Apabetalone (RVX-208): A Potential Epigenetic Therapy for the Treatment of Cardiovascular, Renal, Neurological, Viral, and Cancer Disorders.

Bromodomain and extra-terminal domain proteins (BET proteins) are epigenetic reader proteins that have been implicated in regulating gene expression through binding to chromatin and interaction with transcription factors. These proteins are located in the nucleus and are responsible for recognizing acetylated lysine residues on histones, reading epigenetic messages, recruiting key transcription factors, and thereby regulating gene expression. BET proteins control the transcription of genes responsible for maladaptive effects in inflammation, cancer, and renal and cardiovascular diseases. Given the multifaceted role of BET proteins in the pathogenesis of various diseases, several small molecule inhibitors of BET proteins have been developed as potential therapeutic targets for treating different diseases in recent years. However, while many nonselective BET inhibitors are indicated for the treatment of cancer, a selective BET inhibitor, apabetalone, is the only oral BET inhibitor in phase III clinical trials for the treatment of cardiovascular diseases and others. Thus, this review aims to present and discuss the preclinical and clinical evidence for the beneficial effects and mechanism of action of apabetalone for treating various diseases.

Unlocking the secrets: exploring the influence of the aryl hydrocarbon receptor and microbiome on cancer development.

Gut microbiota regulates various aspects of human physiology by producing metabolites, metabolizing enzymes, and toxins. Many studies have linked microbiota with human health and altered microbiome configurations with the occurrence of several diseases, including cancer. Accumulating evidence suggests that the microbiome can influence the initiation and progression of several cancers. Moreover, some microbiotas of the gut and oral cavity have been reported to infect tumors, initiate metastasis, and promote the spread of cancer to distant organs, thereby influencing the clinical outcome of cancer patients. The gut microbiome has recently been reported to interact with environmental factors such as diet and exposure to environmental toxicants. Exposure to environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) induces a shift in the gut microbiome metabolic pathways, favoring a proinflammatory microenvironment. In addition, other studies have also correlated cancer incidence with exposure to PAHs. PAHs are known to induce organ carcinogenesis through activating a ligand-activated transcriptional factor termed the aryl hydrocarbon receptor (AhR), which metabolizes PAHs to highly reactive carcinogenic intermediates. However, the crosstalk between AhR and the microbiome in mediating carcinogenesis is poorly reviewed. This review aims to discuss the role of exposure to environmental pollutants and activation of AhR on microbiome-associated cancer progression and explore the underlying molecular mechanisms involved in cancer development.

Proteomic insight towards key modulating proteins regulated by the aryl hydrocarbon receptor involved in ovarian carcinogenesis and chemoresistance.

Gynecological malignancies pose a severe threat to female lives. Ovarian cancer (OC), the most lethal gynecological malignancy, is clinically presented with chemoresistance and a higher relapse rate. Several studies have highly correlated the incidence of OC to exposure to environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a process mainly mediated through activating the aryl hydrocarbon receptor (AhR). We have previously reported that exposure of OC cells to TCDD, an AhR activator, significantly modulated the expression of several genes that play roles in stemness and chemoresistance. However, the effect of AhR activation on the whole OC cell proteome aiming at identifying novel druggable targets for both prevention and treatment intervention purposes remains unrevealed. For this purpose, we conducted a comparative proteomic analysis of OC cells A2780 untreated/treated with TCDD for 24 h using a mass spectrometry-based label-free shotgun proteomics approach. The most significantly dysregulated proteins were validated by Western blot analysis. Our results showed that upon AhR activation by TCDD, out of 2598 proteins identified, 795 proteins were upregulated, and 611 were downregulated. STRING interaction analysis and KEGG-Reactome pathway analysis approaches identified several significantly dysregulated proteins that were categorized to be involved in chemoresistance, cancer progression, invasion and metastasis, apoptosis, survival, and prognosis in OC. Importantly, selected dysregulated genes identified by the proteomic study were validated at the protein expression levels by Western blot analysis. In conclusion, this study provides a better understanding of the the cross-talk between AhR and several other molecular signaling pathways and the role and involvement of AhR in ovarian carcinogenesis and chemoresistance. Moreover, the study suggests that AhR is a potential therapeutic target for OC prevention and maintenance. SIGNIFICANCE: To our knowledge, this is the first study that investigates the role and involvement of AhR and its regulated genes in OC by performing a comparative proteomic analysis to identify the critical proteins with a modulated expression upon AhR activation. We found AhR activation to play a tumor-promoting and chemoresistance-inducing role in the pathogenesis of OC. The results of our study help to devise novel therapeutics for better management and prevention and open the doors to finding novel biomarkers for the early detection and prognosis of OC.

Experimental and theoretical investigations of the effect of bis-phenylurea-based aliphatic amine derivative as an efficient green corrosion inhibitor for carbon steel in HCl solution.

A novel bis-phenylurea-based aliphatic amine (BPUA) was prepared via a facile synthetic route, and evaluated as a potential green organic corrosion inhibitor for carbon steel in 1.0 M HCl solutions. NMR spectroscopy experiments confirmed the preparation of the targeted structure. The corrosion inhibitory behavior of the prospective green compound was explored experimentally by electrochemical methods and theoretically by DFT-based quantum chemical calculations. Obtained results revealed an outstanding performance of BPUA, with efficiency of 95.1% at the inhibitor concentration of 50 mg L-1 at 25 °C. The novel compound has improved the steel resistivity and noticeably reduced the corrosion rate from 33 to 1.7 mils per year. Furthermore, the adsorption study elucidates that the mechanism of the corrosion inhibition activity obeys Langmuir isotherm with mixed physisorption/chemisorption modes for BPUA derivatives on the steel surface. Calculated Gibb's free energy of the adsorption process ranges from -35 to -37 kJ mol-1. The SEM morphology analysis validates the electrochemical measurements and substantiates the corrosion-inhibiting properties of BPUA. Additionally, the eco-toxicity assessment on human epithelial MCF-10A cells proved the environmental friendliness of the BPUA derivatives. Density functional theory (DFT) calculations correlated the inhibitor's chemical structure with the corresponding inhibitory behavior. Quantum descriptors disclosed the potentiality of BPUA adsorption onto the surface through the heteroatom-based functional groups and aromatic rings.

Shrinking the battlefield in cancer therapy: Nanotechnology against cancer stem cells.

Cancer remains one of the leading causes of mortality worldwide, presenting a significant healthcare challenge owing to the limited efficacy of current treatments. The application of nanotechnology in cancer treatment leverages the unique optical, magnetic, and electrical attributes of nanomaterials to engineer innovative, targeted therapies. Specifically, manipulating nanomaterials allows for enhanced drug loading efficiency, improved bioavailability, and targeted delivery systems, reducing the non-specific cytotoxic effects characteristic of conventional chemotherapies. Furthermore, recent advances in nanotechnology have demonstrated encouraging results in specifically targeting CSCs, a key development considering the role of these cells in disease recurrence and resistance to treatment. Despite these breakthroughs, the clinical approval rates of nano-drugs have not kept pace with research advances, pointing to existing obstacles that must be addressed. In conclusion, nanotechnology presents a novel, powerful tool in the fight against cancer, particularly in targeting the elusive and treatment-resistant CSCs. This comprehensive review delves into the intricacies of nanotherapy, explicitly targeting cancer stem cells, their markers, and associated signaling pathways.

The Role of p90 Ribosomal S6 Kinase (RSK) in Tyrosine Kinase Inhibitor (TKI)-Induced Cardiotoxicity.

Targeted therapy, such as tyrosine kinase inhibitors (TKIs), has been approved to manage various cancer types. However, TKI-induced cardiotoxicity is a limiting factor for their use. This issue has raised the need for investigating potential cardioprotective techniques to be combined with TKIs. Ribosomal S6-kinases (RSKs) are a downstream effector of the mitogen-activated-protein-kinase (MAPK) pathway; specific RSK isoforms, such as RSK1 and RSK2, have been expressed in cancer cells, in which they increase tumour proliferation. Selective targeting of those isoforms would result in tumour suppression. Moreover, activation of RSKs expressed in the heart has resulted in cardiac hypertrophy and arrhythmia; thus, inhibiting RSKs would result in cardio-protection. This review article presents an overview of the usefulness of RSK inhibitors that can be novel agents to be assessed in future research for their effect in reducing cancer proliferation, as well as protecting the heart from cardiotoxicity induced by TKIs.

Cathine and cathinone disposition kinetics and neurotransmitter profile in several organs of rats exposed to a single dose of Catha edulis (Vahl) Forssk. ex Endl. extract.

OBJECTIVES: Catha edulis (Vahl) Forssk. ex Endl. (Khat) is a stimulant plant that contains cathine and cathinone, which its abuses induce euphoria, alertness, and motor activity. Since the toxicokinetics of these substances remain unclear, this study was carried out to investigate the disposition kinetics of cathine and cathinone, the neurotransmitter profile, following a single dose of C. edulis extract in rats. METHODS: Twenty-four adult male Wistar albino rats (250-300 g) were randomly selected and divided into six groups of four rats each. All groups received a single oral dose of 2,000 mg/kg body weight, and blood and tissue samples from the brain, lung, heart, liver, and kidney were obtained at intervals of 0.5, 1, 2.5, 5, 12, and 24 h. The cathine and cathinone concentrations were identified and quantified using ion trap ultra-high performance liquid chromatography (HPLC-IT/MS). The neurotransmitter profile was detected using the quadrupole time of flight UPLC-QTOF/MS method. RESULTS: The lung, liver, and heart tissues attained the highest levels of cathine, while the highest level of cathinone was determined in the heart. Cathine and cathinone concentrations in the blood and heart peaked at 0.5 h. The concentrations peaked in the brain 2.5 h later, indicating that the heart had an immediate effect, whereas the brain had a longer-lasting one. They have longer half-lives (2.68 and 5.07 h, respectively) and may remain in the brain for longer durations (3.31 and 2.31 h, respectively). The neurotransmitters epinephrine, dopamine, norepinephrine, and serotonin were detected in a delayed, prolonged and organ-specific manner. CONCLUSIONS: Cathine and cathinone were deposited in considerable concentrations in all tissues analyzed, with the highest Cmax in the lung and Tmax in the heart tissues but not in the brain. In addition, neurotransmitters such as adrenaline, dopamine, norepinephrine, and serotonin were differentially detected in all tested samples in a organ-specific fashion. More study is needed to identify cathine and cathinone's effects on neurotransmitter profiles. Nevertheless, these findings provided a further basis for experimental, clinical, and forensic investigations.

6-Formylindolo(3,2-b)carbazole Dampens Inflammation and Reduces Endotoxin-Induced Kidney Injury via Nrf2 Activation.

Patients with sepsis are at a high risk of morbidity and mortality due to multiple organ injuries caused by pathological inflammation. Although sepsis is accompanied by multiple organ injuries, acute renal injury is a significant contributor to sepsis morbidity and mortality. Thus, dampening inflammation-induced renal injury may limit severe consequences of sepsis. As several studies have suggested that 6-formylindolo(3,2-b)carbazole (FICZ) is beneficial for treating various inflammatory diseases, we aimed to examine the potential protective effect of FICZ on the acute endotoxin-induced sepsis model of kidney injury. To test this, male C57Bl/6N mice were injected with FICZ (0.2 mg/kg) or vehicle 1 h prior to an injection of either lipopolysaccharides (LPS) (10 mg/kg), to induce sepsis, or phosphate-buffered saline for 24 h. Thereafter, gene expression of kidney injury and pro-inflammatory markers, circulating cytokines and chemokines, and kidney morphology were assessed. Our results show that FICZ reduced LPS-induced acute injury in kidneys from LPS-injected mice. Furthermore, we found that FICZ dampens both renal and systemic inflammation in our sepsis model. Mechanistically, our data indicated that FICZ significantly upregulates NAD(P)H quinone oxidoreductase 1 and heme oxygenase 1 via aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) in the kidneys to lessen inflammation and improve septic acute kidney injury. Overall, the data of our study show that FICZ possesses a beneficial reno-protective effect against sepsis-induced renal injury via dual activation of AhR/Nrf2.

Crosstalk between aryl hydrocarbon receptor (AhR) and BCL-2 pathways suggests the use of AhR antagonist to maintain normal differentiation state of mammary epithelial cells during BCL-2 inhibition therapy.

INTRODUCTION: Activating the aryl hydrocarbon receptor upon exposure to environmental pollutants promotes development of breast cancer stem cell (CSCs). BCL-2 family proteins protect cancer cells from the apoptotic effects of chemotherapeutic drugs. However, the crosstalk between AhR and the BCL-2 family in CSC development remains uninvestigated. OBJECTIVES: This study explored the interaction mechanisms between AhR and BCL-2 in CSC development and chemoresistance. METHODS: A quantitative proteomic analysis study was performed as a tool for comparative expression analysis of breast cancer cells treated by AhR agonist. The basal and inducible levels of BCL-2, AhR, and CYP1A1 in vitro breast cancer and epithelial cell lines and in vivo mice animal models were determined by RT-PCR, Western blot analysis, immunofluorescence, flow cytometry, silencing of the target, and immunohistochemistry. In addition, an in silico toxicity study was conducted using DEREK software. RESULTS: Activation of the AhR/CYP1A1 pathway in mice increased EpCAMHigh/CD49fLow CD61+ luminal progenitor-like cells in early tumor formation but not in advanced tumors. In parallel, a chemoproteomic study on breast cancer MCF-7 cells revealed that the BCL-2 protein expression was the most upregulated upon AhR activation. The crosstalk between the AhR and BCL-2 pathways in vitro and in vivo modulated the CSCs features and chemoresistance. Interestingly, inhibition of BCL-2 in mice by venetoclax (VCX) increased EpCAMHigh/CD49fLow CD61+ luminal progenitor-like cells, causing inhibition of epithelial lineage markers, disruption of mammary gland branching and induced the epithelial-mesenchymal transition in mammary epithelial cells (MECs). The combined treatment of VCX and AhR antagonists in mice corrected the abnormal differentiation in MECs and protected mammary gland branching and cell identity. CONCLUSIONS: This is the first study to report crosstalk between AhR and BCL-2 in breast CSCs and provides the rationale for using a combined treatment of BCL-2 inhibitor and AhR antagonist for more effective cancer prevention and treatment.

Role of RAS signaling in ovarian cancer.

The RAS family of proteins is among the most frequently mutated genes in human malignancies. In ovarian cancer (OC), the most lethal gynecological malignancy, RAS, especially KRAS mutational status at codons 12, 13, and 61, ranges from 6-65% spanning different histo-types. Normally RAS regulates several signaling pathways involved in a myriad of cellular signaling cascades mediating numerous cellular processes like cell proliferation, differentiation, invasion, and death. Aberrant activation of RAS leads to uncontrolled induction of several downstream signaling pathways such as RAF-1/MAPK (mitogen-activated protein kinase), PI3K phosphoinositide-3 kinase (PI3K)/AKT, RalGEFs, Rac/Rho, BRAF (v-Raf murine sarcoma viral oncogene homolog B), MEK1 (mitogen-activated protein kinase kinase 1), ERK (extracellular signal-regulated kinase), PKB (protein kinase B) and PKC (protein kinase C) involved in cell proliferation as well as maintenance pathways thereby driving tumorigenesis and cancer cell propagation. KRAS mutation is also known to be a biomarker for poor outcome and chemoresistance in OC. As a malignancy with several histotypes showing varying histopathological characteristics, we focus on reviewing recent literature showcasing the involvement of oncogenic RAS in mediating carcinogenesis and chemoresistance in OC and its subtypes.

Insight into the physiological and pathological roles of the aryl hydrocarbon receptor pathway in glucose homeostasis, insulin resistance, and diabetes development.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor that mediates the toxicities of several environmental pollutants. Decades of research have been carried out to understand the role of AhR as a novel mechanism for disease development. Its involvement in the pathogenesis of cancer, cardiovascular diseases, rheumatoid arthritis, and systemic lupus erythematosus have long been known. One of the current hot research topics is investigating the role of AhR activation by environmental pollutants on glucose homeostasis and insulin secretion, and hence the pathogenesis of diabetes mellitus. To date, epidemiological studies have suggested that persistent exposure to environmental contaminants such as dioxins, with subsequent AhR activation increases the risk of specific comorbidities such as obesity and diabetes. The importance of AhR signaling in various molecular pathways highlights that the role of this receptor is far beyond just xenobiotic metabolism. The present review aims at providing significant insight into the physiological and pathological role of AhR and its regulated enzymes, such as cytochrome P450 1A1 (CYP1A1) and CYP1B1 in both types of diabetes. It also provides a comprehensive summary of the current findings of recent research studies investigating the role of the AhR/CYP1A1 pathway in insulin secretion and glucose hemostasis in the pancreas, liver, and adipose tissues. This review further highlights the molecular mechanisms involved, such as gluconeogenesis, hypoxia-inducible factor (HIF), oxidative stress, and inflammation.

Regulation of the aryl hydrocarbon receptor in cancer and cancer stem cells of gynecological malignancies: An update on signaling pathways.

Gynecological malignancies are a female type of cancers that affects the reproductive system. Cancer metastasis or recurrence mediated by cellular invasiveness occurs at advanced stages of cancer progression. Cancer Stem Cells (CSCs) enrichment in tumors leads to chemoresistance, which results in cancer mortality. Exposure to environmental pollutants such as polycyclic aromatic hydrocarbons is associated with an increased the risk of CSC enrichment in gynecological cancers. One of the important pathways that mediates the metabolism and bioactivation of these environmental chemicals is the transcription factor, aryl hydrocarbon receptor (AhR). The present review explores the molecular mechanisms regulating the crosstalk and interaction of the AhR with cancer-related signaling pathways, such as apoptosis, epithelial-mesenchymal transition, immune checkpoints, and G-protein-coupled receptors in several gynecological malignancies such as ovarian, uterine, endometrial, and cervical cancers. The review also discusses the potential of targeting the AhR pathway as a novel chemotherapy for gynecological cancers.

A novel approach of encapsulating curcumin and succinylated derivative in mannosylated-chitosan nanoparticles.

Curcumin (CUR) manifests anti-colon cancer activity but suffers from low solubility, bioavailability, and instability, rendering it not as effective as its chemotherapeutic cousins. Here, we conjugate CUR to succinic anhydride (SA), (CUR.SA conjugate), subsequently formulated in mannose-conjugated chitosan nanoparticles (CUR-NPs and CUR.SA-NPs). Instrumental analyses confirmed formation of CUR.SA and mannosylated chitosan (CM) conjugates, with CUR.SA being less crystalline thus, more soluble. Average particle size of CUR-NPs and CUR.SA-NPs were 268 ± 6 nm and 342 ± 4.6 nm, with drug entrapment of 93.34 ± 0.40 % and 98.46 ± 0.06 % respectively. In vitro releases of CUR and CUR.SA from nanoparticles in pH 1.2 and 6.8 media were slow and sustained over 2 h and 72 h, respectively. The physical characteristics of the nanoparticles were unchanged over 3 weeks of storage. Thus, a successful CUR.SA conjugate has been developed, couriered in CM nanoparticles, with favorable attributes that warrant further anti-colon cancer studies, which is ongoing.

Aryl Hydrocarbon Receptor Promotes Cell Growth, Stemness Like Characteristics, and Metastasis in Human Ovarian Cancer via Activation of PI3K/Akt, ß-Catenin, and Epithelial to Mesenchymal Transition Pathways.

Ovarian cancer (OC) ranks first in cancer-related deaths out of all female reproductive malignancies with high-pitched tumor relapse and chemoresistance. Several reports correlate cancer occurrences with exposure to xenobiotics via induction of a protein receptor named aryl hydrocarbon receptor (AhR). However, the effect of AhR on OC proliferation, expansion, and chemoresistance remains unrevealed. For this purpose, OC cells A2780 and A2780cis cells were treated with AhR activator, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the effects were determined by Real-Time Cell Analyzer, clonogenic assay, flow cytometry, immunoblotting and wound healing assay. Our results showed that activation of AhR by TCDD in A2780 cells induced the PI3K/AKT pathway followed by induction of anti-apoptotic proteins BCL-2, BCL-xl, and MCL-1. In addition, a significant increase in stemness marker aldehyde dehydrogenase (ALDH1) was observed. This effect was also associated with an accumulation of ß-catenin, a Wnt transcription factor. Moreover, we observed induction of epithelial to mesenchymal transition (EMT) upon AhR activation. In conclusion, the results from the current study confirm that AhR mediates OC progression, stemness characteristics, and metastatic potential via activation of PI3K/Akt, Wnt/ß-catenin, and EMT. This study provides a better insight into the modulatory role of AhR that might help in developing novel therapeutic strategies for OC treatment.

Reduced Cardiotoxicity of Ponatinib-Loaded PLGA-PEG-PLGA Nanoparticles in Zebrafish Xenograft Model.

Tyrosine kinase inhibitors (TKIs) are the new generation of anti-cancer drugs with high potential against cancer cells' proliferation and growth. However, TKIs are associated with severe cardiotoxicity, limiting their clinical value. One TKI that has been developed recently but not explored much is Ponatinib. The use of nanoparticles (NPs) as a better therapeutic agent to deliver anti-cancer drugs and reduce their cardiotoxicity has been recently considered. In this study, with the aim to reduce Ponatinib cardiotoxicity, Poly(D,L-lactide-co-glycolide)-b-poly(ethyleneoxide)-b-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymer was used to synthesize Ponatinib in loaded PLGA-PEG-PLGA NPs for chronic myeloid leukemia (CML) treatment. In addition to physicochemical NPs characterization (NPs shape, size, size distribution, surface charge, dissolution rate, drug content, and efficacy of encapsulation) the efficacy and safety of these drug-delivery systems were assessed in vivo using zebrafish. Zebrafish are a powerful animal model for investigating the cardiotoxicity associated with anti-cancer drugs such as TKIs, to determine the optimum concentration of smart NPs with the least side effects, and to generate a xenograft model of several cancer types. Therefore, the cardiotoxicity of unloaded and drug-loaded PLGA-PEG-PLGA NPs was studied using the zebrafish model by measuring the survival rate and cardiac function parameters, and therapeutic concentration for in vivo efficacy studies was optimized in an in vivo setting. Further, the efficacy of drug-loaded PLGA-PEG-PLGA NPs was tested on the zebrafish cancer xenograft model, in which human myelogenous leukemia cell line K562 was transplanted into zebrafish embryos. Our results demonstrated that the Ponatinib-loaded PLGA-PEG-PLGA NPs at a concentration of 0.001 mg/mL are non-toxic/non-cardio-toxic in the studied zebrafish xenograft model.

Metformin attenuates V-domain Ig suppressor of T-cell activation through the aryl hydrocarbon receptor pathway in Melanoma: In Vivo and In Vitro Studies.

Melanoma is an aggressive skin cancer with a high rate of metastasis to other organs. Recent studies specified the overexpression of V-domain Ig suppressor of T-cell activation (VISTA) and Aryl Hydrocarbon Receptor (AHR) in melanoma. Metformin shows anti-tumor activities in several cancer types. However, the mechanism is unclear. This study aims to investigate the inhibitory effect of metformin on VISTA via AHR in melanoma cells (CHL-1, B16) and animal models. VISTA and AHR levels were assessed by qPCR, Western blot, immunofluorescence microscope, flow cytometry, and immunohistochemistry. Here, metformin significantly decreased VISTA and AHR levels in vitro and in vivo. Furthermore, metformin inhibited all AHR-regulated genes. VISTA levels were dramatically inhibited by AHR modulations using shRNA and αNF, confirming the central role of AHR in VISTA. Finally, melanoma cells were xenografted in C57BL/6 and nude mice. Metformin significantly reduced the tumor volume and growth rate. Likewise, VISTA and AHR-regulated protein levels were suppressed in both models. These findings demonstrate for the first time that VISTA is suppressed by metformin and identified a new regulatory mechanism through AHR. The data suggest that metformin could be a new potential therapeutic strategy to treat melanoma patients combined with targeted immune checkpoint inhibitors.

Lead Nitrate Induces Inflammation and Apoptosis in Rat Lungs Through the Activation of NF-κB and AhR Signaling Pathways.

Lead (Pb) is one of the most frequent hazardous air contaminants, where the lungs are particularly vulnerable to its toxicity. However, the Pb distribution and its impact on lung inflammation/apoptosis and particularly the involvement of nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways in Pb-induced lung toxicity have not yet been fully investigated. Adult male Wistar albino rats were exposed to Pb nitrate 25, 50, and 100 mg/kg b.w. orally for 3 days. The histopathological changes of several rat organs were analyzed using hematoxylin and eosin staining. The concentrations of Pb ion in different organ tissues were quantified using inductive coupled plasma mass spectrometry, while gas chromatography-mass spectrometry was used to identify organic compounds. The changes in the mRNA and protein expression levels of inflammatory and apoptotic genes in response to Pb exposure were quantified by using RT-PCR and Western blot analyses, respectively. Treatment of rats with Pb for three consecutive days significantly increased the accumulation of Pb in lung tissues causing severe interstitial inflammation. Pb treatment also increased the percentage of lung apoptotic cells and modulated apoptotic genes (Bc2, p53, and TGF-α), inflammatory markers (IL-4, IL-10, TNF-α), and oxidative stress biomarkers (iNOS, CYP1A1, EphX) in rat lung tissues. These effects were associated with a significant increase in organic compounds, such as 3-nitrotyrosine and myeloperoxidase, and some inorganic elements, such as selenium. Importantly, the Pb-induced lung inflammation and apoptosis were associated with a proportional increase in the expression of NF-κB and AhR mRNAs and proteins. These findings clearly show that Pb induces severe inflammation and apoptosis in rat lungs and suggest that NF-κB and AhR may play a role in Pb-induced lung toxicity.

Involvement of caveolae in hyperglycemia-induced changes in adiponectin and leptin expressions in vascular smooth muscle cells.

Hyperglycemia exerts various harmful effects on the vasculature. Studies have shown an association between the levels of the adipokines leptin and adiponectin (APN) and vascular complications in diabetes mellitus. The aim of our study was to investigate the molecular mechanisms mediated by APN and leptin that are involved in hyperglycemia-induced vascular remodeling, especially at the level of oxidative stress and actin cytoskeleton dynamics. Rat aorta organ culture was used to investigate the effect of hyperglycemia on APN and leptin protein expression in vascular smooth muscle cells (VSMCs) using Western blot analysis and immunohistochemistry. Hyperglycemia lead to a significant increase in APN synthesis in VSMCs, mainly through caveolae, but this increase failed to provide vascular protection because of the decreased expression of APN receptors, especially AdipoR2, which was assessed by qPCR. In addition, hyperglycemia significantly upregulated leptin expression in VSMCs through caveolae and the RhoA/ROCK pathway. These variations lead to a marked increase in reactive oxygen species (ROS) production, detected by dihydroethidium (DHE) staining, and in NADPH oxidase type 4 (Nox4) expression. Moreover, Nox4 mediated the synthesis of APN in hyperglycemia in VSMCs. Finally, hyperglycemia activated the RhoA/ROCK pathway and subsequently induced the polymerization of globular actin (G-actin) into filamentous actin (F-actin), decreasing the G/F-actin ratio. Taken together, these data show that hyperglycemia increases oxidative stress and changes actin cytoskeleton dynamics in the aorta via caveolae, favoring vascular remodeling.

Epigenetic Regulation of Cancer Stem Cells by the Aryl Hydrocarbon Receptor Pathway.

Compelling evidence has demonstrated that tumor bulk comprises distinctive subset of cells generally referred as cancer stem cells (CSCs) that have been proposed as a strong sustainer and promoter of tumorigenesis and therapeutic resistance. These distinguished properties of CSCs have raised interest in understanding the molecular mechanisms that govern the maintenance of these cells. Numerous experimental and epidemiological studies have demonstrated that exposure to environmental toxins such as the polycyclic aromatic hydrocarbons (PAHs) is strongly involved in cancer initiation and progression. The PAH-induced carcinogenesis is shown to be mediated through the activation of a cytosolic receptor, aryl hydrocarbon receptor (AhR)/Cytochrome P4501A pathway, suggesting a possible direct link between AhR and CSCs. Several recent studies have investigated the role of AhR in CSCs self-renewal and maintenance, however the molecular mechanisms and particularly the epigenetic regulations of CSCs by the AhR/CYP1A pathway have not been reviewed before. In this review, we first summarize the crosstalk between AhR and cancer genetics, with a particular emphasis on the mechanisms relevant to CSCs such as Wnt/ß-catenin, Notch, NF-κB, and PTEN-PI3K/Akt signaling pathways. The second part of this review discusses the recent advances and studies highlighting the epigenetic mechanisms mediated by the AhR/CYP1A pathway that control CSC gene expression, self-renewal, and chemoresistance in various human cancers. Furthermore, the review also sheds light on the importance of targeting the epigenetic pathways as a novel therapeutic approach against CSCs.