RESUMEN
Parkinson's disease (PD) is a common and progressively worsening neurodegenerative disorder characterized by abnormal protein homeostasis and the degeneration of dopaminergic neurons, particularly in the substantia nigra pars compacta. The prevalence of PD has doubled in the past 25 years, now affecting over 8.5 million individuals worldwide, underscoring the need for effective management strategies. While current pharmacological therapies provide symptom relief, they face challenges in treating advanced PD stages. Recent research highlights the therapeutic benefits of retinoic acid (RA) in PD, demonstrating its potential to mitigate neuroinflammation and oxidative stress, regulate brain aging, promote neuronal plasticity, and influence circadian rhythm gene expression and retinoid X receptor heterodimerization. Additionally, RA helps maintain intestinal homeostasis and modulates the enteric nervous system, presenting significant therapeutic potential for managing PD. This review explores RA as a promising alternative to conventional therapies by summarizing the molecular mechanisms underlying its role in PD pathophysiology and presenting up-to-date insights into both preclinical and clinical studies of RA in PD treatment. It also delves into cutting-edge formulations incorporating RA, highlighting ongoing efforts to refine therapeutic strategies by integrating RA into novel treatments. This comprehensive overview aims to advance progress in the field, contribute to the development of effective, targeted treatments for PD, and enhance patient well-being. Further research is essential to fully explore RA's therapeutic potential and validate its efficacy in PD treatment.
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Enfermedad de Parkinson , Tretinoina , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Tretinoina/uso terapéutico , Animales , Estrés Oxidativo/efectos de los fármacosRESUMEN
Patulin (PAT) is a food-borne mycotoxin produced by Penicillium and Byssochlamys species. It is widely known for its mutagenic, carcinogenic, and genotoxic effects and has been associated with kidney injury; however, the mechanism of toxicity remains unclear. To address this gap, we conducted a study to explore the changes in α-adrenergic receptor signalling pathways and epigenetic modifications induced by PAT in the kidneys of C57BL/6 mice during acute (1 day) and prolonged (10 days) exposure. The mice (20-22 g) were orally administered PAT (2.5 mg/kg; at 1 and 10 days), and post-treatment, the kidneys were harvested, homogenised and extracted for RNA, DNA, and protein. The relative gene expression of the α-adrenergic receptors (ADRA1, ADRA2A, ADRA2B) and associated signalling pathways (MAPK, MAPK14, ERK, PI3K, and AKT) was assessed by qPCR. The protein expression of ERK1/2 and MAPK was determined by western blot. The impact of PAT on DNA methylation was evaluated by quantifying global DNA methylation; qPCR was used to determine gene expression levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) and demethylase (MBD2). PAT downregulated the expression of ADRA1, ADRA2A, ADRA2B, PI3K, and AKT and upregulated ERK1/2 and MAPK protein expression. Furthermore, PAT induced alterations in DNA methylation patterns by upregulating DNMT1 and MBD2 expressions and downregulating DNMT3A and DNMT3B expressions, resulting in global DNA hypomethylation. In conclusion, PAT disrupts α-1 and α-2 adrenergic receptor signalling pathways and induces epigenetic modifications, that can lead to kidney injury.
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Metilación de ADN , Epigénesis Genética , Riñón , Patulina , Transducción de Señal , Animales , Masculino , Ratones , Metilación de ADN/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones Endogámicos C57BL , Patulina/toxicidad , Transducción de Señal/efectos de los fármacosRESUMEN
The recently discovered coronavirus, known as SARS-CoV-2, is a highly contagious and potentially lethal viral infection that was declared a pandemic by the World Health Organization on March 11, 2020. Since the beginning of the pandemic, an unprecedented number of COVID-19 vaccine candidates have been investigated for their potential to manage the pandemic. Herein, we reviewed vaccine development and the associated research effort, both traditional and forward-looking, to demonstrate the advantages and disadvantages of their technology, in addition to their efficacy limitations against mutant SARS-CoV-2. Moreover, we report repurposed drug discovery, which mainly focuses on virus-based and host-based targets, as well as their inhibitors. SARS-CoV-2 targets include the main protease (Mpro), and RNA-dependent RNA-polymerase (RdRp), which are the most well-studied and conserved across coronaviruses, enabling the development of broad-spectrum inhibitors of these enzymes.
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COVID-19 , Vacunas , Humanos , Vacunas contra la COVID-19/farmacología , SARS-CoV-2 , ARNRESUMEN
The cosmetic industry makes extensive use of kojic acid (KA); however, the toxicity of KA in humans is not well known. By monitoring oxidative stress, mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) signalling in human hepatoma (HepG2) cells after a 24 h exposure, this study aimed to identify the toxicity of KA. KA toxicity [4.22, 8.02 and 12.67 mM] was assessed using mitochondrial output, antioxidant responses, macromolecule damage, MAPK signalling, inflammation, and cell death markers, using spectrophotometry, luminometry, Western blot and qPCR. Apoptosis was confirmed by reduced cell viability and increased caspases -9 (p < 0.0001), -8 (p = 0.0003), and -3/7 (p < 0.0001) activities at 4.22 mM and 8.02 mM. LDH leakage was present at 12.67 mM, providing significant evidence of necrosis. Malondialdehyde (MDA) levels significantly increased at 4.22 mM (p < 0.0001). There was an increase of phosphorylated nuclear factor erythroid-2 factor-2 (p-Nrf2) at 4.22 mM and 8.02 mM, whilst at 12.67 mM decreased p-Nrf2 (p < 0.0001) was observed. KA increased p38 expression (p = 0.0011). The findings point to significant suppression of the NFκB inflammatory pathway at 8.02 mM (p < 0.0001). This study showed that KA initiated MAPK signalling due to oxidative stress and suppressed inflammation. HepG2 cells showed minimal toxicity to KA.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Células Hep G2 , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , FN-kappa B/metabolismo , Inflamación/inducido químicamente , Antiinflamatorios/farmacologíaRESUMEN
Metabolic syndrome (MetS) is a non-communicable disease characterized by a cluster of metabolic irregularities. Alarmingly, the prevalence of MetS in people living with Human Immunodeficiency Virus (HIV) and antiretroviral (ARV) usage is increasing rapidly. Insulin resistance is a common characteristic of MetS that leads to the development of Type 2 diabetes mellitus (T2DM). The progression of insulin resistance is strongly linked to inflammasome activation. This study aimed to draw links between the combinational use of Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC), and Dolutegravir (DTG), and inflammasome activation and subsequent promotion of insulin resistance following a 120 h treatment period in HepG2 liver in vitro cell model. Furthermore, we assess microRNA (miR-128a) expression as a negative regulator of the IRS1/AKT signaling pathway. The relative expression of phosphorylated IRS1 was determined by Western blot. Transcript levels of NLRP3, IL-1ß, JNK, IRS1, AKT, PI3K, and miR-128a were assessed using quantitative PCR (qPCR). Caspase-1 activity was measured using luminometry. Following exposure to ARVs for 120 h, NLRP3 mRNA expression (p = 0.0500) and caspase-1 activity (p < 0.0001) significantly increased. This was followed by a significant elevation in IL-1ß in mRNA expression (p = 0.0015). Additionally, JNK expression (p = 0.0093) was upregulated with coinciding increases in p-IRS1 protein expression (p < 0.0001) and decreased IRS1 mRNA expression (p = 0.0004). Consequently, decreased AKT (p = 0.0005) and PI3K expressions (p = 0.0007) were observed. Interestingly miR-128a expression was significantly upregulated. The results indicate that combinational use of ARVs upregulates inflammasome activation and promotes insulin resistance through dysregulation of the IRS1/PI3K/AKT insulin signaling pathway.
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Diabetes Mellitus Tipo 2 , Infecciones por VIH , Resistencia a la Insulina , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Inflamasomas/genética , Inflamasomas/metabolismo , Resistencia a la Insulina/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Activación Transcripcional , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Hígado/metabolismo , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Caspasas/metabolismoRESUMEN
The prevalence of metabolic syndrome MetS in HIV-infected patients on chronic antiretroviral (ARV) therapy continues to rise rapidly, with an estimated 21% experiencing insulin resistance. The progression of insulin resistance is strongly related to mitochondrial stress and dysfunction. This study aimed to draw links between the singular and combinational use of Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC), and Dolutegravir (DTG) on mitochondrial stress and dysfunction as an underlying mechanism for insulin resistance following a 120 h treatment period using an in vitro system of human liver cells (HepG2). The relative protein expressions of pNrf2, SOD2, CAT, PINK1, p62, SIRT3, and UCP2, were determined using Western blot. Transcript levels of PINK1 and p62 were assessed using quantitative PCR (qPCR). ATP concentrations were quantified using luminometry, and oxidative damage (malondialdehyde (MDA) concentration) was measured using spectrophotometry. The findings suggest that despite the activation of antioxidant responses (pNrf2, SOD2, CAT) and mitochondrial maintenance systems (PINK1 and p62) in selected singular and combinational treatments with ARVs, oxidative damage and reduced ATP production persisted. This was attributed to a significant suppression in mitochondrial stress responses SIRT3 and UCP2 for all treatments. Notable results were observed for combinational treatments with significant increases in pNrf2 (p = 0.0090), SOD2 (p = 0.0005), CAT (p = 0.0002), PINK1 (p = 0.0064), and p62 (p = 0.0228); followed by significant decreases in SIRT3 (p = 0.0003) and UCP2 (p = 0.0119) protein expression. Overall there were elevated levels of MDA (p = 0.0066) and decreased ATP production (p = 0.0017). In conclusion, ARVs induce mitochondrial stress and dysfunction, which may be closely associated with the progression of insulin resistance.
RESUMEN
The World Health Organization (WHO) reported that there are 37 million individuals living with the human immunodeficiency virus (HIV) worldwide, with the majority in South Africa. This chronic disease is managed by the effective use of antiretroviral (ARV) drugs. However, with prolonged use, ARV drug-induced toxicity remains a clinically complex problem. This study investigated the toxicity of ARV drugs on mitochondria and the NRF2 antioxidant pathway and its possible amelioration using Moringa oleifera Lam (MO) leaf extracts. This medicinal plant has a range of functional bioactive compounds. Liver (HepG2) cells were treated with individual ARV drugs: Tenofovir disoproxil fumarate (TDF), Emtricitabine (FTC), and Lamivudine (3TC) for 96 h, followed by MO leaf extracts for 24 h. Intracellular ROS, cytotoxicity, lipid peroxidation, total and reduced glutathione (GSH), ATP, and mitochondrial polarisation were determined. Finally, protein (pNRF2, NRF2, SOD2, CAT, and Sirt3) and mRNA (NRF2, CAT, NQO1 SOD2, Sirt3, and PGC1α) expression were measured using Western blot and qPCR, respectively. TDF, FTC, and 3TC significantly increased intracellular ROS and extracellular levels of both MDA and LDH. ARVs also reduced the GSH and ATP levels and altered the mitochondrial polarization. Further, ARVs reduced the expression of NRF2 SOD2, Sirt3, CAT, NQO1, UCP2 and PGC1α mRNA and consequently pNRF2, NRF2, SOD2, Sirt3 and CAT protein. In contrast, there was a significant reduction in the extracellular MDA and LDH levels post-MO treatment. MO significantly reduced intracellular ROS while significantly increasing GSH, ATP, and mitochondrial membrane polarization. The addition of MO to ARV-treated cells significantly upregulated the expression of NRF2, SOD2, Sirt3, CAT, UCP2, PGC1α, and NQO1 mRNA and pNRF2, NRF2, SOD2, Sirt3 proteins. Thus, MO ameliorates ARV-induced hepatotoxicity by scavenging oxidants by inducing the NRF2 antioxidant pathway. MO shows great therapeutic potential and may be considered a potential supplement to ameliorate ARV drug toxicity.
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Lately, Spirulina platensis (SP), as an antioxidant, has exhibited high potency in the treatment of oxidative stress, diabetes, immune disorder, inflammatory stress, and bacterial and viral-related diseases. This study investigated the possible protective role of Spirulina platensis against ARV-induced oxidative stress in HepG2 cells. Human liver (HepG2) cells were treated with ARVs ((Lamivudine (3TC): 1.51 µg/mL, tenofovir disoproxil fumarate (TDF): 0.3 µg/mL and Emtricitabine (FTC): 1.8 µg/mL)) for 96 h and thereafter treated with 1.5 µg/mL Spirulina platensis for 24 h. After the treatments, the gene and protein expressions of the antioxidant response pathway were determined using a quantitative polymerase chain reaction (qPCR) and Western blots. The results show that Spirulina platensis decreased the gene expressions of Akt (p < 0.0001) and eNOS (↓p < 0.0001) while, on the contrary, it increased the transcript levels of NRF-2 (↑p = 0.0021), Keap1 (↑p = 0.0002), CAT (↑p < 0.0001), and NQO-1 (↑p = 0.1432) in the HepG2 cells. Furthermore, the results show that Spirulina platensis also decreased the protein expressions of NRF-2 (↓p = 0.1226) and pNRF-2 (↓p = 0.0203). Interestingly, HAART-SP induced an NRF-2 pathway response through upregulating NRF-2 (except for FTC-SP) (↑p < 0.0001), CAT (↑p < 0.0001), and NQO-1 (except for FTC-SP) (↑p < 0.0001) mRNA expression. In addition, NRF-2 (↑p = 0.0085) and pNRF-2 (↑p < 0.0001) protein expression was upregulated in the HepG2 cells post-exposure to HAART-SP. The results, therefore, allude to the fact that Spirulina platensis has the potential to mitigate HAART-adverse drug reactions (HAART toxicity) through the activation of antioxidant response in HepG2 cells. We hereby recommend further studies on Spirulina platensis and HAART synergy.
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The highly transmittable and infectious COVID-19 remains a major threat worldwide, with the elderly and comorbid individuals being the most vulnerable. While vaccines are currently available, therapeutic drugs will help ease the viral outbreak and prevent serious health outcomes. Epigenetic modifications regulate gene expression through changes in chromatin structure and have been linked to viral pathophysiology. Since epigenetic modifications contribute to the life cycle of the virus and host immune responses to infection, epigenetic drugs are promising treatment targets to ameliorate COVID-19. Deficiency of the multifunctional secosteroid hormone vitamin D is a global health threat. Vitamin D and its receptor function to regulate genes involved in immunity, apoptosis, proliferation, differentiation, and inflammation. Amassed evidence also indicates the biological relations of vitamin D with reduced disease risk, while its receptor can be modulated by epigenetic mechanisms. The immunomodulatory effects of vitamin D suggest a role for vitamin D as a COVID-19 therapeutic agent. Therefore, this review highlights the epigenetic effects on COVID-19 and vitamin D while also proposing a role for vitamin D in COVID-19 infections.
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COVID-19 , Deficiencia de Vitamina D , Humanos , Anciano , Vitamina D/farmacología , Vitamina D/uso terapéutico , Vitamina D/metabolismo , SARS-CoV-2 , Vitaminas/farmacología , Vitaminas/uso terapéutico , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/genética , Deficiencia de Vitamina D/tratamiento farmacológico , Epigénesis Genética , Hormonas , CromatinaRESUMEN
Highly active antiretroviral therapy (HAART) comprises a combination of two or three antiretroviral (ARV) drugs that are administered together in a single tablet. These drugs target different steps within the human immunodeficiency virus (HIV) life cycle, providing either a synergistic or additive antiviral effect; this enhances the efficiency in which viral replication is suppressed. HIV cannot be completely eliminated, making HAART a lifetime treatment. With long-term HAART usage, an increasing number of patients experience a broadening array of complications, and this significantly affects their quality of life, despite cautious use. The mechanism through which ARV drugs induce toxicity is associated with metabolic complications such as mitochondrial dysfunction, oxidative stress, and inflammation. To address this, it is necessary to improve ARV drug formulation without compromising its efficacy; alternatively, safe supplementary medicine may be a suitable solution. The medicinal plant Moringa oleifera (MO) is considered one of the most important sources of novel nutritionally and pharmacologically active compounds that have been shown to prevent and treat various diseases. MO leaves are rich in polyphenols, vitamins, minerals, and tannins; studies have confirmed the therapeutic properties of MO. MO leaves provide powerful antioxidants, scavenge free radicals, promote carbohydrate metabolism, and repair DNA. MO also induces anti-inflammatory, hepatoprotective, anti-proliferative, and anti-mutagenic effects. Therefore, MO can be a source of affordable and safe supplement therapy for HAART-induced toxicity. This review highlights the potential of MO leaves to protect against HAART-induced toxicity in HIV patients.
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Antimutagênicos , Infecciones por VIH , Moringa oleifera , Antiinflamatorios , Terapia Antirretroviral Altamente Activa/efectos adversos , Antivirales , ADN , Radicales Libres , Infecciones por VIH/tratamiento farmacológico , Humanos , Minerales , Calidad de Vida , Comprimidos , Taninos , VitaminasRESUMEN
The human immunodeficiency virus (HIV) is one of the most prevalent diseases globally. It is estimated that 37.7 million people are infected with HIV globally, and 8.2 million persons are infected with the virus in South Africa. The highly active antiretroviral therapy (HAART) involves combining various types of antiretroviral drugs that are dependent on the infected person's viral load. HAART helps regulate the viral load and prevents its associated symptoms from progressing into acquired immune deficiency syndrome (AIDS). Despite its success in prolonging HIV-infected patients' lifespans, the use of HAART promotes metabolic syndrome (MetS) through an inflammatory pathway, excess production of reactive oxygen species (ROS), and mitochondrial dysfunction. Interestingly, Spirulina platensis (SP), a blue-green microalgae commonly used as a traditional food by Mexican and African people, has been demonstrated to mitigate MetS by regulating oxidative and inflammatory pathways. SP is also a potent antioxidant that has been shown to exhibit immunological, anticancer, anti-inflammatory, anti-aging, antidiabetic, antibacterial, and antiviral properties. This review is aimed at highlighting the biochemical mechanism of SP with a focus on studies linking SP to the inhibition of HIV, inflammation, and oxidative stress. Further, we propose SP as a potential supplement for HIV-infected persons on lifelong HAART.
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Infecciones por VIH , Spirulina , Terapia Antirretroviral Altamente Activa/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Humanos , Carga ViralRESUMEN
COVID-19, resulting from the SARS-CoV-2 virus, is a major pandemic that the world is fighting. SARS-CoV-2 primarily causes lung infection by attaching to the ACE2 receptor on the alveolar epithelial cells. However, the ACE2 receptor is also present in intestinal epithelial cells, suggesting a link between nutrition, virulence and clinical outcomes of COVID-19. Respiratory viral infections perturb the gut microbiota. The gut microbiota is shaped by our diet; therefore, a healthy gut is important for optimal metabolism, immunology and protection of the host. Malnutrition causes diverse changes in the immune system by repressing immune responses and enhancing viral vulnerability. Thus, improving gut health with a high-quality, nutrient-filled diet will improve immunity against infections and diseases. This review emphasizes the significance of dietary choices and its subsequent effects on the immune system, which may potentially impact SARS-CoV-2 vulnerability.
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COVID-19/inmunología , Conducta Alimentaria , Sistema Inmunológico/inmunología , Desnutrición/inmunología , SARS-CoV-2/inmunología , COVID-19/epidemiología , COVID-19/virología , Microbioma Gastrointestinal/inmunología , Estado de Salud , Humanos , Modelos Inmunológicos , Estado Nutricional , Pandemias , SARS-CoV-2/patogenicidad , Virulencia/inmunologíaRESUMEN
Ubiquitous soil fungi parasitise agricultural commodities and produce mycotoxins. Fumonisin B2 (FB2), the structural analogue of the commonly studied Fumonisin B1 (FB1), is a neglected mycotoxin produced by several Fusarium species. Mycotoxins are known for inducing toxicity via mitochondrial stress alluding to mitochondrial degradation (mitophagy). These processes involve inter-related pathways that are regulated by proteins related to SIRT3 and Nrf2. This study aimed to investigate mitochondrial stress responses in human kidney (Hek293) cells exposed to FB2 for 24 h. Cell viability was assessed via the methylthiazol tetrazolium (MTT) assay, and the half-maximal inhibitory concentration (IC50 = 317.4 µmol/L) was estimated using statistical software. Reactive oxygen species (ROS; H2DCFDA), mitochondrial membrane depolarisation (JC1-mitoscreen) and adenosine triphosphate (ATP; luminometry) levels were evaluated to assess mitochondrial integrity. The relative expression of mitochondrial stress response proteins (SIRT3, pNrf2, LONP1, PINK1, p62 and HSP60) was determined by Western blot. Transcript levels of SIRT3, PINK1 and miR-27b were assessed using quantitative PCR (qPCR). FB2 reduced ATP production (p = 0.0040), increased mitochondrial stress marker HSP60 (p = 0.0140) and suppressed upregulation of mitochondrial stress response proteins SIRT3 (p = 0.0026) and LONP1 (p = 0.5934). FB2 promoted mitophagy via upregulation of pNrf2 (p = 0.0008), PINK1 (p = 0.0014) and p62 (p < 0.0001) protein expression. FB2 also suppressed miR-27b expression (p < 0.0001), further promoting the occurrence of mitophagy. Overall, the findings suggest that FB2 increases mitochondrial stress and promotes mitophagy in Hek293 cells.
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Fumonisinas , MicroARNs , Micotoxinas , Sirtuina 3 , Proteasas ATP-Dependientes/metabolismo , Adenosina Trifosfato/metabolismo , Fumonisinas/toxicidad , Células HEK293 , Humanos , Riñón/metabolismo , Proteínas Mitocondriales/metabolismo , Mitofagia , Proteínas Quinasas , Sirtuina 3/genética , Sirtuina 3/metabolismoRESUMEN
The introduction of highly active antiretroviral therapy (HAART) in the treatment of HIV/AIDS has recently gained popularity. In addition, the significant role of microRNA expression in HIV pathogenesis cannot be overlooked; hence the need to explore the mechanisms of microRNA expression in the presence of HAART and Spirulina platensis (SP) in HepG2 cells. This study investigates the biochemical mechanisms of microRNA expression in HepG2 cells in the presence of HAART, SP, and the potential synergistic effect of HAART−SP. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine cell viability following SP treatment. The cellular redox status was assessed using the quantification of intracellular reactive oxygen species (ROS), lipid peroxidation, and a lactate dehydrogenase (LDH) assay. The fluorometric JC-1 assay was used to determine mitochondrial polarisation. The quantitative polymerase chain reaction (qPCR) was also employed for micro-RNA and gene expressions. The results show that MiR-146a (p < 0.0001) and miR-155 (p < 0.0001) levels increased in SP-treated cells. However, only miR-146a (p < 0.0001) in HAART−SP indicated an increase, while miR-155 (p < 0.0001) in HAART−SP treatment indicated a significant decreased expression. Further inflammation analysis revealed that Cox-1 mRNA expression was reduced in SP-treated cells (p = 0.4129). However, Cox-1 expression was significantly increased in HAART−SP-treated cells (p < 0.0001). The investigation revealed that HepG2 cells exposed to HAART−SP treatment showed a significant decrease in Cox-2 (p < 0.0001) expression. mRNA expression also decreased in SP-treated cells (p < 0.0001); therefore, SP potentially controls inflammation by regulating microRNA expressions. Moreover, the positive synergistic effect is indicated by normalised intracellular ROS levels (p < 0.0001) in the HAART−SP treatment. We hereby recommend further investigation on the synergistic roles of SP and HAART in the expression of microRNA with more focus on inflammatory and oxidative pathways.
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ARVs alter the methylation status of the MEKKK1 gene promoter in acute treated Jurkat T cells with inflammatory outcomesInflammation is reduced in patients under going antiretroviral therapy; however the mechanism is not well understood. We investigated DNA methylation of the mitogen-activated protein kinase kinase kinase kinase 1 (MEKKK1) gene promoter in Jurkat T cells to determine whether the antiretroviral drugs, lamivudine, tenofovir disoproxil fumarate, dolutegravir, TLD (a combination of TDF, 3TC and DTG) and efavirenz modify the methylation status of the MEKKK1 gene - a known stimulus of inflammation.Acute antiretroviral treatments (24 h) were not cytotoxic to Jurkat T cells. MEKKK1 promoter hypomethylation occurred in cells treated with 5-aza-2'-deoxycytidine (Aza), TDF and 3TC, and MEKKK1 promoter hypermethylation occurred in cells treated with DTG; however, promoter DNA methylation of the MEKKK1 gene did not influence MEKKK1 gene expression; therefore, these drugs did not epigenetically regulate MEKKK1 and downstream signalling by promoter DNA methylation. Acute TLD and EFV treatments induced inflammation in Jurkat T cells by increasing MEKKK1, MAPK/ERK and NFκB expression, and activating tumour necrosis factor-α (TNF-α) expression. ARVs decreased IL-10 gene expression, showing no anti-inflammatory activity.The data shows that the inflammation caused by ARVs is not related to the methylation status of MEKKK1 gene promoter and suggests an alternative stimulus via post-transcriptional/post-translational modifications may activate the canonical MEKKK1/NFκB pathway that leads to inflammation. Finally, an increase in NFκB activity and pro-inflammatory cytokine activation seemed to occur via the MAPK/ERK pathway following ARV treatments in Jurkat T cells.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Citocinas , Infecciones por VIH/tratamiento farmacológico , Lamivudine/toxicidad , Lamivudine/uso terapéutico , Tenofovir/uso terapéutico , Benzoxazinas , Decitabina/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Linfocitos TRESUMEN
N6-methyladenosine (m6A) is an abundant epitranscriptomic mark that regulates gene expression to execute cellular developmental programmes and environmental adaptation. Fusaric acid (FA) is a mycotoxin that contaminates agricultural foods and exerts toxicity in humans and animals; however, its epitranscriptomic effects are unclear. We investigated the effect of FA on global m6A RNA methylation and mRNA expression levels of key m6A regulatory genes in C57BL/6 mouse livers. C57BL/6 mice (n = 6/group) were orally administered 0.1 M phosphate-buffered saline (PBS) or 50 mg/kg FA. Mice were euthanized 24 h after oral administration, livers were harvested, and RNA was isolated. RNA samples were assayed for global m6A levels using an m6A RNA Methylation Quantification Kit. The mRNA expression of m6A regulators i.e. writers, erasers, and readers were measured by qRT-PCR. FA increased global m6A RNA methylation (p < 0.0001) in mouse livers. FA increased the expression of METTL3 (p = 0.0143) and METTL14 (p = 0.0281), and decreased the expression of FTO (p = 0.0036) and ALKBH5 (p = 0.0035). The expression of YTHDF2 (p = 0.0007), YTHDF3 (p = 0.0061), and YTHDC2 (p = 0.0258) were increased by FA in mouse livers. This study shows that the liver m6A epitranscriptome can be modified by FA exposure in an in vivo model and can be useful for identifying the molecular mechanisms whereby m6A RNA modifications influence the toxicological outcomes of FA exposure.
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Metilación de ADN , Ácido Fusárico , Animales , Genes Reguladores , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Proyectos Piloto , ARN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Bridelia ferruginea Benth. (Euphorbiaceae) is among the medicinal plants commonly used for the management of type 2 diabetes (T2D) and its complications. AIM OF THE STUDY: The hepato-therapeutic effect of the butanol fraction of Bridelia ferruginea leaves was investigated in diabetic rats. METHODS: The butanol fraction of B. ferruginea was given to type 2 diabetic rats at both low and high doses (150 and 300 mg/kg bodyweight, respectively), while metformin and glibenclamide served as the standard anti-diabetic drugs. A normal toxicological group was administered a high dose of the fraction. At the end of the experimental period, the rats were sacrificed, and their livers and psoas muscle collected. The liver was assayed for oxidative stress markers, liver glycogen content, lipid metabolite profile (using GC-MS) and their metabolic pathways were analyzed using the MetaboAnalyst 5.0 online server. The expression of GLUT4 was also assayed in the liver and muscle as well as the identification of signaling pathways associated with GLUT4 expression using the Enrichr online server. In silico molecular docking was used to investigate the molecular interactions of some postulated compound found in B. ferruginea with GLUT4. The ability of the fraction to stimulate muscle glucose uptake was determined in isolated rat psoas muscle ex vivo. RESULTS: Treatment with the high dose of fraction caused an inhibition of lipid peroxidation as well as the elevation of catalase, SOD, glutathione reductase and glutathione peroxidase activities in the rat liver. There was an increased expression of GLUT4 in livers and muscles of diabetic rats following treatment with B. ferruginea. Treatment with the fraction also caused inactivation of diabetes-activated pathways and changes in the distribution of the hepatic lipid metabolites. Molecular docking analysis revealed strong molecular interactions of pyrogallol and sitosterol with GLUT4. CONCLUSIONS: These data illustrate the hepato-protective effect of B. ferruginea in diabetic rats which compare favorably with the tested anti-diabetic drugs (metformin and glibenclamide).
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Euphorbiaceae/química , Transportador de Glucosa de Tipo 4/metabolismo , Insulina/metabolismo , Hígado/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Dominio Catalítico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Transportador de Glucosa de Tipo 4/genética , Gliburida/uso terapéutico , Peroxidación de Lípido , Hígado/metabolismo , Masculino , Metformina/uso terapéutico , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Fitoterapia , Extractos Vegetales/química , Hojas de la Planta/química , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Regulación hacia ArribaRESUMEN
Genetic and epigenetic changes alter gene expression, contributing to cancer. Epigenetic changes in cancer arise from alterations in DNA and histone modifications that lead to tumour suppressor gene silencing and the activation of oncogenes. The acetylation status of histones and non-histone proteins are determined by the histone deacetylases and histone acetyltransferases that control gene transcription. Organoselenium compounds have become promising contenders in cancer therapeutics. Apart from their anti-oxidative effects, several natural and synthetic organoselenium compounds and metabolites act as histone deacetylase inhibitors, which influence the acetylation status of histones and non-histone proteins, altering gene transcription. This review aims to summarise the effect of natural and synthetic organoselenium compounds on histone and non-histone protein acetylation/deacetylation in cancer therapy.
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Inhibidores de Histona Desacetilasas/farmacología , Neoplasias/tratamiento farmacológico , Compuestos de Organoselenio/farmacología , Acetilación/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Epigénesis Genética/efectos de los fármacos , Código de Histonas/efectos de los fármacos , Código de Histonas/genética , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/metabolismo , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Terapia Molecular Dirigida , Nanopartículas , Neoplasias/genética , Neoplasias/metabolismo , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacosRESUMEN
Metabolic syndrome (MetS) is a non-communicable disease characterised by a cluster of metabolic irregularities. Alarmingly, the prevalence of MetS in people living with Human Immunodeficiency Virus (HIV) and antiretroviral (ARV) usage is increasing rapidly. This study aimed to look at biochemical mechanisms and epigenetic modifications associated with HIV, ARVs, and MetS. More specifically, emphasis was placed on mitochondrial dysfunction, insulin resistance, inflammation, lipodystrophy, and dyslipidaemia. We found that mitochondrial dysfunction was the most common mechanism that induced metabolic complications. Our findings suggest that protease inhibitors (PIs) are more commonly implicated in MetS-related effects than other classes of ARVs. Furthermore, we highlight epigenetic studies linking HIV and ARV usage to MetS and stress the need for more studies, as the current literature remains limited despite the advancement in and popularity of epigenetics.
Asunto(s)
Antirretrovirales/efectos adversos , Infecciones por VIH/genética , VIH/metabolismo , Síndrome Metabólico/genética , Animales , Epigénesis Genética , VIH/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Humanos , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patologíaRESUMEN
The Developmental Origins of Health and Disease (DOHaD) concept postulates that in utero exposures influence fetal programming and health in later life. Throughout pregnancy, the placenta plays a central role in fetal programming; it regulates the in utero environment and acts as a gatekeeper for nutrient and waste exchange between the mother and the fetus. Maternal exposure to air pollution, including heavy metals, can reach the placenta, where they alter DNA methylation patterns, leading to changes in placental function and fetal reprogramming. This review explores the current knowledge on placental DNA methylation changes associated with prenatal air pollution (including heavy metals) exposure and highlights its effects on fetal development and disease susceptibility. Prenatal exposure to air pollution and heavy metals was associated with altered placental DNA methylation at the global and promoter regions of genes involved in biological processes such as energy metabolism, circadian rhythm, DNA repair, inflammation, cell differentiation, and organ development. The altered placental methylation of these genes was, in some studies, associated with adverse birth outcomes such as low birth weight, small for gestational age, and decreased head circumference. Moreover, few studies indicate that DNA methylation changes in the placenta were sex-specific, and infants born with altered placental DNA methylation patterns were predisposed to developing neurobehavioral abnormalities, cancer, and atopic dermatitis. These findings highlight the importance of more effective and stricter environmental and public health policies to reduce air pollution and protect human health.