Advanced biology最新文献

Clinical complications frequently follow polytrauma and bleeding fractures, increasing the risk of delayed fracture healing and nonunions, especially in aged patients. Therefore, this study examines age's impact on fracture repair with and without severe bleeding in mice. Young (17-26 weeks) and aged (64-72 weeks) male C57BL/6J mice (n = 72 in total, n = 6 per group) are allocated into 3 groups: the fracture group (Fx) undergoes femur osteotomy stabilized via external fixator, the combined trauma group (THFx) additionally receives pressure-controlled trauma hemorrhage (TH) and Sham animals are implanted with catheter and fixator without blood loss or osteotomy. Femoral bones are evaluated histologically 24 h and 3 weeks post-trauma, while RANKL/OPG and β-CTx are measured systemically via ELISA after 3 weeks. Aging results in less mineralized bone and fewer osteoclasts within the fracture of aged mice in contrast to young groups after three weeks. Systemically, aged animals exhibit increased RANKL and OPG levels after fracture compared to their young counterparts. The RANKL/OPG ratio rises in aged Fx animals compared to young mice, with a similar trend in THFx groups. In conclusion, age has an effect during the later course of fracture healing on the cellular and systemic levels.

Longevity, the length of an organism's lifespan, is impacted by environmental factors, metabolic processes, and genetic determinants. The base excision repair (BER) pathway is crucial for maintaining genomic integrity by repairing oxidatively modified base lesions. Nei-like DNA Glycosylase 1 (NEIL1), part of the BER pathway, is vital in repairing oxidative bases in G-rich DNA regions, such as telomeres and promoters. Hence, in this comprehensive review, it have undertaken a meticulous investigation of the intricate association between NEIL1 and longevity. The analysis delves into the multifaceted aspects of the NEIL1 gene, its various RNA transcripts, and the diverse protein isoforms. In addition, a combination of bioinformatic analysis is conducted to identify NEIL1 mutations, transcription factors, and epigenetic modifications, as well as its lncRNA/pseudogene/circRNA-miRNA-mRNA regulatory network. The findings suggest that the normal function of NEIL1 is a significant factor in human health and longevity, with defects in NEIL1 potentially leading to various cancers and related syndromes, Alzheimer's disease, obesity, and diabetes.

The present study aims to investigate the role of interferon regulatory factor 4 (IRF4) in osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and analyze the underlying signaling of these processes. In this study, IRF4 is upregulated in periodontitis periodontal ligament tissues, as compared to healthy periodontal ligament tissues. IRF4 knockdown increases cell proliferation, decreases levels of tumor necrosis factor-alpha, interleukin-6, and interleukin-8, enhances osteogenic activity, and increases the expression of RUNX family transcription factor 2, Collagen I, and Osteocalcin in PDLSCs. The opposite results are observed in IRF4 overexpressed PDLSCs. Additionally, GSEA shows that IRF4 activates the interleukin-18 (IL-18) signaling pathway. The expressions of IL-18, B-cell translocation gene 2, interleukin-1beta, and caspase-3 are decreased by IRF4 knockdown, while increased by IRF4 overexpression. IL-18 overexpression eliminates the promoting effect of IRF4 knockdown on osteogenic differentiation of PDLSCs. In conclusion, IRF4 suppresses osteogenic differentiation of PDLSCs by activating the IL-18 signaling pathway.

Postoperative cognitive dysfunction (POCD), a postsurgical decline in cognitive function, primarily affects older adults and worsens their prognosis. Although elevated interleukin-12p70 (IL-12p70) is closely correlated with slower cognitive decline in older adults, its role in POCD remains unclear. Here, IL-12p70 is identified as a significant mediator of therapeutic effect of electroacupuncture (EA) on POCD. EA at acupoints ST36, GV20, and GV24 significantly enhanced cognitive behaviors of POCD mice. IL-12p70, downregulated in POCD mice but rescued by EA treatment, is the cytokine closely associated with EA's therapeutic effect. Clinically, IL-12p70 is downregulated in older adults' serum post-surgery. Furthermore, IL-12p70 exerts a potent neuroprotective effect in both neuronal cell lines and primary hippocampal neurons. The PI3K-AKT-BCL2 axis enriched by in silico analysis is validated as the signaling mechanism underlying IL-12p70-induced neuroprotection. In vivo, beneficial effects of EA treatment on the activation of PI3K-AKT-BCL2 axis and POCD are reproduced by IL-12p70 administration but attenuated by IL-12p70 knockdown. The findings reveal a novel mechanism underlying the therapeutic effect of EA on POCD, demonstrating that IL-12p70 exerts a neuroprotective effect by activating PI3K-AKT-BCL2 axis in hippocampal neurons. The newly-discovered function and mechanism of IL-12p70 highlight its potential in treating cognitive disorders.

Extracellular vesicles (EVs) are components of the senescence-associated secretory phenotype (SASP) that influence cellular functions via their cargo. Here, the interaction between EVs derived from senescent (SEVs) and non-senescent (N-SEVs) fibroblasts and the immune system is investigated. Via endocytosis, SEVs are phagocytosed by monocytes, neutrophils, and B cells. Studies with the monocytic THP-1 cell line find that pretreatment with SEVs results in a 32% (p < 0.0001) and 66% (p < 0.0001) increase in lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-α) production when compared to vehicle control or N-SEVs respectively. Interestingly, relative to vehicle control, THP-1 cells exposed to N-SEVs exhibit a 20% decrease in TNF-α secretion (p < 0.05). RNA sequencing reveals significant differences in gene expression in THP-1 cells treated with SEVs or N-SEVs, with vesicle-mediated transport and cell cycle regulation pathways featuring predominantly with N-SEV treatment, while pathways relating to SLITS/ROBO signaling, cell metabolism, and cell cycle regulation are enriched in THP-1 cells treated with SEVs. Proteomic analysis also reveals significant differences between SEV and N-SEV cargo. These results demonstrate that phagocytes and B cells uptake SEVs and drive monocytes toward a more proinflammatory phenotype upon LPS stimulation. SEVs may therefore contribute to the more proinflammatory immune response seen with aging.

Viruses are biological entities embodied in protein-based nanoparticles devoid of metabolic activity. Hence, the colloidal, interfacial, and chemical reactivity of virus particles (VPs) profoundly affects the fate of natural and artificial viruses in biotic or abiotic aqueous systems. These rely on the physical chemistry at the outer surface of VPs. In other words, whether wild or synthetic VPs and regardless of the scientific fields involved, taming viruses implies thus managing the physical chemistry at the VP external surface. The surface hydrophobicity (SH) of VPs is a critical feature that must be looked at. Still, the literature dealing with nanoscale hydrophobic domains at the proteinaceous surface of VPs underlying their global SH is like a fragmented puzzle. This article provides an overview of the topic from the perspective of modern protein biophysics for updating the classic physicochemical picture of outer VP/water interfaces hitherto accepted. Patterns of non-polar and "false-polar" patches, expressing variable hydrophobic degrees according to neighboring polar patches, are now drawn. The extensive discussion of reviewed data generates such fresh ideas to explore in the coming years for better modeling the SH of wild virions or engineered virus-based nanoparticles, paving the way for new directions in fundamental virology and virus-based chemistry.

Oocyte meiotic errors can cause infertility, miscarriage, and birth defects. Here the role and the underlying mechanism of p21 activated kinase 4 (PAK4) in mouse oocyte meiosis is evaluated. It is found that PAK4 expression and its phosphorylation are detected in high level at germinal vesicle (GV) stage, and gradually decreased after meiotic resumption in oocytes. PAK4 has direct physical interaction with both mitogen-activated protein kinases 1/2 (MEK1/2) and Paxillin, they are colocalized on the spindle structure during metaphases I and II. Phospho-PAK4 is distributed beneath the cytoplasmic membrane and on the chromosomes, and colocalized with the microtubule organizing center (MTOC) proteins, Pericentrin and γ-tubulin, as well as phosphor-MEK1/2 and phosphor-Paxillin on spindle poles. PAK4 inhibition by chemical inhibitor LCH-7749944, specific Pak4 morpholino oligo or the dominant negative mutant Pak4^{K350, 351 M} influence the meiotic resumption, spindle assembly and its cortical migration, and associated with the downregulation in the dephosphorylation of cyclin dependent kinase 1 (CDK1) and the levels of Cyclin B1, MEK1/2, Paxillin, g-tubulin, acetylated a-tubulin, Arp3, and Cofilin phosphorylation in oocytes. In sum, PAK4 functions to sustain the rational levels of Cyclin B1, MEK1/2, Paxillin, y-tubulin, acetylated a-tubulin, Arp3, and phosphor-Cofilin in mouse oocytes, thereby promotes the meiotic resumption, spindle assembly, and migration during meiotic maturation.

Developing bioinspired materials to convert sunlight into electricity efficiently is paramount for sustainable energy production. Fluorescent proteins are promising candidates as photoactive materials due to their high fluorescence quantum yield and absorption extinction coefficients in aqueous media. However, developing artificial bioinspired photosynthetic systems requires a detailed understanding of molecular interactions and energy transfer mechanisms in the required operating conditions. Here, the supramolecular self-assembly and photophysical properties of fluorescent proteins complexed with organic dyes are investigated in aqueous media. Supercharged mGreenLantern protein, mutated to have a charge of +22, is complexed together with anionic zinc phthalocyanines having 4 or 16 carboxylate groups. The structural characterization reveals a strong electrostatic interaction between the moieties, accompanied by partial conformational distortion of the protein structure, yet without compromising the mGreenLantern chromophore integrity as suggested by the lack of emission features related to the neutral form of the chromophore. The self-assembled biohybrid shows a total quenching of protein fluorescence, in favor of an energy transfer process from the protein to the phthalocyanine, as demonstrated by fluorescence lifetime and ultrafast transient absorption measurements. These results provide insight into the rich photophysics of fluorescent protein-dye complexes, anticipating their applicability as water-based photoactive materials.

Sarcopenia is a geriatric condition characterized by a decrease in skeletal muscle mass and function, significantly impacting both quality of life and overall health. Mitochondria are the main sites of energy production within the cell, and also produce reactive oxygen species (ROS), which maintain mitochondrial homeostasis-mitophagy (clearing damaged mitochondria); mitochondrial dynamics, which involve fusion and fission to regulate mitochondrial morphology; mitochondrial biogenesis, which ensures the functionality and homeostasis of mitochondria. Sarcopenia is linked to mitochondrial dysfunction, suggesting that muscle mitochondrial function therapy should be investigated. Extrinsic therapies are extensively examined to identify new treatments for muscular illnesses including sarcopenia. Changes in muscle physiology and lifestyle interventions, such as pharmacological treatments and exercise, can modulate mitochondrial activity in older adults. This PubMed review encompasses the most significant mitophagy and sarcopenia research from the past five years. Animal models, cellular models, and human samples are well covered. The review will inform the development of novel mitochondria-targeted therapies aimed at combating age-related muscle atrophy.

The present study explored the natural compound Isotelekin isolated from Inula racemose against anti-inflammatory and immunomodulatory potential in LPS-induced RAW264.7 cell lines and immune-elevated SRBC-sensitized animal models. Isotelekin in in vitro studies, inhibited the production of Th-1 cytokines Interleukin-6 (IL-6), Tumour necrosis factor (TNF-α), and Interferon-gamma (INF-γ), and increased Th-2 cytokines Interleukin-10 (IL-10). Whereas it inhibited the nitrites and reactive oxygen species (ROS) production by mitigating the effect of LPS significantly. In vivo immunomodulatory activity in Delayed-type hypersensitivity (DTH) and Hemagglutinating antibody (HA), Isotelekin suppressed the cellular as well as humoral immunity in immune-affected and SRBC-sensitized mice. Isotelekin decreased the phagocytic responses against carbon particles and plaque-forming mainly IgG (Immunoglobulin G) production. Additionally, Isotelekin showed immunosuppressive potential through the evaluation of splenocytes, allograft acceptance, and haematological parameters. Molecular studies, including western blot analysis and immunocytochemistry, revealed that Isotelekin reduced the expression of iNOS (Inducible nitric oxide synthase), COX-2 (Cyclo-Oxygenase 2), and p-IkBα (Phospho I-kappa-B-alpha), and significantly inhibited the nuclear translocation of NF-κB/p65. Based on these results, Isotelekin at 10 µm in in vitro and at 30 mg kg^-1 in in vivo demonstrated strong anti-inflammatory and immunosuppressive therapeutic potential.