Biology Direct最新文献

Background: Peripheral artery disease (PAD), caused by atherosclerosis resulting in reduced blood flow in the lower extremities, impairs both skeletal muscle mass and function in humans, and its molecular mechanism is not clear. Recent studies have demonstrated that Nicotinamide phosphoribosyl transferase (NAMPT) influences skeletal muscle mass and function by modulating NAD⁺ levels and cellular Ca²⁺ homeostasis. However, its role in muscle fiber type transition remains to be elucidated.

Results: NAMPT is downregulated in ischemic skeletal muscle and CoCl₂-treated C2C12 myotubes. NAMPT enhances the functional performance of ischemic limbs, reduces apoptosis, increases the formation of oxidative muscle fibers, and improves mitochondrial function. The cGMP‒PKG pathway is activated by NAMPT in ischemic limbs. Exogenous inhibition of cGMP-PKG signaling inhibits the formation of oxidative muscle fibers induced by NAMPT.

Conclusions: NAMPT protects against ischemic limb injury via the cGMP‒PKG signaling pathway, suggesting that it is a promising therapeutic and predictive target for myopathy associated with PAD.

Clinical trial number: Not applicable.

Background: Disruption of circadian rhythm (DCR) has been connected with breast cancer (BC) susceptibility; whereas it is unclear whether status of key clock genes could be used in predicting BC prognosis, tumor immune microenvironment, and immunotherapy responses.

Results: Circadian clock genes demonstrate significant dysregulation in BC, where elevated CLOCK expression emerges as an independent prognostic factor strongly correlated with adverse clinical outcomes. CLOCK-overexpressing BC cells exhibit enhanced proliferative ability and strong resistance to chemotherapy drugs doxorubicin and gemcitabine. High CLOCK expression correlates with reduced CD8⁺ T cell infiltration and increased M2 macrophage polarization, consistent with increased immune checkpoint molecule PD-L1 expression in the TCGA BC dataset. Additionally, patients with high CLOCK expression display lower Tumor Immune Dysfunction and Exclusion (TIDE) score. Mechanistically, RNA-sequencing identified suppressed NF-κB, TNF, MAPK pathways, and PD-L1 expression in sh-CLOCK MCF-7 cells. Subsequent in vitro validation demonstrated that CLOCK mediates NF-κB p65 acetylation at K56 site, potentiating its transcriptional activation of PD-L1, thereby facilitating immune evasion in BC.

Conclusions: CLOCK functions as a critical prognostic biomarker in BC by promoting tumor proliferation, chemoresistance, and immune evasion. Mechanistically, CLOCK mediates NF-κB p65 acetylation to enhance PD-L1 transcription, promoting immune evasion in BC.

Ca²⁺ signaling is essential for neuronal development, migration, synaptic activity, spine plasticity, neurotransmitter release, membrane excitability, and long-term synaptic plasticity, as well as for the coupling between membrane depolarization and downstream signaling. Traditionally, Plasma Membrane Ca²⁺ ATPases (PMCAs) were considered high-affinity, low-capacity calcium extruders. However, recent evidence reveals that the PMCA-Neuroplastin complex facilitates ultrafast Ca²⁺ clearance at kilohertz frequencies, reshaping our understanding of calcium regulation, in particular in neurons. For bulk Ca²⁺ clearance, they are overshadowed by more powerful low-affinity/high-capacity systems on the plasma membrane. This raises key questions: what is the specific physiological and pathological role of PMCAs? Why do cells require a high-affinity/low-capacity, ATP-dependent extrusion mechanism? What is the functional meaning of the diversity of isoforms (four) and splice variants (over thirty)? And why do neurons localize distinct PMCA pumps to pre- and postsynaptic sites? The prevailing hypothesis is that PMCAs fine-tune Ca²⁺ microdomains through local regulation and interactions with specific protein partners. Finally, understanding their role in Purkinje cells (PCs) is particularly relevant, as alterations in PMCA function have been implicated in cerebellar pathology and ataxia.

Background: The early evolution of animals is characterized by the emergence of complex tissues, organs, and integument, made possible in part by the diversification of groups of structural proteins. The abundance of this new kind of organic material in the environment would have provided novel nutrient opportunities for microbes, as part of the beginnings of animal-microbial coevolution. Indeed, a diverse ensemble of extant microbial groups appear to possess the enzymatic ability to cleave collagen, the most abundant animal-specific protein, through the use of matrix metalloproteinases (MMPs). In animals, MMPs serve to reshape the extracellular matrix in the course of development, but their prevalence in the microbial world has been largely overlooked.

Results: MMPs have extensive diversity in Bacteria, Eumetazoa, and Streptophyta. We show that in marine metagenomes, MMP abundance is highly correlated with chitinase abundance, implying that even microbial MMPs are associated with animal-derived substrates. Reconstructing the phylogeny of MMP proteins reveals a history of rapid diversification, as well as multiple interkingdom and interdomain horizontal gene transfers. Included among these is a transfer to the ancestral lineage of the archaeal family Methanosarcinaceae, constraining this group to postdate the evolution of collagen, and therefore animal diversification.

Conclusions: MMPs have an unusual genetic history, marked by multiple instances of gene transfer between bacteria and multicellular eukaryotes, a smoking gun for some of the earliest coevolution between prokaryotes and metazoans. By calculating an end-Permian divergence of Methanosarcina, we demonstrate that the phylogenies of substrate-specific enzymes can provide valuable older-bound age calibrations for improving molecular clock age estimates across the Tree of Life.