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Despite advances in the treatment of atherosclerotic cardiovascular disease, it remains the leading cause of death in patients with diabetes. Even when risk factors are mitigated, the disease progresses, and thus newer targets need to be identified that directly inhibit the underlying pathobiology of atherosclerosis in diabetes. A single cell sequencing approach was utilised to distinguish the proatherogenic transcriptional profile in aortic cells in diabetes using a streptozotocin induced-diabetic Apoe-/- mouse model. Human carotid endarterectomy specimens from individuals with and without diabetes were also evaluated via immunohistochemical analysis. Further mechanistic studies were performed in human aortic endothelial cells and human THP-1 derived macrophages. We then performed a preclinical study using an AP-1 inhibitor in a diabetic Apoe-/- mouse model. Single cell RNA sequencing analysis identified the AP-1 complex as a novel target in diabetes-associated atherosclerosis. AP-1 levels were elevated in carotid endarterectomy specimens from diabetic when compared to non-diabetic individuals. AP-1 was validated as a mechanosensitive transcription factor via immunofluorescence staining for regional heterogeneity of endothelial cells of the aortic region exposed to turbulent blood flow and by performing microfluidics experiments in HAECs. AP-1 inhibition with T-5224 blunted endothelial cell activation as assessed by a monocyte adhesion assay and expression of genes relevant to endothelial function. Furthermore, AP-1 inhibition attenuated foam cell formation. Critically, treatment with T-5224 attenuated atherosclerosis development in diabetic Apoe-/- mice. This study has identified the AP-1 complex as a novel target, inhibition of which treats the underlying pathobiology of atherosclerosis in diabetes.
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Cardiovascular diseases (CVD), including coronary heart disease and stroke, comprise the number one cause of mortality worldwide. A major contributor to CVD is atherosclerosis, which is a low-grade inflammatory disease of vasculature that involves a pathological build-up of plaque within the arterial walls. Studies have shown that regulation of gene expression via transcription factors and epigenetic mechanisms play a fundamental role in transcriptomic changes linked to the development of atherosclerosis. Chromatin remodeling is a reversible phenomenon and studies have supported the clinical application of chromatin-modifying agents for the prevention and treatment of CVD. In addition, pre-clinical studies have identified multiple transcription factors as potential therapeutic targets in combating atherosclerotic CVD. Although interaction between transcription factors and epigenetic mechanisms facilitate gene regulation, a limited number of studies appreciate this crosstalk in the context of CVD. Here, we reviewed this gene regulatory mechanism underappreciated in atherosclerosis, which will highlight the mechanisms underlying novel therapeutics targeting epigenetic modifiers and transcription factors in atherosclerosis.
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Aterosclerosis , Epigénesis Genética , Factores de Transcripción , Humanos , Aterosclerosis/genética , Aterosclerosis/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Animales , Ensamble y Desensamble de Cromatina , Regulación de la Expresión Génica , Metilación de ADN , Predisposición Genética a la Enfermedad , Placa AteroscleróticaRESUMEN
BACKGROUND: Histone modifications play a critical role in chromatin remodelling and regulate gene expression in health and disease. Histone methyltransferases EZH1, EZH2, and demethylases UTX, JMJD3, and UTY catalyse trimethylation of lysine 27 on histone H3 (H3K27me3). This study was designed to investigate whether H3K27me3 triggers hyperglycemia-induced oxidative and inflammatory transcriptional programs in the endothelium. METHODS: We studied human aortic endothelial cells exposed to high glucose (HAEC) or isolated from individuals with diabetes (D-HAEC). RT-qPCR, immunoblotting, chromatin immunoprecipitation (ChIP-qPCR), and confocal microscopy were performed to investigate the role of H3K27me3. We determined superoxide anion (O2-) production by ESR spectroscopy, NF-κB binding activity, and monocyte adhesion. Silencing/overexpression and pharmacological inhibition of chromatin modifying enzymes were used to modulate H3K27me3 levels. Furthermore, isometric tension studies and immunohistochemistry were performed in aorta from wild-type and db/db mice. RESULTS: Incubation of HAEC to high glucose showed that upregulation of EZH2 coupled to reduced demethylase UTX and JMJD3 was responsible for the increased H3K27me3. ChIP-qPCR revealed that repressive H3K27me3 binding to superoxide dismutase and transcription factor JunD promoters is involved in glucose-induced O2- generation. Indeed, loss of JunD transcriptional inhibition favours NOX4 expression. Furthermore, H3K27me3-driven oxidative stress increased NF-κB p65 activity and downstream inflammatory genes. Interestingly, EZH2 inhibitor GSK126 rescued these endothelial derangements by reducing H3K27me3. We also found that H3K27me3 epigenetic signature alters transcriptional programs in D-HAEC and aortas from db/db mice. CONCLUSIONS: EZH2-mediated H3K27me3 represents a key epigenetic driver of hyperglycemia-induced endothelial dysfunction. Targeting EZH2 may attenuate oxidative stress and inflammation and, hence, prevent vascular disease in diabetes.
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Diabetes Mellitus , Hiperglucemia , Ratones , Animales , Humanos , Histonas , FN-kappa B/metabolismo , Células Endoteliales/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Metilación , Diabetes Mellitus/metabolismo , Hiperglucemia/genética , Hiperglucemia/metabolismo , Endotelio , Glucosa/toxicidad , Glucosa/metabolismoRESUMEN
This letter aims to explore the potential impact of the Turkey-Syria earthquake on the psychological well-being of the affected children and adolescents. It emphasises the crucial importance of prompt identification and management of emerging mental health disorders in this vulnerable population. The letter draws on existing research evidence to highlight the need for suitable mental health interventions to mitigate the anticipated suffering of many children and adolescents affected by the earthquake. A comprehensive overview of the mediating factors which may play a role in the extent of the impact of an earthquake on the mental health of children is discussed. A range of appropriate strategies and interventions are recommended and the call for continued global support is renewed. We have concluded that major earthquakes can potentially contribute to the development of mental health disorders among children and adolescents. However, by providing timely and effective support, it is possible to prevent long-term psychological consequences and facilitate early recovery. We propose the urgent implementation of effective mental health interventions in the aftermath of the Turkey-Syria earthquake to foster the recovery and resilience of the affected young population.
Mental health disorders are more prevalent in children affected by earthquakes.Prompt identification of emerging mental health disorders among this population is crucial.Management of the psychological impact in this context must be practical and needs-based.A focused and continued global support response is needed to manage the long-term challenges.
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Terremotos , Trastornos Mentales , Adolescente , Niño , Humanos , Trastornos Mentales/epidemiología , Trastornos Mentales/terapia , Salud Mental , Siria , Turquía , Desastres NaturalesAsunto(s)
Hospitales Generales , Servicios de Salud Mental , Humanos , Adulto , Qatar , Pacientes InternosRESUMEN
Autoimmune neuroinflammatory diseases are a group of disorders resulting from abnormal immune responses in the nervous system, causing inflammation and tissue damage. The interleukin (IL) family of cytokines, especially IL-1, IL-6, and IL-17, plays a critical role in the pathogenesis of these diseases. IL-1 is involved in the activation of immune cells, production of pro-inflammatory cytokines, and promotion of blood-brain barrier breakdown. IL-6 is essential for the differentiation of T cells into Th17 cells and has been implicated in the initiation and progression of neuroinflammation. IL-17 is a potent pro-inflammatory cytokine produced by Th17 cells that plays a crucial role in recruiting immune cells to sites of inflammation. This review summarizes the current understanding of the roles of different interleukins in autoimmune neuroinflammatory diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, neuromyelitis optica, and autoimmune encephalitis, and discusses the potential of targeting ILs as a therapeutic strategy against these diseases. We also highlight the need for further research to better understand the roles of ILs in autoimmune neuroinflammatory diseases and to identify new targets for treating these debilitating diseases.
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Enfermedades Autoinmunes , Enfermedades Neuroinflamatorias , Humanos , Interleucina-17 , Interleucina-6 , Interleucinas , Inflamación/tratamiento farmacológico , Citocinas , Células Th17 , Interleucina-1/uso terapéuticoRESUMEN
This study aimed to investigate the effect of the sympatholytic drug moxonidine on atherosclerosis. The effects of moxonidine on oxidised low-density lipoprotein (LDL) uptake, inflammatory gene expression and cellular migration were investigated in vitro in cultured vascular smooth muscle cells (VSMCs). The effect of moxonidine on atherosclerosis was measured by examining aortic arch Sudan IV staining and quantifying the intima-to-media ratio of the left common carotid artery in apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II. The levels of circulating lipid hydroperoxides in mouse plasma were measured by ferrous oxidation-xylenol orange assay. Moxonidine administration increased oxidised LDL uptake by VSMCs via activation of α2 adrenoceptors. Moxonidine increased the expression of LDL receptors and the lipid efflux transporter ABCG1. Moxonidine inhibited mRNA expression of inflammatory genes and increased VSMC migration. Moxonidine administration to ApoE-/- mice (18 mg/kg/day) decreased atherosclerosis formation in the aortic arch and left common carotid artery, associated with increased plasma lipid hydroperoxide levels. In conclusion, moxonidine inhibited atherosclerosis in ApoE-/- mice, which was accompanied by an increase in oxidised LDL uptake by VSMCs, VSMC migration, ABCG1 expression in VSMCs and lipid hydroperoxide levels in the plasma.
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Aterosclerosis , Imidazoles , Lipoproteínas LDL , Músculo Liso Vascular , Animales , Ratones , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Proliferación Celular , Células Cultivadas , Peróxidos Lipídicos/metabolismo , Lipoproteínas LDL/metabolismo , Ratones Endogámicos C57BL , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Imidazoles/farmacologíaRESUMEN
Although the evidence base regarding the impact of the COVID-19 pandemic on children has been growing, descriptions of their experiences remain scarce. In this cross-sectional study, the authors used the Child-Reported Spence Children's Anxiety Scale to collect data from 91 children visiting a pediatric emergency center in Qatar during the pandemic. Around 25% of the children reported elevated levels of overall anxiety. Obsessive-compulsive symptoms were the most common, with 59.3% of children reporting elevated symptoms. The mean score of physical injury fears was significantly affected by gender, with females having higher scores. Overall rates for elevated anxiety symptoms were similar in natives and expatriate children. The findings suggest that the effects of the pandemic on children may depend on several vulnerability factors, including developmental age and gender. This study highlights the need to plan multidisciplinary strategies to enhance children's access to mental health services during and after the current health crisis.
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COVID-19 , Femenino , Niño , Humanos , Pandemias , Estudios Transversales , Qatar/epidemiología , Ansiedad/epidemiologíaRESUMEN
The current study explored the effects of natural compounds, berbamine, bergapten, and carveol on paclitaxel-associated neuroinflammatory pain. Berbamine, an alkaloid obtained from BerberisamurensisRuprhas been previously researched for anticancer and anti-inflammatory potential. Bergapten is 5-methoxsalenpsoralen previously investigated in cancer, vitiligo, and psoriasis. Carveol obtained from caraway is a component of essential oil. The neuropathic pain model was induced by administering 2 mg/kg of paclitaxel (PTX) every other day for a week. After the final PTX injection, a behavioral analysis was conducted, and subsequently, tissue was collected for molecular analysis. Berbamine, bergapten, and carveol treatment attenuated thermal hypersensitivity, improved latency of falling, normalized the changes in body weight, and increased the threshold for pain sensation. The drugs increased the protective glutathione (GSH) and glutathione S-transferase (GST) levels in the sciatic nerve and spinal cord while lowering inducible nitric oxide synthase (iNOS) and lipid peroxidase (LPO). Hematoxylin and eosin (H and E) and immunohistochemistry (IHC) examinations confirmed that the medication reversed the abnormal alterations. The aforementioned natural substances inhibited cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κb) overexpression, as evidenced by enzyme-linked immunosorbant assay (ELISA) and Western blot and hence provide neuroprotection in chronic constriction damage.
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Dolor Crónico , Neuralgia , Fármacos Neuroprotectores , 5-Metoxipsoraleno/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Humanos , FN-kappa B/metabolismo , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Óxido Nítrico Sintasa de Tipo II/metabolismo , Paclitaxel/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Since pre-Columbian era, the resin of Araucaria araucana tree has been used traditionally for the treatment of ulcers and wounds. Araucaria species have also been used to treat inflammation, respiratory problems, viral infections, ulcers, and rheumatoid, cardiovascular, and neurological disorders. AIMS AND OBJECTIVE: Due to its popular use, the authors aimed to scrutinize the potential of this plant as an antispasmodic and an antiemetic agent. Furthermore broncho- and vasodilatory effects of this plant was explored to rationalize its folkloric uses. MATERIALS AND METHODS: Araucaria araucana crude extract (Aa.Cr) was evaluated in isolated preparations of rabbit jejunum, trachea, aorta, and atria to investigate the antispasmodic, bronchodilator, and vasodilator effects. The potential mechanistic approaches were compared with the standard drug 'verapamil'. The antiemetic activity was determined and compared with the standard drug 'domperidone' via chick emesis model. RESULTS: Aa.Cr dose-dependently relaxed both spontaneous and K+-induced contractions in the isolated jejunum preparations of rabbits. In concentration-response curves of calcium (Ca++), Aa.Cr also triggered the rightward shift like verapamil. Applying carbachol and phenylephrine (1 µM) and K+ (80 mM) to the isolated tracheal and aortic tissue preparation, respectively, resulted in broncho- and vasodilatory activities, respectively which may be due to the inhibition of Ca++ channels. Aa.Cr inhibited atrial force and spontaneous contractions in the rabbit's right atria. Aa.Cr exhibited significant antiemetic activity (P < 0.001 vs. saline) in dose-dependent (50-150 mg/kg) manner like domperidone. In silico molecular docking was performed to investigate the biological targets of purified components of Aa.Cr which revealed that cadinol dominantly targets ß2 receptors to cause bronchodilation, however, eudesmin binds non-specifically to all the selected targets, while secoisolariciresinol mediated high hydrogen bonding with muscarinic receptors (M1 and M3) and Ca++ channels, thus shows the suggested mechanistic pathways of targeted activities. CONCLUSIONS: The results of this study indicates that Aa.Cr may exhibit antispasmodic activity, bronchodilation, and vasodilation by inhibiting voltage-dependent Ca++ channels and release of subcellular calcium. This explains its folkloric use in hypertension, bronchospasms, gastrointestinal spasms, and emesis.
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Antieméticos , Parasimpatolíticos , Animales , Antieméticos/farmacología , Araucaria araucana , Broncodilatadores/farmacología , Broncodilatadores/uso terapéutico , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio , Fármacos Gastrointestinales/farmacología , Yeyuno , Simulación del Acoplamiento Molecular , Parasimpatolíticos/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Conejos , Tráquea , Úlcera/tratamiento farmacológico , Vasodilatadores/farmacología , Vasodilatadores/uso terapéutico , Verapamilo/farmacología , Vómitos/tratamiento farmacológicoRESUMEN
The innate immune system is the first line of host's defense against invading pathogens. Multiple cellular sensors that detect viral components can induce innate antiviral immune responses. As a result, interferons and pro-inflammatory cytokines are produced which help in the elimination of invading viruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to Coronaviridae family, and has a single-stranded, positive-sense RNA genome. It can infect multiple hosts; in humans, it is responsible for the novel coronavirus disease 2019 (COVID-19). Successful, timely, and appropriate detection of SARS-CoV-2 can be very important for the early generation of the immune response. Several drugs that target the innate immune receptors as well as other signaling molecules generated during the innate immune response are currently being investigated in clinical trials. In this review, we summarized the current knowledge of the mechanisms underlying host sensing and innate immune responses against SARS-CoV-2 infection, as well as the role of innate immune receptors in terms of their therapeutic potential against SARS-CoV-2. Moreover, we discussed the drugs undergoing clinical trials and the FDA approved drugs against SARS-CoV-2. This review will help in understanding the interactions between SARS-CoV-2 and innate immune receptors and thus will point towards new dimensions for the development of new therapeutics, which can be beneficial in the current pandemic.
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Seafood products have been one of the main drivers behind the popularity of high-pressure processing (HPP) in the food industry owing to a high demand for fresh ready-to-eat seafood products and food safety. This review provides an overview of the advanced knowledge available on the use of HPP for production of wholesome and highly nutritive clean label fish and shellfish products. Out of 653 explored items, 65 articles published during 2016-2021 were used. Analysis of the literature showed that most of the earlier work evaluated the HPP effect on physicochemical and sensorial properties, and limited information is available on nutritional aspects. HPP has several applications in the seafood industry. Application of HPP (400-600 MPa) eliminates common seafood pathogens, such as Vibrio and Listeria spp., and slows the growth of spoilage microorganisms. Use of cold water as a pressure medium induces minimal changes in sensory and nutritional properties and helps in the development of clean label seafood products. This technology (200-350 MPa) is also useful to shuck oysters, lobsters, crabs, mussels, clams, and scallops to increase recovery of the edible meat. High-pressure helps to preserve organoleptic and functional properties for an extended time during refrigerated storage. Overall, HPP helps seafood manufacturers to maintain a balance between safety, quality, processing efficiency, and regulatory compliance. Further research is required to understand the mechanisms of pressure-induced modifications and clean label strategies to minimize these modifications.
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Alimentos Marinos , Mariscos , Animales , Peces , Inocuidad de los Alimentos , CarneRESUMEN
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has been recently identified as a novel member of beta coronaviruses (CoVs) and the cause of coronavirus disease 2019 (COVID-19). It has been first discovered in China and soon has spread across continents with an escalating number of mortalities. There is an urgent need for developing a COVID-19 vaccine to control the rapid transmission and the deleterious impact of the virus. The potent vaccine should have a good tolerable and efficacious profile to induce target-specific humoral and cellular immune responses. It should also exhibit no or minimal detrimental effects in children, young adults, and elderly people with or without co-morbidities from different racial backgrounds. Previously published findings of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) played vital role in the characterization of surface spike proteins as the tool of entry of the SARS-CoV-2 into host cells. It has become evident that SARS-CoVs have high genetic similarity and this implies antecedent vaccination strategies could be implicated in the production of COVID-19 vaccines. Although several vaccines have been approved and rolled out, only a handful of them have passed the three phases of clinical studies. This review highlights the completed, and ongoing clinical trials of COVID-19 vaccines and efforts are being made globally to avert the pandemic.
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This paper summarizes a novel initiative by Qatar mental health services to support Afghan refugee children and adolescents. The project involved evaluating needs, establishing a dedicated team, and setting up a suitable needs-based service. After identifying the needs, a range of appropriate psychiatric, psychological, and allied health interventions was commenced. This unique program has been tremendously successful in providing quality care and has received an immensely positive response. We have demonstrated that a targeted, non-stigmatizing and collaborative mental health response can be highly effective in catering to the needs of individuals affected by a humanitarian crisis.
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Servicios de Salud Mental , Refugiados , Adolescente , Niño , Familia , Humanos , Salud Mental , QatarRESUMEN
Despite significant technological advancements in conventional therapies, cancer remains one of the main causes of death worldwide. Although substantial progress has been made in the control and treatment of cancer, several limitations still exist, and there is scope for further advancements. Several adverse effects are associated with modern chemotherapy that hinder cancer treatment and lead to other critical disorders. Since ancient times, plant-based medicines have been employed in clinical practice and have yielded good results with few side effects. The modern research system and advanced screening techniques for plants' bioactive constituents have enabled phytochemical discovery for the prevention and treatment of challenging diseases such as cancer. Phytochemicals such as vincristine, vinblastine, paclitaxel, curcumin, colchicine, and lycopene have shown promising anticancer effects. Discovery of more plant-derived bioactive compounds should be encouraged via the exploitation of advanced and innovative research techniques, to prevent and treat advanced-stage cancers without causing significant adverse effects. This review highlights numerous plant-derived bioactive molecules that have shown potential as anticancer agents and their probable mechanisms of action and provides an overview of in vitro, in vivo and clinical trial studies on anticancer phytochemicals.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Fitoquímicos/química , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico , Plantas/químicaRESUMEN
The meat industry is continuously facing challenges with food safety, and quality losses caused by thermal processing. This systematic review reports recent clean label approaches in high-pressure production of meat. A literature search was performed using Scopus, Web of Science, PubMed, and Springer databases for studies published in 2018-2021. In this regard, 69 articles were assessed out of 386 explored research articles in the identified stage. The findings indicate that most of the earlier work on high-pressure processing (HPP) focused on physicochemical and sensorial meat quality rather than providing nutritional aspects and clean-label solutions. However, few advanced studies report effective and innovative solutions to develop low salt/fat, and reduced nitrite for raw and cured meat products. HPP could help on increasing the shell life by five times in meat products; however, it depends on the formulation and packaging, etc. HPP can also preserve nutrients by using this non-thermal technology and reduce food waste as once the shelf life of products is known, it easily reduces the shrinkage in the marketplace. This review explores the latest trend of experimental research in high-pressure processing alone, or multi-hurdle techniques employed to increase the effect of clean-label ingredients for enhanced meat safety/quality.
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Productos de la Carne , Eliminación de Residuos , Manipulación de Alimentos , Conservación de Alimentos , CarneRESUMEN
Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from SDS patients (SDS-OBs), we show that SDS-OBs displayed reduced SBDS gene expression and reduced/undetectable SBDS protein compared to osteoblasts from healthy subjects (H-OBs). SDS-OBs cultured in an osteogenic medium displayed a lower mineralization capacity compared to H-OBs. Whole transcriptome analysis showed significant differences in the gene expression of SDS-OBs vs. H-OBs, particularly in the ossification pathway. SDS-OBs expressed lower levels of the main genes responsible for osteoblastogenesis. Of all downregulated genes, Western blot analyses confirmed lower levels of alkaline phosphatase and collagen type I in SDS-OBs than in H-OBs. Interestingly, SDS-OBs showed higher protein levels of p53, an inhibitor of osteogenesis, compared to H-OBs. Silencing of Tp53 was associated with higher collagen type I and alkaline phosphatase protein levels and an increase in SDS-OB mineralization capacity. In conclusion, our results show that the reduced capacity of SDS-OBs to mineralize is mediated, at least in part, by the high levels of p53 and highlight an important role of SBDS in osteoblast functions.