Environmental and Genetic Traffic in the Journey from Sperm to Offspring.

Recent advancements in the understanding of how sperm develop into offspring have shown complex interactions between environmental influences and genetic factors. The past decade, marked by a research surge, has not only highlighted the profound impact of paternal contributions on fertility and reproductive outcomes but also revolutionized our comprehension by unveiling how parental factors sculpt traits in successive generations through mechanisms that extend beyond traditional inheritance patterns. Studies have shown that offspring are more susceptible to environmental factors, especially during critical phases of growth. While these factors are broadly detrimental to health, their effects are especially acute during these periods. Moving beyond the immutable nature of the genome, the epigenetic profile of cells emerges as a dynamic architecture. This flexibility renders it susceptible to environmental disruptions. The primary objective of this review is to shed light on the diverse processes through which environmental agents affect male reproductive capacity. Additionally, it explores the consequences of paternal environmental interactions, demonstrating how interactions can reverberate in the offspring. It encompasses direct genetic changes as well as a broad spectrum of epigenetic adaptations. By consolidating current empirically supported research, it offers an exhaustive perspective on the interwoven trajectories of the environment, genetics, and epigenetics in the elaborate transition from sperm to offspring.

Cholesterol-linoleic acid liposomes induced extracellular vesicles secretion from immortalized adipose-derived mesenchymal stem cells for in vitro cell migration.

Extracellular vesicles (EVs) are small vesicles that are naturally released by cells and play a crucial role in cell-to-cell communication, tissue repair and regeneration. As naturally secreted EVs are limited, liposomes with different physicochemical properties, such as 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and linoleic acid (LA) with modifications have been formulated to improve EVs secretion for in vitro wound healing. Various analyses, including dynamic light scattering (DLS) and transmission electron microscopy (TEM) were performed to monitor the successful preparation of different types of liposomes. The results showed that cholesterol-LA liposomes significantly improved the secretion of EVs from immortalized adipose-derived mesenchymal stem cells (AD-MSCs) by 1.5-fold. Based on the cell migration effects obtained from scratch assay, both LA liposomal-induced EVs and cholesterol-LA liposomal-induced EVs significantly enhanced the migration of human keratinocytes (HaCaT) cell line. These findings suggested that LA and cholesterol-LA liposomes that enhance EVs secretion are potentially useful and can be extended for various tissue regeneration applications.

Application of Platelet-Rich Plasma as a Stem Cell Treatment - an Attempt to Clarify a Common Public Misconception.

In recent years, there has been a significant increase in the practice of regenerative medicine by health practitioners and direct-to-consumer businesses globally. Among different tools of regenerative medicine, platelet-rich plasma (PRP) and stem cell-based therapies have received considerable attention. The use of PRP, in particular, has gained popularity due to its easy access, simple processing techniques, and regenerative potential. However, it is important to address a common misconception amongst the general public equating to PRP and stem cells due to the demonstrated efficacy of PRP in treating musculoskeletal and dermatological disorders. Notably, PRP promotes regeneration by providing growth factors or other paracrine factors only. Therefore, it cannot replenish or replace the lost cells in conditions where a large number of cells are required to regenerate tissues and/or organs. In such cases, cell-based therapies are the preferred option. Additionally, other tools of regenerative medicine, such as bioprinting, organoids, and mechanobiology also rely on stem cells for their success. Hence, healthcare and commercial entities offering direct-to-customer regenerative therapies should not mislead the public by claiming that the application of PRP is a stem cell-based therapy. Furthermore, it is important for regulatory bodies to strictly monitor these profit-driven entities to prevent them from providing unregulated regenerative treatments and services that claim a broad variety of benefits with little proof of efficacy, safety concerns, and obscure scientific justification.

Chemical Advances in Therapeutic Application of Exosomes and Liposomes.

Exosomes and liposomes are vesicular nanoparticles that can encapsulate functional cargo. The chemical similarities between naturally occurring exosomes and synthetic liposomes have accelerated the development of exosome mimetics as a therapeutic drug delivery platform under physiological and pathological environments. To maximise the applications of exosomes and liposomes in the clinical setting, it is essential to look into their basic chemical properties and utilise these characteristics to optimise the preparation, loading, modification and hybridisation. This review summarises the chemical and biological properties of both exosomal and liposomal systems as well as some of the challenges related to their production and application. This article concludes with a discussion on potential perspectives for the integration of exosomal and liposomal technologies in mapping better approaches for their biomedical use, especially in therapeutics.

Wound Healing Properties of Exosomes - A Review and Modelling of Combinatorial Analysis Strategies.

Wound healing is an elaborated process, well-regulated via cell migration and proliferation. Although the physiological basics of wound healing have been thoroughly investigated and reported, much remains to be studied. Particularly, various studies have demonstrated the immunomodulatory roles of exosomes derived from plant cells, mammalian cells, and mesenchymal stem cells (MSCs) in the healing and repairing system. The paracrine and therapeutic effects of exosomes are mainly associated with the broad exosomal cargo content comprising growth factors, cytokines, enzymes, nucleic acids, proteins, and lipid signaling molecules. Nevertheless, the functional or mechanism pathway of exosomes with reference to overall exosomal cargo remains undetermined. To date, combinatorial analysis strategies employing Database for Annotation, Visualization, and Integrated Discovery (DAVID), STRING tools, Gene Ontology (GO), Kyoto Encyclopedia of Genes, Genomes (KEGG) pathway enrichment analysis, as well as Ingenuity Pathway Analysis (IPA) have been applied in elucidating network interaction and functional pathway of exosomes. In this review paper, the application of combinatorial analysis strategies is demonstrated to better understand the therapeutic potentials of exosomes in the wound healing process. In conclusion, functional modulation of exosomal cargo for specific biological treatment is achievable, and modelling of combinatorial analysis strategies will hopefully bridge the research gap and provide a paradigm shift to regenerative processes.

Protein adaptors assemble functional proteins on DNA scaffolds.

DNA is an attractive molecular building block to construct nanoscale structures for a variety of applications. In addition to their structure and function, modification the DNA nanostructures by other molecules opens almost unlimited possibilities for producing functional DNA-based architectures. Among the molecules to functionalize DNA nanostructures, proteins are one of the most attractive candidates due to their vast functional variations. DNA nanostructures loaded with various types of proteins hold promise for applications in the life and material sciences. When loading proteins of interest on DNA nanostructures, the nanostructures by themselves act as scaffolds to specifically control the location and number of protein molecules. The methods to arrange proteins of interest on DNA scaffolds at high yields while retaining their activity are still the most demanding task in constructing usable protein-modified DNA nanostructures. Here, we provide an overview of the existing methods applied for assembling proteins of interest on DNA scaffolds. The assembling methods were categorized into two main classes, noncovalent and covalent conjugation, with both showing pros and cons. The recent advance of DNA-binding adaptor mediated assembly of proteins on the DNA scaffolds is highlighted and discussed in connection with the future perspectives of protein assembled DNA nanoarchitectures.

Young adult survivors of childhood acute lymphoblastic leukemia show evidence of chronic inflammation and cellular aging.

BACKGROUND: Large epidemiologic studies have reported the premature onset of age-related conditions, such as ischemic heart disease and diabetes mellitus, in childhood cancer survivors, decades earlier than in their peers. The authors investigated whether young adult survivors of childhood acute lymphoblastic leukemia (ALL) have a biologic phenotype of cellular ageing and chronic inflammation. METHODS: Plasma inflammatory cytokines were measured using a cytometric bead array in 87 asymptomatic young adult survivors of childhood ALL (median age, 25 years; age range, 18-35 years) who attended annual follow-up clinic and compared with healthy, age-matched and sex-matched controls. Leukocyte telomere length (LTL) was measured using Southern blot analysis. RESULTS: Survivors had significant elevation of plasma interleukin-2 (IL-2), IL-10, IL-17a, and high-sensitivity C-reactive protein levels (all P < .05). A raised high-sensitivity C-reactive protein level (>0.8 mg/dL) was related to increased odds of having metabolic syndrome (odds ratio, 7.256; 95% confidence interval, 1.501-35.074). Survivors also had significantly shorter LTL compared with controls (median, 9866 vs 10,392 base pairs; P = .021). Compared with published data, LTL in survivors was similar to that in healthy individuals aged 20 years older. Survivors who received cranial irradiation had shorter LTL compared with those who had not (P = .013). CONCLUSIONS: Asymptomatic young adult survivors of childhood ALL demonstrate a biologic profile of chronic inflammation and telomere attrition, consistent with an early onset of cellular processes that drive accelerated aging. These processes may explain the premature development of age-related chronic conditions in childhood cancer survivors. Understanding their molecular basis may facilitate targeted interventions to disrupt the accelerated aging process and its long-term impact on overall health. Cancer 2017;123:4207-4214. © 2017 American Cancer Society.

Construction of ratiometric fluorescent sensors by ribonucleopeptides.

Ratiometric fluorescent sensors were constructed from RNA aptamers by generating modular ribonucleopeptide complexes. Fluorescent ribonucleopeptides containing fluorophore seminaphthorhodafluor tethered to their peptide subunit revealed a dual emission property, which permitted a ratiometric fluorescent measurement of a substrate-binding event. The strategy successfully afforded ratiometric fluorescent sensors for biologically active small ligands, tetracycline, dopamine and streptomycin.

A ribonucleopeptide module for effective conversion of an RNA aptamer to a fluorescent sensor.

Ribonucleopeptide (RNP) is a new class of scaffold for modular fluorescent sensors. We report here a short RNA motif that induces an efficient communication between the structural changes associated with the ligand-binding event of RNA aptamer and an optical response of a fluorescent RNP module. An optimized short RNA motif was used as a communication module for the rational design of modular RNP sensors. A modular combination of a GTP-binding RNA aptamer, the short RNA motif and the fluorophore-labeled RNP module afforded a fluorescent GTP sensor that retain the ligand-binding affinity of the parent aptamer.

Construction of dopamine sensors by using fluorescent ribonucleopeptide complexes.

A facile strategy of stepwise molding of a ribonucleopeptide (RNP) complex affords fluorescent RNP sensors with selective dopamine recognition. In vitro selection of a RNA-derived RNP library, a complex of the Rev peptide and its binding site Rev Responsive Element (RRE) RNA appended with random nucleotides in variable lengths, afforded RNP receptors specific for dopamine. The modular structure of the RNP receptor enables conversion of dopamine-binding RNP receptors to fluorescent dopamine sensors. Application of conditional selection schemes, such as the variation of salt concentrations and application of a counter-selection step by using a competitor ligand norepinephrine resulted in isolation of RNP receptors with defined dopamine-binding characteristics. Increasing the salt condition at the in vitro selection stage afforded RNP receptors with higher dopamine affinity, while addition of norepinephrine in the in vitro selection milieu at the counter-selection step reinforced the selectivity of RNP receptors to dopamine against norepinephrine. Thermodynamic analyses and circular dichroismic studies of the dopamine-RNP complexes suggest that the dopamine-binding RNP with higher selectivity against norepinephrine forms a pre-organized binding pocket and that the dopamine-binding RNP with higher affinity binds dopamine through the induced-fit mechanism. These results indicate that the selection condition controls the ligand-binding mechanism of RNP receptors.

Design strategies of fluorescent biosensors based on biological macromolecular receptors.

Fluorescent biosensors to detect the bona fide events of biologically important molecules in living cells are increasingly demanded in the field of molecular cell biology. Recent advances in the development of fluorescent biosensors have made an outstanding contribution to elucidating not only the roles of individual biomolecules, but also the dynamic intracellular relationships between these molecules. However, rational design strategies of fluorescent biosensors are not as mature as they look. An insatiable request for the establishment of a more universal and versatile strategy continues to provide an attractive alternative, so-called modular strategy, which permits facile preparation of biosensors with tailored characteristics by a simple combination of a receptor and a signal transducer. This review describes an overview of the progress in design strategies of fluorescent biosensors, such as auto-fluorescent protein-based biosensors, protein-based biosensors covalently modified with synthetic fluorophores, and signaling aptamers, and highlights the insight into how a given receptor is converted to a fluorescent biosensor. Furthermore, we will demonstrate a significance of the modular strategy for the sensor design.