The impact of COVID-19 and other factors on the usage status of the biologic drug therapies for rheumatoid arthritis: A study from Vietnam.

OBJECTIVES: To describe the status of using biological Disease Modifying Anti Rheumatic Drugs (bDMARDs) to treat rheumatoid arthritis (RA) and related factors. In addition, the study determined the impact of COVID-19 on the usage of bDMARDs. METHODS: This is a cross-sectional study and included 219 RA patients over 18 years old. The Kaplan-Meier method and the log-rank test (p<0.05) were used to estimate the retention time and compare between different times. Cox regression analysis was used to determine the factors affecting the retention time of biological drugs (p<0.05). RESULTS: Out of 1967 courses of treatment, there were 149 (7.6%) drug discontinuations, 760 (38.6%) doses extensions and 64 (3.3%) drug switch. Moderate disease level and choosing tumor necrosis factor (TNF) inhibitors initially were associated with retention time of COVID-19. Drug discontinuations and dose extensions increased after COVID-19 emergence. The retention time during COVID-19 was significantly different from that of pre-COVID-19. Gender, type of first-used bDMARD, conventional synthetic DMARDs (csDMARDs) and corticoid usage status, disease activity levels were associated with retention time. CONCLUSION: The presence of COVID-19 has a significant effect on usage status of the biologic drug. Further longitudinal studies are needed to clarify the relationship between COVID-19 and drug usage as well as related factors.

RNA therapeutics for regenerative medicine.

It is estimated that millions of people around the world experience various types of tissue injuries every year. Regenerative medicine was born and developed for understanding and application with the aim of replacing affected organs or some cells. The research, manufacture, production, and distribution of RNA in cells have acted as a basic foundation for the development and testing of therapies and treatments that are widely applied in different fields of medicine. Vaccines against COVID-19 are considered one of the brilliant and outstanding successes of RNA therapeutics research. With the characteristics of bio-derived RNA therapeutics, the mechanism of rapid implementation, safe production, and flexibility to create proteins depending on actual requirements. Based on the advantages above in this review, we discuss RNA therapeutics for regenerative medicine, and the types of RNA therapies currently being used for regenerative medicine. The relationship between disease and regenerative medicine is currently being studied or tested in RNA therapeutics. We have also covered the mechanisms of action of RNA therapy for regenerative medicine and some of the limitations in our current understanding of the effects of RNA therapy in this area. Additionally, we have also covered developing RNA therapeutics for regenerative medicine, focusing on RNA therapeutics for regenerative medicine. As a final point, we discuss potential applications for therapeutics for regenerative medicine in the future, as well as their mechanisms.

RNA therapeutics for diarrhea.

Diarrhea is caused by a variety of bacterial and viral agents, inflammatory conditions, medications, and hereditary conditions. Secretory diarrhea involves several ion and solute transporters, activation of the cyclic nucleotide and Ca2+ signaling pathways, as well as intestinal epithelial secretion. In many cases of secretory diarrhea, activation of Cl- channels, such as the cystic transmembrane conduction regulator and the Ca2+stimulated Cl- channel fibrosis, promote secretion while concurrently inhibiting Na+ transport expressing fluid absorption. Current diarrhea therapies include rehydration and electrolyte replacement via oral rehydration solutions, as well as medications that target peristalsis or fluid secretion. The rising understanding of RNA function and its importance in illness has encouraged the use of various RNAs to operate selectively on "untreatable" proteins, transcripts, and genes. Some RNA-based medications have received clinical approval, while others are currently in research or preclinical studies. Despite major obstacles in the development of RNA-based therapies, many approaches have been investigated to improve intracellular RNA trafficking and metabolic stability.

Biosafety and regulatory issues of RNA therapeutics.

RNA therapy has recently emerged as a therapy targeting specific genes or proteins. With its outstanding advantages, this therapy has opened promising doors for treating and preventing diseases. The great application potential has driven the need for a comprehensive understanding of these therapies, particularly on biosafety and regulatory issues. This chapter began by discussing the risks to RNA therapy, such as off-target effects, immunogenicity and immune responses, and long-term effects. Since then, this therapy's intricate landscape of biosafety issues has been elucidated. Common biosecurity measures applied around the world have also been reviewed. In addition, this chapter emphasized the importance of regulations and laws in applying RNA therapy to prevent and treat human and animal diseases. At the same time, the current legal regulations in the world for RNA therapies have also been thoroughly discussed. To sum up, this chapter has provided a comprehensive perspective on biosafety and regulatory issues for developing RNA therapies. Understanding the biosafety and regulatory issues in RNA therapy can help researchers use this promising new technology safely and effectively in the future.

An introduction to RNA therapeutics and their potentials.

RNA therapeutics is a biological term regarding the usage of RNA-based molecules for medical purposes. Thanks to the success of mRNA-vaccine production against COVID-19, RNA therapeutics has gained more and more attention and investigation from worldwide scientists. It is considered as one of the promising alternatives for conventional drugs. In this first chapter, we presented an overview of the history and perspectives of RNA therapeutics' development. This chapter also explained the underlying mechanisms of different RNA-based molecules, including antisense oligonucleotide, interfering RNA (iRNA), aptamer, and mRNA, from degrading mRNA to inactivating targeted protein. Although there are many advantages of RNA therapeutics, its challenges in designing RNA chemical structure and the delivery vehicle need to be discussed. We described advanced technologies in the development of drug delivery systems that are positively correlated to the efficacy of the drug. Our aim is to provide a general background of RNA therapeutics to the audience before introducing plenty of more detailed parts, including clinical applications in certain diseases in the following chapters of the "RNA therapeutics" book.

RNA therapeutics for metabolic disorders.

The prevalence of metabolic disorders is increasing exponentially and has recently reached epidemic levels. Over the decades, a large number of therapeutic options have been proposed to manage these diseases but still show several limitations. In this circumstance, RNA therapeutics have rapidly emerged as a new hope for patients with metabolic diseases. 57 years have elapsed from the discovery of mRNA, a large number of RNA-based drug candidates have been evaluated for their therapeutic effectiveness and clinical safety under clinical studies. To date, there are seven RNA drugs for treating metabolic disorders receiving official approval and entering the global market. Their targets include hereditary transthyretin-mediated amyloidosis (hATTR), familial chylomicronemia syndrome, acute hepatic porphyria, primary hyperoxaluria type 1 and hypercholesterolemia, which are all related to liver proteins. All of these seven RNA drugs are antisense oligonucleotides (ASO) and small interfering RNA (siRNA). These two types of treatment are both based on oligonucleotides complementary to target RNA through Watson-Crick base-pairing, but their mechanisms of action include different nucleases. Such treatments show greatest potential among all types of RNA therapeutics due to consecutive achievements in chemical modifications. Another method, mRNA therapeutics also promise a brighter future for patients with a handful of drug candidates currently under development.

Computational tools supporting known miRNA identification.

The study of small RNAs is a field that is expanding quickly. Other functional short RNA molecules other than microRNAs, and gene expression regulators, have been found in animals and plants. MicroRNAs play a significant role in host-microbe interactions, and parasite microRNAs may affect the host's innate immunity. Furthermore, short RNAs are intriguing non-invasive biomarker possibilities because they can be found in physiological fluids. These trends suggest that for many researchers, quick and simple techniques for expression profiling and subsequent downstream analysis of miRNA-seq data are crucial. We selected sRNAtoolbox to make integrated sRNA research easier. Each tool can be used separately or to explore and analyze sRNAbench results in further depth. A special focus was placed on the tools' usability. We review available miRNA research tools to have an overview of the evaluation of the tools. Mainly we evaluate the tool sRNAtoolbox.

RNA therapeutics for respiratory diseases.

It has become increasingly common to utilize RNA treatment to treat respiratory illnesses. Experimental research on both people and animals has advanced quickly since the turn of the twenty-first century in an effort to discover a treatment for respiratory ailments that could not be accomplished with earlier techniques, specifically in treating prevalent respiratory diseases such as lung cancer, chronic obstructive pulmonary disease (COPD), respiratory infections caused by viruses, and asthma. This chapter has provided a comprehensive overview of the scientific evidence in applying RNA therapy to treat respiratory diseases. The chapter describes the development of this therapy for respiratory diseases. At the same time, the types of RNA therapy for respiratory diseases have been highlighted. In addition, the mechanism of this therapy for respiratory diseases has also been covered. These insights are indispensable if this therapy is to be developed widely.

RNA therapeutics for treatment of diabetes.

Diabetes is an ongoing global problem as it affects health of more than 537 million people around the world. Diabetes leaves many serious complications that affect patients and can cause death if not detected and treated promptly. Some of the complications of diabetes include impaired vascular system, increased risk of stroke, neurological diseases that cause pain and numbness, diseases related to the retina leading to blindness, and other complications affecting kidneys, heart failure, muscle weakness, muscle atrophy. All complications of diabetes seriously affect the health of patients. Recently, gene therapy has emerged as a viable treatment strategy for various diseases. DNA and RNA are among the target molecules that can change the structure and function of proteins and are effective methods of treating diseases, especially genetically inherited diseases. RNA therapeutics has attracted deep interest as it has been approved for application in the treatment of functional system disorders such as spinal muscular atrophy, and muscular dystrophy. In this review, we cover the types of RNA therapies considered for treatment of diabetes. In particular, we delve into the mechanism of action of RNA therapies for diabetes, and studies involving testing of these RNA therapies. Finally, we have highlighted the limitations of the current understanding in the mechanism of action of RNA therapies.

Application of data science and bioinformatics in RNA therapeutics.

Nowadays, information technology (IT) has been holding a significant role in daily life worldwide. The trajectory of data science and bioinformatics promises pioneering personalized therapies, reshaping medical landscapes and patient care. For RNA therapy to reach more patients, a comprehensive understanding of the application of data science and bioinformatics to this therapy is essential. Thus, this chapter has summarized the application of data science and bioinformatics in RNA therapeutics. Data science applications in RNA therapy, such as data integration and analytics, machine learning, and drug development, have been discussed. In addition, aspects of bioinformatics such as RNA design and evaluation, drug delivery system simulation, and databases for personalized medicine have also been covered in this chapter. These insights have shed light on existing evidence and opened potential future directions. From there, scientists can elevate RNA-based therapeutics into an era of tailored treatments and revolutionary healthcare.

RNA therapeutics for disorders of excretory system.

The excretory system is responsible for removing wastes from the human body, which plays a crucial role in our lives. Current treatments for diseases related to this system have shown several limitations; therefore, there is a rising need for novel methods. In this circumstance, RNA-based therapeutics have rapidly emerged as new and promising candidates. In fact, to date, a handful of potential drugs have passed the development step and entered the clinical pipeline. Among them, one drug received FDA approval to enter the global market, which is Oxlumo (Lumasiran) for the treatment of primary hyperoxaluria type 1. For other excretory diseases, such as paroxysmal nocturnal hemoglobinuria, urothelial cancer or renal cancer, RNA-based candidates are also being tested under clinical trials. Currently, the most potential types of RNA therapeutics to treat disorders of the excretory system are those based on small interfering RNA (siRNA), antisense oligonucleotides (ASO) and messenger RNA (mRNA), Among them, siRNA therapeutics seem to be the most promising, including Oxlumo and two other developing drug candidates. This chapter will provide a general overview on the application of RNA therapeutics in disorders of the excretory system.

RNA therapeutics: Molecular mechanisms, and potential clinical translations.

RNA therapies involve the utilization of natural and artificial RNA molecules to control the expression and function of cellular genes and proteins. Initializing from 1990s, RNA therapies now show the rapid growth in the development and application of RNA therapeutics for treating various conditions, especially for undruggable diseases. The outstanding success of recent mRNA vaccines against COVID-19 infection again highlighted the important role of RNA therapies in future medicine. In this review, we will first briefly provide the crucial investigations on RNA therapy, from the first pieces of discovery on RNA molecules to clinical applications of RNA therapeutics. We will then classify the mechanisms of RNA therapeutics from various classes in the treatment of diseases. To emphasize the huge potential of RNA therapies, we also provide the key RNA products that have been on clinical trials or already FDA-approved. With comprehensive knowledge on RNA biology, and the advances in analysis, technology and computer-aid science, RNA therapies can bring a promise to be more expanding to the market in the future.

RNA therapeutics for the treatment of blood disorders.

Blood disorders are defined as diseases related to the structure, function, and formation of blood cells. These diseases lead to increased years of life loss, reduced quality of life, and increased financial burden for social security systems around the world. Common blood disorder treatments such as using chemical drugs, organ transplants, or stem cell therapy have not yet approached the best goals, and treatment costs are also very high. RNA with a research history dating back several decades has emerged as a potential method to treat hematological diseases. A number of clinical trials have been conducted to pave the way for the use of RNA molecules to cure blood disorders. This novel approach takes advantage of regulatory mechanisms and the versatility of RNA-based oligonucleotides to target genes and cellular pathways involved in the pathogenesis of specific diseases. Despite positive results, currently, there is no RNA drug to treat blood-related diseases approved or marketed. Before the clinical adoption of RNA-based therapies, challenges such as safe delivery of RNA molecules to the target site and off-target effects of injected RNA in the body need to be addressed. In brief, RNA-based therapies open novel avenues for the treatment of hematological diseases, and clinical trials for approval and practical use of RNA-targeted are crucial.

Evaluation of the safety and immune stimulatory effects of multi-strain Lab Mix product on laboratory animals.

Background & aims: Probiotics are alive and beneficial bacteria used as food complements with sufficient amounts to improve and balance the intestinal flora in the human gastrointestinal tract and inhibit harmful microorganisms. In this study, we conducted experiments to evaluate he safety and the effect of one of our probiotics on selected biochemical parameters in animal models. Methods: LabMix is a probiotic product containing three bacterial strains, including Lactobacillus acidophilus LA 304.17, Lactobacillus casei LC 304.08, and Bifidobacterium bifidum BF 304.98, with a density of 9 × 109 CFU/g and being mixed with suitable excipients. In this study, we conducted experiments to evaluate LabMix's acute ttoxicity in mice as well as subchronic toxicity in rats. Results: The LD50 dose in mice of this product could not be determined since no death or disorder was recorded. In rats receiving LabMix with doses of 2.52 × 109 CFU/kg and 12.6 × 109 CFU/kg continuously for 28 days, this product caused no significant changes in the amount of red and white blood cells and platelets. Similarly, no significant changes were recorded in serum concentrations of hemoglobin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose, protein, cholesterol, bilirubin, and creatinine. Besides, LabMix products also did not cause any changes in the histology of the liver, kidney, and spleen in rats. Moreover, LabMix was well tolerated without affecting the normal growth and feeding of rats. Furthermore, LabMix also decreased serum cytokines and increased serum and gut mucosal IgA antibodies. Conclusions: LabMix product is possibly considered safe for human., and this sproduct reduced the release of pro-inflammatory cytokines (IL-6 and TNF-α), but increased IgA levels. However, it is necessary to further evaluate the product's effectiveness in the preclinical phase as well as in further phases before mass production and commercialization.

Phage for cancer therapy.

Cancer is currently a global health challenge, characterized by dysfunction of organs due to the uncontrolled growth of cells exponentially. The therapies used to treat cancer in patients so far are widely used. However, there are also some problems, such as the high cost of surgery and chemotherapy. Thus, there are many barriers to care for patients with cancer, especially in low and middle-income countries. In addition, the many risks and adverse effects of radiation treatment. Therefore, to reduce mortality in patients with the disease, we need a newer therapy with more targeted treatment, fewer side effects, and cheaper cost. The application of bacteria in cancer treatment was first developed in 1983. Currently, this therapy is attracting the attention of scientists due to its great potential in cancer treatment. This chapter discusses the successful research on the bacteriophage for cancer, the mechanism and its potential. In addition, some types of bacteria that are most important for cancer treatment and limitations on the widespread application of this therapy were also mentioned. Reviewing all the researches on bacteriotherapy in cancer are essential to increase the knowledge in this area and make this therapy more optimal in the future.

Phage for regenerative medicine and cosmetics.

Phage or bacteriophage is a specific virus with the ability to defeat bacteria. Because of the rising prevalence of antimicrobial-resistant bacteria, the bacteriophage is now receiving interest again, with it application in skin infection or acne treatment. Moreover, bacteriophages also express their efficacy in wound healing or skin regeneration. Thanks to the development of bioengineering technology, phage display, which is a technique using bacteriophage as a tool, has recently been applied in many biotechnological and medical fields, especially in regenerative medicines. Bacteriophages can be used as nanomaterials, delivery vectors, growth factor alternatives, or in several bacteriophage display-derived therapeutics and stem cell technology. Although bacteriophage is no doubt to be a potential and effective alternative in modern medicine, there are still controversial evidence about the antibacterial efficacy as well as the affinity to expected targets of bacteriophage. Future mission is to optimize the specificity, stability, affinity and biodistribution of phage-derived substances. In this chapter, we focused on introducing several mechanisms and applications of bacteriophage and analyzing its future potential in regenerative medicines as well as cosmetics via previous research's results.

CRISPR-dCas9 system for epigenetic editing towards therapeutic applications.

In the past few decades, epigenetics has emerged as an important area of study to enable a better understanding of gene expression and its regulation. Due to epigenetics, stable phenotypic changes have been possible without alterations in DNA sequences. Epigenetic changes may occur due to DNA methylation, acetylation, phosphorylation and other such mechanisms which alter the level of gene expression without making any difference to DNA sequences. In this chapter, CRISPR-dCas9 used to bring about epigenome modifications for regulating gene expression towards a therapeutic approaches for treating human diseases have been discussed.

Epigenetics in cancer development, diagnosis and therapy.

Cancer is a dangerous disease and one of the leading causes of death in the world. In 2020, there were nearly 10 million cancer deaths and approximately 20 million new cases. New cases and deaths from cancer are expected to increase further in the coming years. To have a deeper insight into the mechanism of carcinogenesis, epigenetics studies have been published and received much attention from scientists, doctors, and patients. Among alterations in epigenetics, DNA methylation and histone modification are studied by many scientists. They have been reported to be a major contributor in tumor formation and are involved in metastasis. From the understanding of DNA methylation and histone modification, effective, accurate and cost-effective methods for diagnosis and screening of cancer patients have been introduced. Furthermore, therapeutic approaches and drugs targeting altered epigenetics have also been clinically studied and have shown positive results in combating tumor progression. Several cancer drugs that rely on DNA methylation inactivation or histone modification have been approved by the FDA for the treatment of cancer patients. In summary, epigenetics changes such as DNA methylation or histone modification are take part in tumor growth, and they also have great prospect to study diagnostic and therapeutic methods of this dangerous disease.

Histone modifications in fat metabolism and obesity.

The World Health Organization (WHO) has identified the obesity epidemic as one of the leading causes of overall morbidity and mortality. Obesity affects individual health, and quality of life and has negative long-term economic implications on society and the entire country. In recent years, studies on histone modifications in fat metabolism and obesity have received great attention. Processes such as methylation, histone modification, chromatin remodeling, and microRNA expression are mechanisms in epigenetic regulation. These processes play a particularly important role in cell development and differentiation through gene regulation. In this chapter, we discuss the types of histone modifications in adipose tissue under different conditions, the role of histone modifications in adipose tissue development, and the relationship between histone modifications and biosynthesis in the body. In addition, the chapter provides detailed information on histone modifications in obesity, the relationship between histone modifications and food consumption status, and the role of histone modifications in overweight and obesity.

Role of DNA methylation in diabetes and obesity.

Due to the fact that the upward trend of several metabolic disorders such as diabetes and obesity, in individuals especially monozygotic twins, who are under the same effects from the environment, are not similar, the role of epigenetic elements like DNA methylation needs taking into account. In this chapter, emerging scientific evidence supporting the strong relationship between changes in DNA methylation and those diseases' development was summarized. Changing in the expression level of diabetes/obesity-related genes through being silenced by methylation can be the underlying mechanism of this phenomenon. Genes with abnormal methylation status are potential biomarkers for early prediction and diagnosis. Moreover, methylation-based molecular targets should be investigated as a new treatment for both T2D and obesity.