiation. Thus, our data suggests a particular role for Akt in myoblast differentiation through interaction with p300. Our studies also establish the potential of exploiting p300 regulation and Akt activation to decipher the complex signaling cascades involved in skeletal muscle development.

Stepwise acetyltransferase association and histone acetylation at the Myod1 locus during myogenic differentiation.

While chromatin modifications can offer a useful readout for enhancer activities, it is less clear whether these modification marks are a cause or consequence of transcription factor occupancy and enhancer activation. We have examined in details the temporal events of acetyltransferase associations and histone acetylations at different regulatory regions of the Myod1 locus. Our studies demonstrate that the histone acetyltransferase (HAT) p300 is stepwise enriched at distinct Myod1 regulatory regions during myogenic differentiation. This enrichment of p300 is associated with increased histone acetylation in a discrete pattern. Inhibition of p300 HAT activity impedes myogenic differentiation, which is coupled with decreased histone acetylation at specific Myod1 regulatory regions. We show for the first time that p300 is directly involved in the early regulation of Myod1 enhancer, and provide molecular insights into how p300 HAT activity and histone acetylation are related to enhancer activation and, consequently, gene transcription.