Recent advances in protein 3D structure prediction using deep learning have focused on the importance of amino acid residue-residue connections (i.e., pairwise atomic contacts) for accuracy at the expense of mechanistic interpretability. Therefore, we decided to perform a series of analyses based on an alternative framework of residue-residue connections making primary use of the TOP2018 dataset. This framework of residue-residue connections is derived from amino acid residue pairing models both historic and new, all based on genetic principles complemented by relevant biophysical principles. Of these pairing models, three new models (named the GU, Transmuted and Shift pairing models) exhibit the highest observed-over-expected ratios and highest correlations in statistical analyses with various intra- and inter-chain datasets, in comparison to the remaining models. In addition, these new pairing models are universally frequent across different connection ranges, secondary structure connections, and protein sizes. Accordingly, following further statistical and other analyses described herein, we have come to a major conclusion that all three pairing models together could represent the basis of a universal proteomic code (second genetic code) sufficient, in and of itself, to "encode" for both protein folding mechanisms and protein-protein interactions.
- Klíčová slova
- Contact map, Protein 3D structure, Protein folding, Protein-protein interactions, Proteomic code, Sense-antisense,
- MeSH
- aminokyseliny * chemie genetika MeSH
- databáze proteinů MeSH
- lidé MeSH
- molekulární modely * MeSH
- proteiny * chemie genetika metabolismus MeSH
- proteomika * MeSH
- sbalování proteinů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aminokyseliny * MeSH
- proteiny * MeSH
The increasing spread of Acne vulgaris makes antibacterial agents increasingly important, especially for patients, who cannot use systemic antibacterial therapeutics. Recently, polymeric nano- and submicron-fibers with have attracted increasing interest in cosmetic and dermatological applications. Combined with the Vapor Phase Infiltration (VPI) process, the fibers serve as containers for the growth of metal oxides for a later use. We address the use of antibacterial agents by developing active antibacterial polymer-inorganic composites without any ZnO nanoparticles on the surface that are loose and would potentially detach. We fabricate poly(vinyl alcohol) fibers by centrifugal spinning and then infiltrate them with ZnO by applying 1 to 128 VPI cycles in the fluidized bed Atomic Layer Deposition reactor. The fibers´ morphology and structure is investigated by Scanning and Transmission Electron Microscopies and X-ray diffractometry. The presence of Zn and its uniform distribution on the surface is confirmed by scanning TEM Energy Dispersive X-ray spectroscopy. The prepared materials are subsequently tested for their antibacterial activity against Cutibacterium acnes and Staphylococcus epidermidis, main acne-causing bacteria. The results of antibacterial activity show that PVA fibers infiltrated with ZnO nanocrystals by >32 VPI cycles effectively inhibit growth of the acne-causing bacteria. Moreover, the homogeneous distribution of ZnO nanocrystals infiltrated within the fibers ensures the immediate release of Zn2+ while preserving the fibrous structure, in contrast to fibers with nanoparticles prepared directly from the spinning solution. Therefore, the study suggests that the PVA fibers infiltrated with ZnO exhibit promising potential as a material for anti-acne face masks.
- Klíčová slova
- Acne vulgaris, Antibacterial activity, Centrifugal spinning, Nanocrystals, Vapor phase infiltration, ZnO,
- Publikační typ
- časopisecké články MeSH
PI3K signaling pathway is crucial for a plethora of cellular processes and is extensively linked with tumorigenesis and chemo-/radioresistance. Although a number of small molecule inhibitors have been synthesized to control PI3K-mediated signaling, only a limited clinical success has been reached. Thus, the search for novel promising candidates is still ongoing. Herein, we present a novel series of N-(5-(2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)acylamides designed to simultaneously inhibit PI3K and DNA-PK activity. Compared to a commercial DNA-PK/PI3K inhibitor AZD7648, synthesized compounds generally exhibited markedly lower baseline cytotoxicity in all tested cell lines (MC38, B16F10, 4T1, CT26 and HEK-239). Through an array of biological experiments, we selected two most promising compounds, 2 and 6. While in cell-free conditions, 6 acted as a very efficient pan-PI3K and DNA-PK inhibitor, in physiological conditions, 2 performed better and acted as a potent chemosensitizer able to increase the amount of DNA double strand breaks induced by doxorubicin. This was plausibly due to its improved ability to accumulate in nuclei as evidenced by confocal analyses. Importantly, using P-gp overexpressing CT26 cells, we found that 2 is an efficient inhibitor of multidrug resistance (MDR) able to down-regulate expression of mRNA encoding MDR-driving proteins ABCB1A, ABCB1B and ABCC1. We also demonstrate that 2 can be simply loaded into lipid nanoparticles that retain its chemosensitizing properties. Taken together, the presented study provides a solid basis for a subsequent rational structure optimization towards new generation of multitarget inhibitors able to control crucial signaling pathways involved in tumorigenesis and drug resistance.
- Klíčová slova
- Chemosensitization, DNA-Dependent protein kinase, Doxorubicin, Drug delivery, Multitarget inhibition, Phoshphoinositide-3-kinases inhibitors, Resistance,
- Publikační typ
- časopisecké články MeSH
In the dynamic realm of translational nanorobotics, the endeavor to develop nanorobots carrying therapeutics in rational in vivo applications necessitates a profound understanding of the biological landscape of the human body and its complexity. Within this landscape, biological membranes stand as critical barriers to the successful delivery of therapeutic cargo to the target site. Their crossing is not only a challenge for nanorobotics but also a pivotal criterion for the clinical success of therapeutic-carrying nanorobots. Nevertheless, despite their urgency, strategies for membrane crossing in translational nanorobotics remain relatively underrepresented in the scientific literature, signaling an opportunity for further research and innovation. This review focuses on nanorobots with various propulsion mechanisms from chemical and physical to hybrid mechanisms, and it identifies and describes four essential biological membranes that represent the barriers needed to be crossed in the therapeutic journey of nanorobots in in vivo applications. First is the entry point into the blood stream, which is the skin or mucosa or intravenous injection; next is the exit from the bloodstream across the endothelium to the target site; further is the entry to the cell through the plasma membrane and, finally, the escape from the lysosome, which otherwise destroys the cargo. The review also discusses design challenges inherent in translating nanorobot technologies to real-world applications and provides a critical overview of documented membrane crossings. The aim is to underscore the need for further interdisciplinary collaborations between chemists, materials scientists and chemical biologists in this vital domain of translational nanorobotics that has the potential to revolutionize the field of precision medicine.
- MeSH
- buněčná membrána * metabolismus chemie MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- nanotechnologie MeSH
- robotika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Publikační typ
- tisková chyba MeSH
Hepatic fibrosis progresses concomitantly with a variety of biomechanical alternations, especially increased liver stiffness. These biomechanical alterations have long been considered as pathological consequences. Recently, growing evidence proposes that these alternations result in the fibrotic biomechanical microenvironment, which drives the activation of hepatic stellate cells (HSCs). Here, an inorganic ascorbic acid-oxidase (AAO) mimicking nanozyme loaded with liquiritigenin (LQ) is developed to trigger remodeling of the fibrotic biomechanical microenvironment. The AAO mimicking nanozyme is able to consume intracellular ascorbic acid, thereby impeding collagen I deposition by reducing its availability. Simultaneously, LQ inhibits the transcription of lysyl oxidase like 2 (LOXL2), thus impeding collagen I crosslinking. Through its synergistic activities, the prepared nanosystem efficiently restores the fibrotic biomechanical microenvironment to a near-normal physiological condition, promoting the quiescence of HSCs and regression of fibrosis. This strategy of remodeling the fibrotic biomechanical microenvironment, akin to "pulling the rug out from under", effectively treats hepatic fibrosis in mice, thereby highlighting the importance of tissue biomechanics and providing a potential approach to improve hepatic fibrosis treatment.
- Klíčová slova
- biomechanical microenvironment, collagen I, hepatic fibrosis, hepatic stellate cell quiescence,
- MeSH
- biomechanika MeSH
- buněčné mikroprostředí účinky léků MeSH
- flavanony farmakologie chemie MeSH
- jaterní cirhóza * farmakoterapie metabolismus patologie MeSH
- jaterní hvězdicovité buňky * metabolismus cytologie účinky léků MeSH
- kolagen typu I metabolismus MeSH
- kyselina askorbová * farmakologie metabolismus chemie MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- flavanony MeSH
- kolagen typu I MeSH
- kyselina askorbová * MeSH
Aging is generally regarded as an irreversible process, and its intricate relationship with the immune system has garnered significant attention due to its profound implications for the health and well-being of the aging population. As people age, a multitude of alterations occur within the immune system, affecting both innate and adaptive immunity. In the realm of innate immunity, aging brings about changes in the number and function of various immune cells, including neutrophils, monocytes, and macrophages. Additionally, certain immune pathways, like the cGAS-STING, become activated. These alterations can potentially result in telomere damage, the disruption of cytokine signaling, and impaired recognition of pathogens. The adaptive immune system, too, undergoes a myriad of changes as age advances. These include shifts in the number, frequency, subtype, and function of T cells and B cells. Furthermore, the human gut microbiota undergoes dynamic changes as a part of the aging process. Notably, the interplay between immune changes and gut microbiota highlights the gut's role in modulating immune responses and maintaining immune homeostasis. The gut microbiota of centenarians exhibits characteristics akin to those found in young individuals, setting it apart from the microbiota observed in typical elderly individuals. This review delves into the current understanding of how aging impacts the immune system and suggests potential strategies for reversing aging through interventions in immune factors.
- Klíčová slova
- adaptive immunity, aging, cGAS-STING, gut microbiota, gut microbiota aging, innate immunity,
- MeSH
- adaptivní imunita * MeSH
- lidé MeSH
- přirozená imunita * MeSH
- stárnutí * imunologie MeSH
- střevní mikroflóra * imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Aging encompasses a wide array of detrimental effects that compromise physiological functions, elevate the risk of chronic diseases, and impair cognitive abilities. However, the precise underlying mechanisms, particularly the involvement of specific molecular regulatory proteins in the aging process, remain insufficiently understood. Emerging evidence indicates that c-Jun N-terminal kinase (JNK) serves as a potential regulator within the intricate molecular clock governing aging-related processes. JNK demonstrates the ability to diminish telomerase reverse transcriptase activity, elevate β-galactosidase activity, and induce telomere shortening, thereby contributing to immune system aging. Moreover, the circadian rhythm protein is implicated in JNK-mediated aging. Through this comprehensive review, we meticulously elucidate the intricate regulatory mechanisms orchestrated by JNK signaling in aging processes, offering unprecedented molecular insights with significant implications and highlighting potential therapeutic targets. We also explore the translational impact of targeting JNK signaling for interventions aimed at extending healthspan and promoting longevity.
- Klíčová slova
- JNK, aging, longevity, molecular insights, therapeutic targets,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated β-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of β-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate β-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1β secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases.
- Klíčová slova
- Alzheimer’s disease, Amyloid β · tau protein, Cellular senescence, Neurodegenerative diseases, Telomere shortening,
- MeSH
- Alzheimerova nemoc MeSH
- amyloidní beta-protein metabolismus MeSH
- lidé MeSH
- neurodegenerativní nemoci * MeSH
- Parkinsonova nemoc metabolismus MeSH
- sekreční fenotyp asociovaný se senescencí MeSH
- signální transdukce MeSH
- stárnutí buněk * účinky léků MeSH
- zkracování telomer účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- amyloidní beta-protein MeSH
Current diabetic retinopathy (DR) treatment involves blood glucose regulation combined with laser photocoagulation or intravitreal injection of vascular endothelial growth factor (VEGF) antibodies. However, due to the complex pathogenesis and cross-interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood-retinal barrier (BRB) injury can attenuate DR. For this, a glucose-responsive hydrogel named Cu-PEI/siMyD88@GEMA-Con A (CSGC) is developed that effectively delivers Cu-PEI/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu-PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu-PEI NPs decreases IL-18 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross-interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR.
- Klíčová slova
- diabetic retinopathy, primary BRB injury, retinal microenvironment reshaping, secondary BRB injury, siMyD88,
- MeSH
- buněčné mikroprostředí účinky léků MeSH
- diabetická retinopatie * farmakoterapie metabolismus MeSH
- glukosa * metabolismus MeSH
- hematoretinální bariéra * metabolismus účinky léků MeSH
- hydrogely * farmakologie MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nanočástice MeSH
- retina účinky léků metabolismus MeSH
- retinální pigmentový epitel metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- glukosa * MeSH
- hydrogely * MeSH
