Treatment Of Human Diseases Research Articles

Prevalence, antibiogram and molecular characterization of Listeria monocytogenes from ruminants and humans in New Valley and Beheira Governorates, Egypt

BackgroundListeriosis is a global health threat to both animals and humans, especially in developing countries. This study was designed to isolate Listeria monocytogenes from faeces; environmental samples; and cow, sheep and goat milk, as well as human stool, to study its molecular characteristics and antibiotic sensitivity in the New Valley and Beheira Governorates, Egypt. The isolation and identification of L. monocytogenes were carried out using traditional culture and biochemical methods, followed by antibiography, genus confirmation of some isolates and detection and sequencing of InlB genes via PCR.ResultsOut of 2097 examined samples, the prevalence of L. monocytogenes was 13.4% in animals; the prevalence was 9.2%, 2.4%, 25.4%, 4%, 42.4%, and 6.4% in cattle faeces, cattle milk, sheep faeces, sheep milk, goat faeces, and goat milk, respectively. However, the prevalence of L. monocytogenes was 8.3% in human samples. Both animal and human isolates showed 100% resistance to trimethoprim-sulfamethoxazole, and the isolates showed the highest sensitivity to flumequine (100%), amikacin (99.2%), gentamicin (97.6%), and levofloxacin (94.6%). Multidrug resistance (MDR) was detected in 86.9% of the tested isolates. The 16 S rRNA and inlB genes were detected in 100% of the randomly selected L. monocytogenes isolates. Phylogenetic analysis of three isolates based on the inlB gene showed 100% identity between faecal, milk and human stool isolates.ConclusionsFaeces and milk are major sources of listeriosis, and the high degree of genetic similarity between animal and human isolates suggests the possibility of zoonotic circulation. The high prevalence of MDR L. monocytogenes in both animal and human samples could negatively impact the success of prevention and treatments for animal and human diseases, thereby imposing serious risks to public health.

A heterogeneous information network learning model with neighborhood-level structural representation for predicting lncRNA-miRNA interactions

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are closely related to the treatment of human diseases. Traditional biological experiments often require time-consuming and labor-intensive in their search for mechanisms of disease. Computational methods are regarded as an effective way to predict unknown lncRNA-miRNA interactions (LMIs). However, most of them complete their tasks by mainly focusing on a single lncRNA-miRNA network without considering the complex mechanism between biomolecular in life activities, which are believed to be useful for improving the accuracy of LMI prediction. To address this, a heterogeneous information network (HIN) learning model with neighborhood-level structural representation, called HINLMI, to precisely identify LMIs. In particular, HINLMI first constructs a HIN by integrating nine interactions of five biomolecules. After that, different representation learning strategies are applied to learn the biological and network representations of lncRNAs and miRNAs in the HIN from different perspectives. Finally, HINLMI incorporates the XGBoost classifier to predict unknown LMIs using final embeddings of lncRNAs and miRNAs. Experimental results show that HINLMI yields a best performance on the real dataset when compared with state-of-the-art computational models. Moreover, several analysis experiments indicate that the simultaneous consideration of biological knowledge and network topology of lncRNAs and miRNAs allows HINLMI to accurately predict LMIs from a more comprehensive perspective. The promising performance of HINLMI also reveals that the utilization of rich heterogeneous information can provide an alternative insight for HINLMI to identify novel interactions between lncRNAs and miRNAs.

The Role of Short Chain Fatty Acids in Inflammation and Body Health.

Short chain fatty acids (SCFAs), mainly including acetate, propionate and butyrate, are produced by intestinal bacteria during the fermentation of partially digested and indigestible polysaccharides. SCFAs play an important role in regulating intestinal energy metabolism and maintaining the homeostasis of the intestinal environment and also play an important regulatory role in organs and tissues outside the gut. In recent years, many studies have shown that SCFAs can regulate inflammation and affect host health, and two main signaling mechanisms have also been identified: the activation of G-protein coupled receptors (GPCRs) and inhibition of histone deacetylase (HDAC). In addition, a growing body of evidence highlights the importance of every SCFA in influencing health maintenance and disease development. In this review, we summarized the recent advances concerning the biological properties of SCFAs and their signaling pathways in inflammation and body health. Hopefully, it can provide a systematic theoretical basis for the nutritional prevention and treatment of human diseases.

Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists

BackgroundMas-related G-protein coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell-mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. ObjectiveWe identified and characterized novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease. MethodsAntagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell-derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-/-) knockout (KO) and Mrgprb2em(MRGPRX2) transgenic human MRGPRX2 knock-in (KI) mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. ResultsMRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested, in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 KI mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. ConclusionMRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.

Chiral Separation- Its Significance in the Pharmacological Treatment of Human Diseases

Chirality plays a pivotal role in the pharmacological activity of many chemical compounds, as the spatial arrangement of enantiomers can significantly influence their biological effects. Separation of chiral drugs is of great importance in the pharmacological treatment of human diseases because it distinguishes the pharmacological active enantiomer of a chiral drug from the other enantiomer that has low or inactive pharmacological activity or undesirable toxic effects. The availability of novel chiral stationary phases makes the separation of enantiomers effective and rapid. This review presents (i) different chiral stationary phases encountered in chiral chromatography and their various interaction mechanisms with chiral drugs, (ii) types of mobile phases involved in the chiral separation, (iii) various analytic techniques utilized and different methods in chiral separation, (iv) some examples of chiral drugs, (v) factors that affect chiral separation and (vi) significance of chiral separation in the treatment of human diseases.

Future Perspectives of Wharton's Jelly Mesenchymal Stem Cells and their Soluble Factors in Radioprotection.

Acute radiation syndrome (ARS) is also known as triple syndrome, which develops after whole-body radiation exposure. During unforeseen exposures, these syndromes are set in depending on the dose of radiation. Cell-based therapy, especially using stem cells and their soluble factors, is gaining wide attention in the field of regenerative medicine to treat various diseases, including degenerative diseases. Stem cells attract prime attention because of their profound inherent tissue repair capability and regeneration potential. Further, stem cell therapy can be one of the promising strategies for the amelioration of ARS because of its ability to lodge in damaged tissue and release regenerative cytokines by sensing the local injury. In this regard, human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs) have gained substantial attention for their applications in the treatment of various human diseases due to several advantages offered by them. This article is intended to provide future perspective on the use of WJ-MSCs for the management of accidental radiation injury in pre-clinical models, and finally, their utility in regeneration of damaged tissues and organs.

Conotoxins Targeting Voltage-Gated Sodium Ion Channels.

Voltage-gated sodium (NaV) channels are intimately involved in the generation and transmission of action potentials, and dysfunction of these channels may contribute to nervous system diseases, such as epilepsy, neuropathic pain, psychosis, autism, and cardiac arrhythmia. Many venom peptides selectively act on NaV channels. These include conotoxins, which are neurotoxins secreted by cone snails for prey capture or self-defense but which are also valuable pharmacological tools for the identification and/or treatment of human diseases. Typically, conotoxins contain two or three disulfide bonds, and these internal crossbraces contribute to conotoxins having compact, well defined structures and high stability. Of the conotoxins containing three disulfide bonds, some selectively target mammalian NaV channels and can block, stimulate, or modulate these channels. Such conotoxins have great potential to serve as pharmacological tools for studying the functions and characteristics of NaV channels or as drug leads for neurologic diseases related to NaV channels. Accordingly, discovering or designing conotoxins targeting NaV channels with high potency and selectivity is important. The amino acid sequences, disulfide bond connectivity, and three-dimensional structures are key factors that affect the biological activity of conotoxins, and targeted synthetic modifications of conotoxins can greatly improve their activity and selectivity. This review examines NaV channel-targeted conotoxins, focusing on their structures, activities, and designed modifications, with a view toward expanding their applications. SIGNIFICANCE STATEMENT: NaV channels are crucial in various neurologic diseases. Some conotoxins selectively target NaV channels, causing either blockade or activation, thus enabling their use as pharmacological tools for studying the channels' characteristics and functions. Conotoxins also have promising potential to be developed as drug leads. The disulfide bonds in these peptides are important for stabilizing their structures, thus leading to enhanced specificity and potency. Together, conotoxins targeting NaV channels have both immediate research value and promising future application prospects.

Toxicity Study of Sulfonamides Antibiotics

Antibiotics refer to organic substances produced by plants, animals, microorganisms and other organisms in the course of their life activities or obtained by other methods, which can selectively inhibit or affect other organisms at low concentrations. According to the chemical structure, sulfonamides (SAs), tetracycline, etc. can be divided into sulfonamides, and veterinary antibiotics, agricultural antibiotics, medical antibiotics, etc. can be divided into sulfonamides according to the source. Antibiotics can inhibit cell growth and reproduction, and have been continuously synthesized since the advent of penicillin in 1929. At present, antibiotics have become one of the most widely used and used drugs in the world, not only for the prevention and treatment of human and animal diseases, but also as animal feed.

Mechanisms of host adaptation by bacterial pathogens.

The emergence of new infectious diseases poses a major threat to humans, animals, and broader ecosystems. Defining factors that govern the ability of pathogens to adapt to new host species is therefore a crucial research imperative. Pathogenic bacteria are of particular concern, given dwindling treatment options amid the continued expansion of antimicrobial resistance. In this review, we summarize recent advancements in the understanding of bacterial host species adaptation, with an emphasis on pathogens of humans and related mammals. We focus particularly on molecular mechanisms underlying key steps of bacterial host adaptation including colonization, nutrient acquisition, and immune evasion, as well as suggest key areas for future investigation. By developing a greater understanding of the mechanisms of host adaptation in pathogenic bacteria, we may uncover new strategies to target these microbes for the treatment and prevention of infectious diseases in humans, animals, and the broader environment.

Plant-Derived Compounds with Therapeutic Potential for the Treatment of Human Coronavirus Diseases

Plant-Derived Compounds with Therapeutic Potential for the Treatment of Human Coronavirus Diseases

An Online Native Mass Spectrometry Approach for Fast, Sensitive, and Quantitative Assessment of Adeno-Associated Virus Capsid Content Ratios.

Adeno-associated viruses (AAVs) have emerged as a leading platform for in vivo therapeutic gene delivery and offer tremendous potential in the treatment and prevention of human disease. The fast-paced development of this growing class of therapeutics, coupled with their intrinsic structural complexity, places a high demand on analytical methods capable of efficiently monitoring product quality to ensure safety and efficacy, as well as to support manufacturing and process optimization. Importantly, the presence and relative abundance of both empty and partially filled AAV capsid subpopulations are of principal concern, as these represent the most common product-related impurities in AAV manufacturing and have a direct impact on therapeutic potential. For this reason, the capsid content, or ratio of empty and partial capsids to those packaged with the full-length therapeutic genome, has been identified by regulatory agencies as a critical quality attribute (CQA) that must be carefully controlled to meet clinical specifications. Established analytical methods for the quantitation of capsid content ratios often suffer from long turnaround times, low throughput, and high sample demands that are not well-suited to the narrow timelines and limited sample availability typical of process development. In this study, we present an integrated online native mass spectrometry platform that aims to minimize sample handling and maximize throughput and robustness for rapid and sensitive quantitation of AAV capsid content ratios. The primary advantages of this platform for AAV analysis include the ability to perform online buffer exchange under low flow conditions to maintain sample stability with minimal sample dilution, as well as the ability to achieve online charge reduction via dopant-modified desolvation gas. By exploiting the latter, enhanced spectral resolution of signals arising from empty, partial, and full AAV capsids was accomplished in the m/z domain to facilitate improved spectral interpretation and quantitation that correlated well with the industry standard analytical ultracentrifugation (AUC) method for capsid content ratio determination. The utility of this approach was further demonstrated in several applications, including the rapid and universal screening of different AAV serotypes, evaluation of capsid content for in-process samples, and the monitoring of capsid stability when subjected to thermal stress conditions.

Medicinal Plants Recommendation System using ROC and MOORA

Kalimantan has extraordinary biodiversity, including medicinal plants. Medicinal plants are a type of plant that certain parts, such as roots, leaves, bark, stems, and the results of their excretions. However, people sometimes need help choosing plants that suit their needs because of the many types of medicinal plants and the need for knowledge regarding their use. Decision support systems (DSS) combine computer capabilities with data processing or manipulation that utilizes unstructured models or solution rules. Furthermore, the method of documenting knowledge of traditional medicine is through the media of information systems. This system helps select medicinal plants according to user needs. This research developed a DSS using Rank Order Centroid (ROC) and Multi-Objective Optimization by Ratio Analysis (MOORA) methods to select medicinal plants for fungal and skin infections, including Furuncles, Tinea corporis, Tinea versicolor, and Acne. ROC method for determining criteria weight values. This research has four criteria: plant part, processing method, use method, and habitus. Determining recommendations for alternative ranking results using the MOORA method. This study aims to help the public get recommendations for medicinal plants in human skin disease treatment. This study aims to increase the preservation of biodiversity, particularly sustainable medicinal plants in the tropical rainforest of East Kalimantan.

Regulatory roles of N6-methyladenosine (m6A) methylation in RNA processing and non-communicable diseases.

Post-transcriptional RNA modification is an emerging epigenetic control mechanism in cells that is important in many different cellular and organismal processes. N6-methyladenosine (m6A) is one of the most prevalent, prolific, and ubiquitous internal transcriptional alterations in eukaryotic mRNAs, making it an important topic in the field of Epigenetics. m6A methylation acts as a dynamical regulatory process that regulates the activity of genes and participates in multiple physiological processes, by supporting multiple aspects of essential mRNA metabolic processes, including pre-mRNA splicing, nuclear export, translation, miRNA synthesis, and stability. Extensive research has linked aberrations in m6A modification and m6A-associated proteins to a wide range of human diseases. However, the impact of m6A on mRNA metabolism and its pathological connection between m6A and other non-communicable diseases, including cardiovascular disease, neurodegenerative disorders, liver diseases, and cancer remains in fragmentation. Here, we review the existing understanding of the overall role of mechanisms by which m6A exerts its activities and address new discoveries that highlight m6A's diverse involvement in gene expression regulation. We discuss m6A deposition on mRNA and its consequences on degradation, translation, and transcription, as well as m6A methylation of non-coding chromosomal-associated RNA species. This study could give new information about the molecular process, early detection, tailored treatment, and predictive evaluation of human non-communicable diseases like cancer. We also explore more about new data that suggests targeting m6A regulators in diseases may have therapeutic advantages.

Protective properties of the edible halophyte Carpobrotus edulis (L.) N.E.Br. towards neoformed food contaminants-related oxidative stress and genotoxicity

Carpobrotus edulis (L.) N.E.Br. is an edible halophyte native to South Africa, where it has been traditionally consumed as food, revealing its nutritional value, and used in the treatment of human diseases probably due to the accumulation of bioactive compounds such as polyphenols. These compounds have potential to display valuable biological activities that could bring several benefits to the human being, including the mitigation of toxicity induced by food contaminants. Therefore, this study investigated biological activities with health-promoting potential of a C. edulis ethanol extract (CEE), such as antioxidant, antigenotoxic, and antimutagenic. CEE was shown by LC-DAD-ESI/MSn to be composed of 16 polyphenols. The extract exhibited antioxidant properties by protecting Saccharomyces cerevisiae viability and improving the redox state of HepG2 cells under oxidative stress. Antigenotoxicity of CEE against H2O2-induced oxidative damage was detected in HepG2 and Caco-2 cells by comet assay and subsequently observed in the dominant deletion assay in S. cerevisiae. Antigenotoxicity and antimutagenicity of CEE towards the neoformed contaminant benzo[a]pyrene was found in HepG2 and Caco-2 cells by comet assay and in Salmonella typhimurium using the Ames test, respectively. The disclosed antigenotoxic and antimutagenic properties of C. edulis further advance its potential for application in food and nutraceutical industries for health benefits.

Ephedra: An anti-asthamatic medicinal plant

ailments such as cold, cough, asthma, fever and flu. It is distributed in many regions such as Asia, Europe, North Africa, Western North America and South America. It has more than 100 active compounds with effects. It contains flavonoids, alkanes, tannins, sugars and organic phenolic acids. It is used in the treatment of asthma, liver disease, skin disease and other diseases, the most important among the effectiveness of the treatment of the disease is COVID-19. It is considered an ancient group and is appreciated for its abundant fossil record. Ephedra, known as "Ephedra" in China, is a gymnosperm plant. It is a dry straw stalk associated with the lung and bladder meridians. Ephedra is one of the largest genera of the Ephedra family and is found in arid and semi-arid regions of the world. In traditional medicine in many countries, some of these species are frequently used to treat asthma, colds, flu, colds, fever, headaches, nasal congestion and cough. The chemical composition of the ephedra plant has been a focus of interest for decades due to its content of ephedrine alkaloids and its medicinal properties. Other chemical compounds such as phenolics and amino acid derivatives are also of interest and provide evidence-based support for the ethnomedical use of Ephedra. Medicinal plants contain many phytochemical compounds related to various treatments (Naiá et al., 2005; Ghoíbani, 2005). Therefore, this medicinal herb is used in various ephedrine formulations and has many adverse effects on diseases such as liver diseases, angle-closure glaucoma, kidney stones, neurodegenerative diseases and heart toxicity. Indian Ayurveda is a traditional herbal medicine with a long history and strong foundations. Medicinal plants play an important role in the prevention and treatment of human diseases. This plant usually grows on dry rocks and soil because it needs high, dry mountain forests to grow. Many parts of plants such as branches and roots are used in various applications for medicinal purposes. For example, the dry part of the plant is used in vartonic medicine systems such as Ayurveda, Siddha and traditional Chinese medicine to treat many diseases such as asthma, hay fever, pain or inflammation, lung disease, heart disease. Aches, coughs, and colds are considered flu-like symptoms.

Polyphenolic content, phytochemical profile composition, and bioactive properties of Castilla Rose (Purshia plicata)

One of the greatest risks to human and animal health are infectious diseases caused by pathogenic bacteria, as these microorganisms develop mechanisms of resistance to antimicrobials, as a consequence of the indiscriminate and prolonged use of antimicrobials. This makes the treatment of infectious diseases increasingly difficult, in addition to an increase in treatment costs. These disadvantages have led to the search for alternative therapies based on bioactive compounds such as tannins, and flavonoids. Thus, some plant-derived compounds have been used to counteract infectious diseases and other health disorders. This study aimed to identify polyphenols of purified extract from Purshia plicata, and evaluate the antioxidant potential and the response of in vitro antibacterial activity against pathogen microorganisms of clinical importance for humans and animals. An aqueous extraction was performed and the compounds were purified using liquid chromatography. The total polyphenolic content was measured employing the Folin Ciocalteu and butanol-HCI methods. The polyphenolic profile was identified by HPLC/ESI/MS. These compounds were screened for in vitro antibacterial activity using the agar diffusion method and antioxidant activity was determined by ABTS•+, DPPH•, and FRAP methods. The compounds showed effectiveness against Klebsiella sp, Escherichia coli, and Salmonella sp, and moderate inhibition against Staphylococcus aureus. The total hydrolyzable polyphenols content was 45.7 mg g-1; the total condensed polyphenols content was 27 mg g-1. The results of the antioxidant activity showed that IC50 was reached at 150 µgml-1, 250 µgml-1, and 150 µgml-1. Twelve compounds were identified by HPCL/ESI/MS, the most important being anthocyanins and ellagitannins. The polyphenolic compounds of P. plicata have the potential to be used as pharmacological products with antibacterial and antioxidant properties for the treatment of infectious diseases in animals and humans.

In vivo tracking of ex vivo generated 89 Zr-oxine labeled plasma cells by PET in a non-human primate model.

B cells are an attractive platform for engineering to produce protein-based biologics absent in genetic disorders, and potentially for the treatment of metabolic diseases and cancer. As part of pre-clinical development of B cell medicines, we demonstrate a method to collect, ex vivo expand, differentiate, radioactively label, and track adoptively transferred non-human primate (NHP) B cells. These cells underwent 10- to 15-fold expansion, initiated IgG class switching, and differentiated into antibody secreting cells. Zirconium-89-oxine labeled cells were infused into autologous donors without any preconditioning and tracked by PET/CT imaging. Within 24 hours of infusion, 20% of the initial dose homed to the bone marrow and spleen and distributed stably and equally between the two. Interestingly, approximately half of the dose homed to the liver. Image analysis of the bone marrow demonstrated inhomogeneous distribution of the cells. The subjects experienced no clinically significant side effects or laboratory abnormalities. A second infusion of B cells into one of the subjects resulted in an almost identical distribution of cells, suggesting a non-limiting engraftment niche and feasibility of repeated infusions. This work supports the NHP as a valuable model to assess the potential of B cell medicines as potential treatment for human diseases.

Comparison the effect of plant extracts and antibiotics on gram negative bacteria isolated from patients with urinary tract infection in Tikrit city

Background: With increasing bacterial resistance for antibiotic, there is an increasing interest in medicinal herbal as a new source of an antimicrobial agents and with less side effects than conventional drugs. Objective: Was to evaluate the potential of Syzygium aromaticum and rosemarinus officinalis extract on Proteus mirabilis isolates in vitro. Methods: Six pathogenic gram negative bacilli belonging to three different genus (E.coli, Proteus mirabilis, and Enterobacter aerogenes) and two isolates from each species were used in this study and four concentration (100%, 75%, 50%, 25% mg/ml ) from each plant extracts (aqueous and ethanolic of Syzygium aromaticum and rosemarinus officinalis extracts ) were prepared to be antibacterial agent. antibacterial activity was measured by using wells method and five antibiotics using to compare with the activity of antibacterial agent. Results: The result of the study shown that the ethanolic extracts of Syzygium aromaticum is a strong antibacterial agent (with diameter of inhibition zone 25 mm) against Proteus mirabilis. Enterobacter aerogenes with (15mm) of inhibition zon, E.coli did not show any inhibition zone also the aqueous and ethanolic of rosemarinus officinalis extracts and aqueous of Syzygium aromaticum extracts did not show any activity towards any gram negative bacilli also the results of the study show resistance isolates of E.coli and Proteus mirabilis toward several antibiotic while Enterobacter aerogenes is sensitive for more antibiotics that used in this study. Conclusions: Our study concluded that the extract of Syzygium aromaticum has high potential as antibacterial agent against UTI that caused by Proteus mirabilis, clove (syzygium aromaticum) can be used in pharmaceutical for the production of new synthetic agents. There is an increasing interest in phytochemicals as new sources of natural antioxidant and antimicrobial agents. The natural compounds which have biological activities are interest to pharmaceutical industries especially for treatment of human disease of microbial origin and several pathological disorders such as cancergenesis, coronary atherosclerosis, as well as in ageing processes.

ANT2 functions as a translocon for mitochondrial cross-membrane translocation of RNAs.

Bidirectional transcription of mammalian mitochondrial DNA generates overlapping transcripts that are capable of forming double-stranded RNA (dsRNA) structures. Release of mitochondrial dsRNA into the cytosol activates the dsRNA-sensing immune signaling, which is a defense mechanism against microbial and viral attack and possibly cancer, but could cause autoimmune diseases when unchecked. A better understanding of the process is vital in therapeutic application of this defense mechanism and treatment of cognate human diseases. In addition to exporting dsRNAs, mitochondria also export and import a variety of non-coding RNAs. However, little is known about how these RNAs are transported across mitochondrial membranes. Here we provide direct evidence showing that adenine nucleotide translocase-2 (ANT2) functions as a mammalian RNA translocon in the mitochondrial inner membrane, independent of its ADP/ATP translocase activity. We also show that mitochondrial dsRNA efflux through ANT2 triggers innate immunity. Inhibiting this process alleviates inflammation in vivo, providing a potential therapeutic approach for treating autoimmune diseases.

Mechanisms and Delivery of tRNA Therapeutics.

Transfer ribonucleic acid (tRNA) therapeutics will provide personalized and mutation specific medicines to treat human genetic diseases for which no cures currently exist. The tRNAs are a family of adaptor molecules that interpret the nucleic acid sequences in our genes into the amino acid sequences of proteins that dictate cell function. Humans encode more than 600 tRNA genes. Interestingly, even healthy individuals contain some mutant tRNAs that make mistakes. Missense suppressor tRNAs insert the wrong amino acid in proteins, and nonsense suppressor tRNAs read through premature stop signals to generate full length proteins. Mutations that underlie many human diseases, including neurodegenerative diseases, cancers, and diverse rare genetic disorders, result from missense or nonsense mutations. Thus, specific tRNA variants can be strategically deployed as therapeutic agents to correct genetic defects. We review the mechanisms of tRNA therapeutic activity, the nature of the therapeutic window for nonsense and missense suppression as well as wild-type tRNA supplementation. We discuss the challenges and promises of delivering tRNAs as synthetic RNAs or as gene therapies. Together, tRNA medicines will provide novel treatments for common and rare genetic diseases in humans.