ABSTRACT
Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.
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Recent reports based on a substantial number of cases, warrant need for population-based research to determine implications of constitutional methylation of tumor suppressor genes such as BRCA1 occurring in healthy tissue in the prediction of cancer. However, the detection of the constitutional methylation in DNA extracted from blood has already been shown to be technologically challenging, mainly because epimutations appear to be present in blood at a very low level. The analytical sensitivity required for low-level methylation detection can be provided by NGS, but this technique is still labor and cost-intensive. We assessed if PCR-based MS-HRM and BeadChip microarray technologies, which are standardized and cost-effective technologies for methylation changes screening, provide a sufficient level of analytical sensitivity for constitutional BRCA1 methylation detection in blood samples. The study included whole blood samples from 67 healthy women, 35 with previously confirmed and 32 with no detectable BRCA1 promoter methylation for which we performed both MS-HRM based BRCA1 gene methylation screening and genome wide methylation profiling with EPIC microarray. Our results shown, that low-level BRCA1 methylation can be effectively detected in DNA extracted from blood by PCR-based MS-HRM. At the same time, EPIC microarray does not provide conclusive results to unambiguously determine the presence of BRCA1 constitutional methylation in MS-HRM epimutation positive samples. The analytical sensitivity of MS-HRM is sufficient to detect low level BRCA1 constitutional epimutation in DNA extracted from blood and BeadChip technology-based microarrays appear not to provide that level of analytical sensitivity.
Subject(s)
Genes, BRCA1 , Labor, Obstetric , Female , Humans , Pregnancy , Research Design , Genetic Profile , Health Status , BRCA1 Protein/geneticsABSTRACT
INTRODUCTION: Heart failure is a complex clinical syndrome resulting from the unsuccessful compensation of symptoms of myocardial damage. Mitochondrial dysfunction is a process that occurs because of an attempt to adapt to the disruption of metabolic and energetic pathways occurring in the myocardium. This, in turn, leads to further dysfunction in cardiomyocyte processes. Currently, many therapeutic strategies have been implemented to improve mitochondrial function, but their effectiveness varies widely. AREAS COVERED: This review focuses on new models of therapeutic strategies targeting mitochondrial function in the treatment of heart failure. EXPERT OPINION: Therapeutic strategies targeting mitochondria appear to be a valuable option for treating heart failure. Currently, the greatest challenge is to develop new research models that could restore the disrupted metabolic processes in mitochondria as comprehensively as possible. Only the development of therapies that focus on improving as many dysregulated mitochondrial processes as possible in patients with heart failure will be able to bring the expected clinical improvement, along with inhibition of disease progression. Combined strategies involving the reduction of the effects of oxidative stress and mitochondrial dysfunction, appear to be a promising possibility for developing new therapies for a complex and multifactorial disease such as heart failure.
Subject(s)
Heart Failure , Mitochondria, Heart , Humans , Mitochondria, Heart/metabolism , Heart Failure/drug therapy , Myocardium , Myocytes, Cardiac/metabolism , Oxidative StressABSTRACT
INTRODUCTION/OBJECTIVES: Rheumatoid arthritis (RA) is a disease affecting around 1% of the population in developed countries and can be treated with leflunomide. The higher prevalence of RA among women and numerous previous studies suggested the crucial role of sex hormones. Cytochrome CYB5A regulates the synthesis of androgens. Therefore, the aim of this study was to determine the association between common CYB5A gene polymorphism and the response to leflunomide in women with RA. METHODS: This study included 111 patients. All of them received oral leflunomide monotherapy at a dose of 20 mg daily. Women were genotyped for the presence of CYB5A rs1790834 polymorphism and evaluated monthly for 6 months following the initiation of treatment. RESULTS: After 6 months of therapy, patients with the GG genotype had higher DAS28 values and less improvement in DAS28 compared to patients with the GA and AA genotypes (p = 0.04). No statistically significant differences were found in relation to other disease activity parameters. CONCLUSIONS: The results of the current study suggest a possible association of the CYB5A rs1790834 polymorphism with some disease activity parameters in RA patients treated with leflunomide during the initial therapy period. However, confirmation of the effect of this polymorphism on the efficacy of leflunomide treatment requires further studies. Key Points ⢠Leflunomide is the synthetic disease-modifying anti-rheumatic drug used in the therapy of rheumatoid arthritis. ⢠CYB5A rs1790834 gene polymorphism may influence the clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Humans , Female , Leflunomide/therapeutic use , Isoxazoles/therapeutic use , Isoxazoles/adverse effects , Treatment Outcome , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/chemically induced , Antirheumatic Agents/adverse effects , Polymorphism, Genetic , Cytochromes b5/geneticsABSTRACT
Understanding of the gut microbiome's role in human physiology developed rapidly in recent years. Moreover, any alteration of this microenvironment could lead to a pathophysiological reaction of numerous organs. It results from the bidirectional communication of the gastrointestinal tract with the central nervous system, called the gut-brain axis. The signals in the gut-brain axis are mediated by immunological, hormonal, and neural pathways. However, it is also influenced by microorganisms in the gut. The disturbances in the gut-brain axis are associated with gastrointestinal syndromes, but recently their role in the development of different types of pain was reported. The gut microbiome could be the factor in the central sensitization of chronic pain by regulating microglia, astrocytes, and immune cells. Dysbiosis could lead to incorrect immune responses, resulting in the development of inflammatory pain such as endometriosis. Furthermore, chronic visceral pain, associated with functional gastrointestinal disorders, could result from a disruption in the gut microenvironment. Any alteration in the gut-brain axis could also trigger migraine attacks by affecting cytokine expression. Understanding the gut microbiome's role in pain pathophysiology leads to the development of analgetic therapies targeting microorganisms. Probiotics, FODMAP diet, and fecal microbiota transplantation are reported to be beneficial in treating visceral pain.
Subject(s)
Chronic Pain , Gastrointestinal Microbiome , Microbiota , Probiotics , Visceral Pain , Female , Humans , Visceral Pain/pathology , Brain/pathology , Dysbiosis/pathology , Gastrointestinal Microbiome/physiologyABSTRACT
BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and is associated with a poor prognosis in patients presenting with recurrent or metastatic disease. The unfolded protein response (UPR) plays pivotal roles in tumor development and resistance to therapy, including RMS. METHODS: In this study, we used immunohistochemistry and a tissue microarray (TMA) on human RMS and normal skeletal muscle to evaluate the expression of key UPR proteins (GRP78/BiP, IRE1α and cytosolic/nuclear XBP1 (spliced XBP1-sXBP1)) in the four main RMS subtypes: alveolar (ARMS), embryonal (ERMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS. We also investigated the correlation of these proteins with the risk of RMS and several clinicopathological indices, such as lymph node involvement, distant metastasis, tumor stage and tumor scores. RESULTS: Our results revealed that the expression of BiP, sXBP1, and IRE1α, but not cytosolic XBP1, are significantly associated with RMS (BiP and sXBP1 p-value = 0.0001, IRE1 p-value = 0.001) in all of the studied types of RMS tumors (n = 192) compared to normal skeletal muscle tissues (n = 16). In addition, significant correlations of BiP with the lymph node score (p = 0.05), and of IRE1α (p value = 0.004), cytosolic XBP1 (p = 0.001) and sXBP1 (p value = 0.001) with the stage score were observed. At the subtype level, BiP and sXBP1 expression were significantly associated with all subtypes of RMS, whereas IRE1α was associated with ARMS, PRMS and ERMS, and cytosolic XBP1 expression was associated with ARMS and SRMS. Importantly, the expression levels of IRE1α and sXBP1 were more pronounced in ARMS than in any of the other subtypes. The results also showed correlations of BiP with the lymph node score in ARMS (p value = 0.05), and of sXBP1 with the tumor score in PRMS (p value = 0.002). CONCLUSIONS: In summary, this study demonstrates that the overall UPR is upregulated and, more specifically, that the IRE1/sXBP1 axis is active in RMS. The subtype and stage-specific dependency on the UPR machinery in RMS may open new avenues for the development of novel targeted therapeutic strategies and the identification of specific tumor markers in this rare but deadly childhood and young-adult disease.
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HLA matching, transplantation technique, or underlying disease greatly influences the probability of long-term transplantation success. It has been hypothesised that genetic variation affecting antigen presentation also contributes to the outcomes of both solid organ transplantation and allogeneic haematopoietic stem cell transplantation (AHSCT). Those genes, along with those responsible for innate and adaptive immunity, have become targets of investigation. In this review, we focus on the role of CTLA4 in the process of acute graft rejection and summarise the progress in our understanding of its role in predicting the outcome. We present the results of the latest studies investigating the link between CTLA4 gene variability and AHSCT, as well as organ transplantation outcomes. While some studies found a link between +49 A/G and -318 C/T and transplantation outcomes, comprehensive meta-analyses have failed to present any association. The most recent field reviews suggest that the -1772 T/C (rs733618) CC genotype is weakly associated with a lower risk of acute graft rejection, while +49 A/G might be clinically meaningful when investigated in the context of combinations with other polymorphisms. Studies verifying associations between 12 CTLA4 gene SNPs and AHSCT outcomes present inexplicit results. Some of the most commonly studied polymorphisms in this context include +49 A/G (rs231775) and CT60 A/G (rs3087243). The results signify that, in order to understand the role of CTLA4 and its gene polymorphisms in transplantology, further studies must be conducted.
Subject(s)
CTLA-4 Antigen/genetics , Genetic Predisposition to Disease , Hematopoietic Stem Cell Transplantation , Polymorphism, Genetic , Humans , Immunomodulation , Treatment OutcomeABSTRACT
Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.
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The COVID-19 pandemic is one of the greatest threats to human health in the 21st century with more than 257 million cases and over 5.17 million deaths reported worldwide (as of November 23, 2021. Various agents were initially proclaimed to be effective against SARS-CoV-2, the etiological agent of COVID-19. Hydroxychloroquine, lopinavir/ritonavir, and ribavirin are all examples of therapeutic agents, whose efficacy against COVID-19 was later disproved. Meanwhile, concentrated efforts of researchers and clinicians worldwide have led to the identification of novel therapeutic options to control the disease including PAXLOVID™ (PF-07321332). Although COVID-19 cases are currently treated using a comprehensive approach of anticoagulants, oxygen, and antibiotics, the novel Pfizer agent PAXLOVID™ (PF-07321332), an investigational COVID-19 oral antiviral candidate, significantly reduced hospitalization time and death rates, based on an interim analysis of the phase 2/3 EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomized, double-blind study of non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness. The scheduled interim analysis demonstrated an 89 % reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset (primary endpoint). However, there still exists a great need for the development of additional treatments, as the recommended therapeutic options are insufficient in many cases. Thus far, mRNA and vector vaccines appear to be the most effective modalities to control the pandemic. In the current review, we provide an update on the progress that has been made since April 2020 in clinical trials concerning the effectiveness of therapies available to combat COVID-19. We focus on currently recommended therapeutic agents, including steroids, various monoclonal antibodies, remdesivir, baricitinib, anticoagulants and PAXLOVID™ summarizing the latest original studies and meta-analyses. Moreover, we aim to discuss other currently and previously studied agents targeting COVID-19 that either show no or only limited therapeutic activity. The results of recent studies report that hydroxychloroquine and convalescent plasma demonstrate no efficacy against SARS-CoV-2 infection. Lastly, we summarize the studies on various drugs with incoherent or insufficient data concerning their effectiveness, such as amantadine, ivermectin, or niclosamide.
Subject(s)
COVID-19 , Pharmaceutical Preparations , Adult , Antiviral Agents/therapeutic use , COVID-19/therapy , Humans , Immunization, Passive , Lactams , Leucine , Nitriles , Pandemics , Proline , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome , COVID-19 SerotherapyABSTRACT
The statin drugs ('statins') potently inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by competitively blocking the active site of the enzyme. Statins decrease de novo cholesterol biosynthesis and thereby reduce plasma cholesterol levels. Statins exhibit "pleiotropic" properties that are independent of their lipid-lowering effects. For example, preclinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. Furthermore, statins show chemo-sensitizing effects by impairing Ras family GTPase signaling. However, whether statins have clinically meaningful anti-cancer effects remains an area of active investigation. Both preclinical and clinical studies on the potential mechanisms of action of statins in several cancers have been reviewed in the literature. Considering the contradictory data on their efficacy, we present an up-to-date summary of the pleiotropic effects of statins in cancer therapy and review their impact on different malignancies. We also discuss the synergistic anti-cancer effects of statins when combined with other more conventional anti-cancer drugs to highlight areas of potential therapeutic development.
Subject(s)
Antineoplastic Agents/pharmacology , Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Neoplasms/drug therapy , ras Proteins/antagonists & inhibitors , rho GTP-Binding Proteins/antagonists & inhibitors , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Molecular Structure , Neoplasms/metabolism , Neoplasms/pathology , Signal Transduction/drug effects , ras Proteins/metabolism , rho GTP-Binding Proteins/metabolismABSTRACT
Since the end of 2019, the whole world has been struggling with the pandemic of the new Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Available evidence suggests that pain is a common symptom during Coronavirus Disease 2019 (COVID-19). According to the World Health Organization, many patients suffer from muscle pain (myalgia) and/or joint pain (arthralgia), sore throat and headache. The exact mechanisms of headache and myalgia during viral infection are still unknown. Moreover, many patients with respiratory failure get admitted to the intensive care unit (ICU) for ventilatory support. Pain in ICU patients can be associated with viral disease itself (myalgia, arthralgia, peripheral neuropathies), may be caused by continuous pain and discomfort associated with ICU treatment, intermittent procedural pain and chronic pain present before admission to the ICU. Undertreatment of pain, especially when sedation and neuromuscular blocking agents are used, prone positioning during mechanical ventilation or extracorporeal membrane oxygenation (ECMO) may trigger delirium and cause peripheral neuropathies. This narrative review summarizes current knowledge regarding challenges associated with pain assessment and management in COVID-19 patients. A structured prospective evaluation should be undertaken to analyze the probability, severity, sources and adequate treatment of pain in patients with COVID-19 infection.
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In December 2019, a novel SARS-CoV-2 coronavirus emerged, causing an outbreak of life-threatening pneumonia in the Hubei province, China, and has now spread worldwide, causing a pandemic. The urgent need to control the disease, combined with the lack of specific and effective treatment modalities, call for the use of FDA-approved agents that have shown efficacy against similar pathogens. Chloroquine, remdesivir, lopinavir/ritonavir or ribavirin have all been successful in inhibiting SARS-CoV-2 in vitro. The initial results of a number of clinical trials involving various protocols of administration of chloroquine or hydroxychloroquine mostly point towards their beneficial effect. However, they may not be effective in cases with persistently high viremia, while results on ivermectin (another antiparasitic agent) are not yet available. Interestingly, azithromycin, a macrolide antibiotic in combination with hydroxychloroquine, might yield clinical benefit as an adjunctive. The results of clinical trials point to the potential clinical efficacy of antivirals, especially remdesivir (GS-5734), lopinavir/ritonavir, and favipiravir. Other therapeutic options that are being explored involve meplazumab, tocilizumab, and interferon type 1. We discuss a number of other drugs that are currently in clinical trials, whose results are not yet available, and in various instances we enrich such efficacy analysis by invoking historic data on the treatment of SARS, MERS, influenza, or in vitro studies. Meanwhile, scientists worldwide are seeking to discover novel drugs that take advantage of the molecular structure of the virus, its intracellular life cycle that probably elucidates unfolded-protein response, as well as its mechanism of surface binding and cell invasion, like angiotensin converting enzymes-, HR1, and metalloproteinase inhibitors.
Subject(s)
Antiviral Agents/administration & dosage , COVID-19 Drug Treatment , Drug Approval/methods , SARS-CoV-2/drug effects , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/metabolism , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/metabolism , Antimalarials/administration & dosage , Antimalarials/metabolism , Antiviral Agents/metabolism , COVID-19/metabolism , Clinical Trials as Topic/methods , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/metabolism , Drug Therapy, Combination , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/metabolism , SARS-CoV-2/metabolism , United States/epidemiologyABSTRACT
In December 2019, a novel coronavirus, SARS-CoV-2, appeared, causing a wide range of symptoms, mainly respiratory infection. In March 2020, the World Health Organization (WHO) declared Coronavirus Disease 2019 (COVID-19) a pandemic, therefore the efforts of scientists around the world are focused on finding the right treatment and vaccine for the novel disease. COVID-19 has spread rapidly over several months, affecting patients across all age groups and geographic areas. The disease has a diverse course; patients may range from asymptomatic to those with respiratory failure, complicated by acute respiratory distress syndrome (ARDS). One possible complication of pulmonary involvement in COVID-19 is pulmonary fibrosis, which leads to chronic breathing difficulties, long-term disability and affects patients' quality of life. There are no specific mechanisms that lead to this phenomenon in COVID-19, but some information arises from previous severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) epidemics. The aim of this narrative review is to present the possible causes and pathophysiology of pulmonary fibrosis associated with COVID-19 based on the mechanisms of the immune response, to suggest possible ways of prevention and treatment.
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INTRODUCTION: Methotrexate (MTX) is a folate antagonist and a first-line drug for the treatment of rheumatoid arthritis (RA). However, in up to 30% of cases, MTX monotherapy is insufficient, while a further 30% of patients suffer with severe adverse effects. Despite extensive clinical evidence, it is not currently possible to predict therapy outcomes and drug toxicity for MTX. Therefore, to establish biomarkers of toxicity and successful disease remission, pharmacogenomic approaches are rapidly becoming more popular. AREAS: This review summarizes recent pharmacogenomic studies evaluating MTX efficacy and toxicity. In recent years, multiple genetic alterations associated with MTX therapy outcomes and toxicity have been identified in genes associated with MTX metabolism and effector pathways. However, the data are inconsistent and require further validation. EXPERT OPINION: To date, several single nucleotide polymorphisms (SNPs) have been linked with MTX efficacy. However, thanks to equivocal data, pharmacogenomic testing in routine clinical practice remains a distant prospect. Genome-wide association studies (GWAS) could facilitate the evaluation of current SNPs, and support searches for new genetic variations Once achieved, only then will it be possible to introduce more personalized and individualized therapies for RA patients.
Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Methotrexate/administration & dosage , Animals , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/genetics , Biomarkers/metabolism , Genome-Wide Association Study , Humans , Methotrexate/adverse effects , Pharmacogenetics , Polymorphism, Single Nucleotide , Precision Medicine , Treatment OutcomeABSTRACT
Regenerative medicine based on transplants obtained from donors or foetal and new-born mesenchymal stem cells, encounter important obstacles such as limited availability of organs, ethical issues and immune rejection. The growing demand for therapeutic methods for patients being treated after serious accidents, severe organ dysfunction and an increasing number of cancer surgeries, exceeds the possibilities of the therapies that are currently available. Reprogramming and transdifferentiation provide powerful bioengineering tools. Both procedures are based on the somatic differentiated cells, which are easily and unlimitedly available, like for example: fibroblasts. During the reprogramming procedure mature cells are converted into pluripotent cells - which are capable to differentiate into almost any kind of desired cells. Transdifferentiation directly converts differentiated cells of one type into another differentiated cells type. Both procedures allow to obtained patient's dedicated cells for therapeutic purpose in regenerative medicine. In combination with biomaterials, it is possible to obtain even whole anatomical structures. Those patient's dedicated structures may serve for them upon serious accidents with massive tissue damage but also upon cancer surgeries as a replacement of damaged organ. Detailed information about reprogramming and transdifferentiation procedures as well as the current state of the art are presented in our review.
Subject(s)
Cell Transdifferentiation , Cellular Reprogramming , Regenerative Medicine , Animals , HumansABSTRACT
Betulin (B) and Betulinic acid (BA) are natural pentacyclic lupane-structure triterpenoids which possess a wide range of pharmacological activities. Recent evidence indicates that B and BA have several properties useful for the treatment of metabolic disorders, infectious diseases, cardiovascular disorders, and neurological disorders. In the current review, we discuss B and BA structures and derivatives and then comprehensively explain their pharmacological effects in relation to various diseases. We also explain antiviral, antibacterial and anti-cancer effects of B and BA. Finally, we discuss the delivery methods, in which these compounds most effectively target different systems.
Subject(s)
Triterpenes/chemistry , Anti-Bacterial Agents , Antiviral AgentsABSTRACT
Diabetes mellitus (DM) is a heterogeneous group of disorders whose common trait is chronic hyperglycemia. Gestational diabetes mellitus (GDM) is one of the subtypes of DM that manifests during pregnancy. It is believed that 2%-5% of pregnancies worldwide are complicated with GDM, with the prevalence having significantly increased over the last decade. While the pathogenesis of the disease remains largely unknown, GDM is believed to be a result of interactions between genetic, epigenetic, and environmental factors. Linkage and association studies, including those that are genome-wide, have allowed us to identify complex genetic and epigenetic mechanisms that lead to the development of GDM. Multiple common variants in candidate genes such as potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11), glucokinase (GCK), or hepatocyte nuclear factor 1α (HNF1A) have been found to increase the disease risk. In this review, we provide a detailed overview of the current knowledge concerning the influence of genetics and epigenetics on the development of GDM.
Subject(s)
Diabetes, Gestational/pathology , Epigenesis, Genetic , Genetic Linkage , Genetic Predisposition to Disease , Diabetes, Gestational/genetics , Female , Humans , PregnancyABSTRACT
Introduction: Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by chronic inflammation of the joints and affects 1% of the population. Polymorphisms of genes that encode proteins that primarily participate in inflammation may influence RA occurrence or become useful biomarkers for certain types of anti-rheumatic treatment.Areas covered: The authors summarize the recent progress in our understanding of the genetics of RA. In the last few years, multiple variants of genes that are associated with RA risk have been identified. The development of new technologies and the detection of new potential therapeutic targets that contribute to novel drug discovery are also described.Expert opinion: There is still the need to search for new genes which may be a potential target for RA therapy. The challenge is to develop appropriate strategies for achieving insight into the molecular pathways involved in RA pathogenesis. Understanding the genetics, immunogenetics, epigenetics and immunology of RA could help to identify new targets for RA therapy. The development of new technologies has enabled the detection of a number of new genes, particularly genes associated with proinflammatory cytokines and chemokines, B- and T-cell activation pathways, signal transducers and transcriptional activators, which might be potential therapeutic targets in RA.
Subject(s)
Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/genetics , Drug Discovery , Genetic Predisposition to Disease , Antirheumatic Agents/therapeutic use , Humans , Polymorphism, Single NucleotideABSTRACT
Aspirin (acetylsalicylic acid), the oldest synthetic drug, was originally used as an anti-inflammatory medication. Being an irreversible inhibitor of COX (prostaglandin-endoperoxide synthase) enzymes that produce precursors for prostaglandins and thromboxanes, it has gradually found several other applications. Sometimes these applications are unrelated to its original purpose for example its use as an anticoagulant. Applications such as these have opened opportunities for new treatments. In this case, it has been tested in patients with cardiovascular disease to reduce the risk of myocardial infarct. Its function as an anticoagulant has also been explored in the prophylaxis and treatment of pre-eclampsia, where due to its anti-inflammatory properties, aspirin intake may be used to reduce the risk of colorectal cancer. It is important to always consider both the risks and benefits of aspirin's application. This is especially important for proposed use in the prevention and treatment of neurologic ailments like Alzheimer's disease, or in the prophylaxis of myocardial infarct. In such cases, the decision if aspirin should be applied, and at what dose may be guided by specific molecular markers. In this revived paper, the pleiotropic application of aspirin is summarized.