Bioscience Reports最新文献

Parkinson's disease (PD) significantly affects millions of people worldwide due to the progressive degeneration of dopamine-producing neurons in the substantia nigra pars compacta. Despite extensive research efforts, effective treatments that can halt or reverse the progression of PD remain elusive. In recent years, nanotechnology has emerged as a promising new avenue for addressing this challenge, with zinc oxide nanoparticles (ZnO-NPs) standing out for their extensive therapeutic potential. ZnO-NPs have shown remarkable promise in neuroprotection through several key mechanisms. The multifaceted properties of ZnO-NPs suggest that they could play a crucial role in intervening across various fundamental mechanisms implicated in PD. By targeting these mechanisms, ZnO-NPs offer new insights and potential strategies for managing and treating PD. This review aims to provide a thorough examination of the molecular mechanisms through which ZnO-NPs exert their neuroprotective effects. It highlights their potential as innovative therapeutic agents for PD and outlines directions for future research to explore and harness their full capabilities.

Human malaria, caused by Plasmodium parasites, is a fatal disease that disrupts the host's physiological balance and affects the neuroendocrine system. This review explores how malaria influences and is influenced by hormones. Malaria activates the Hypothalamus-Pituitary-Adrenal axis, leading to increased cortisol, aldosterone, and epinephrine. Cortisol, while reducing inflammation, aids parasite survival, whereas epinephrine helps manage hypoglycemia. The Hypothalamus-Pituitary-Gonad and Hypothalamus-Pituitary-Thyroid axes are also impacted, resulting in lower sex and thyroid hormone levels. Malaria disrupts the renin-angiotensin-aldosterone system (RAAS), causing higher angiotensin-II and aldosterone levels, contributing to edema, hyponatremia and hypertension. Malaria-induced anemia is exacerbated by increased hepcidin, which impairs iron absorption, reducing both iron availability for the parasite and red blood cell formation, despite elevated erythropoietin. Hypoglycemia is common due to decreased glucose production and hyperinsulinemia, although some cases show hyperglycemia due to stress hormones and inflammation. Hypocalcemia, and hypophosphatemia are associated with low Vitamin D3 and parathyroid hormone but high calcitonin. Hormones such as DHEA, melatonin, PTH, Vitamin D3, hepcidin, progesterone, and erythropoietin protects against malaria. Furthermore, synthetic analogs, receptor agonists and antagonists or mimics of hormones like DHEA, melatonin, serotonin, PTH, vitamin D3, estrogen, progesterone, angiotensin, and somatostatin are being explored as potential antimalarial treatments or adjunct therapies. Additionally, hormones like leptin and PCT are being studied as probable markers of malaria infection.

Background: Pure frailty and obese frailty are common types of frailty syndrome. However, the overlapping and distinct characteristics between pure frailty and obese frailty remain unclear. This study aims to reveal the overlapping/distinct physical and biological phenotypes of pure frailty and obese frailty, providing theoretical support for their prevention, diagnosis, and treatment.

Method: Mice were fed either a normal or high-fat diet and assessed at 20 months of age. They were assigned to one of the four groups: control, obesity, pure frailty, and obese frailty. Grip strength, walking speed, physical activity, endurance, and body weight were measured to determine pure frailty and obese frailty. Physical and biological phenotypes were assessed.

Results: Distinct physical phenotypes were observed between pure frailty and obese frailty in terms of body weight, lean mass, fat mass, fat mass in tissue, grip strength, endurance, and physical activity, while walking speed overlapped. In biological phenotypes, levels of Smad2/3, FoxO3a, P62, LAMP-2, and cathepsin L expression were distinct, while AKT, p-AKT, mTOR, p-mTOR, p-Smad2/3, p-FoxO3a, Beclin-1, ATG7, and LC3 overlapped.

Conclusion: Distinct physical phenotypes observed in obese frailty are primarily attributable to the effect of obesity, with further impairment of muscle function resulting from the combined effects of frailty syndromes and obesity. Pure frailty and obese frailty share overlapping biological phenotypes, particularly in the regulation of muscle protein synthesis. Moreover, the interaction between obesity and frailty syndromes gives rise to both overlapping and distinct biological phenotypes, especially in the regulation of specific degradation signaling proteins.

Early-onset pre-eclampsia is believed to arise from defective placentation in the first trimester, leading to placental ischaemia/reperfusion (I/R) and oxidative stress. However, our current understanding of the effects of I/R and oxidative stress on trophoblast function is ambiguous in part due to studies exposing trophoblasts to hypoxia instead of I/R, and which report conflicting results. Here, we present a model of simulated ischaemia/reperfusion (SI/R) to recapitulate the pathophysiological events of early-onset pre-eclampsia (PE), by exposing first trimester cytotrophoblast HTR-8/SVneo cells to a simulated ischaemia buffer followed by reperfusion. We examined different ischaemia and reperfusion times and observed that 1 h ischaemia and 24 h reperfusion induced an increase in reactive oxygen species (ROS) production (P<0.0001) and oxygen consumption rate (P<0.01). SI/R-exposed trophoblast cells exhibited deficits in migration, proliferation, and invasion (P<0.01). While the deficits in migration and proliferation were rescued by antioxidants, suggesting an ROS-dependent mechanism, the loss of invasion was not affected by antioxidants, which suggests a divergent ROS-independent pathway. In line with this, we observed a decrease in MMP-9, the key regulatory enzyme necessary for trophoblast invasion (P<0.01), which was similarly unaffected by antioxidants, and pharmacological inhibition of MMP-9 replicated the phenotype of deficient invasion (P<0.01). Collectively, these data demonstrate that I/R impairs trophoblast migration and proliferation via a ROS-dependent mechanism, and invasion via an ROS-independent loss of MMP-9, disambiguating the role of oxidative stress and providing insights into the response of trophoblasts to I/R in the context of early-onset PE.

Background: This study investigated the causal relationship between gut microbiota (GM), serum metabolome, and host transcriptome in the development of gout and hyperuricemia (HUA) using genome-wide association studies (GWAS) data and HUA mouse model experiments.

Methods: Mendelian randomization (MR) analysis of GWAS summary statistics was performed using an inverse variance weighted (IVW) approach to determine or predict the causal role of the GM on gout. The HUA mouse model was used to characterize changes in the gut microbiome, host metabolome, and host kidney transcriptome by integrating cecal 16S rRNA sequencing, untargeted serum metabolomics, and host mRNA sequencing.

Results: Our analysis demonstrated causal effects of seven GM taxa on gout, including genera of Ruminococcus, Odoribacter, and Bacteroides. Thirty eight immune cell traits were associated with gout. Dysbiosis of Dubosiella, Lactobacillus, Bacteroides, Alloprevotella, and Lachnospiraceae_NK4A136_group genera were associated with changes in the serum metabolites and kidney transcriptome of the HUA model mice. The changes in the gut microbiome of the HUA model mice correlated significantly with alterations in the levels of serum metabolites such as taurodeoxycholic acid, phenylacetylglycine, vanylglycol, methyl hexadecanoic acid, carnosol, 6-aminopenicillanic acid, sphinganine, p-hydroxyphenylacetic acid, pyridoxamine, and de-o-methylsterigmatocystin, and expression of kidney genes such as CNDP2, SELENOP, TTR, CAR3, SLC12A3, SCD1, PIGR, CD74, MFSD4B5, and NAPSA.

Conclusion: Our study demonstrated a causal relationship between GM, immune cells, and gout. HUA development involved alterations in the vitamin B6 metabolism because of GM dysbiosis that resulted in altered pyridoxamine and pyridoxal levels, dysregulated sphingolipid metabolism, and excessive inflammation.

Inflammasomes are multiprotein complexes that regulate the bioactive production of IL-1β and IL-18, being implicated in the inflammatory response of different diseases. The inflammasome formed by the cytosolic sensor NLRP3 is highly promiscuous, as it could be activated by different pathogen- and sterile-signals. However, few models have studied the implication of NLRP3 in tissue damage-induced inflammation, particularly the implication of NLRP3 in tendinopathies. Here, we aimed to investigate the implication of NLRP3 in a mouse model of tendinopathy by collagenase degradation of the extracellular matrix in the Achilles' mice tendon. We found that NLRP3 was involved in the production of IL-1β, but another ASC-dependent inflammasome was required to produce IL-18 during sterile tissue damage. Our study suggests that in the immune response to extracellular matrix degradation different inflammasomes, probably expressed in different cell compartments, were able to differentially control IL-1β and IL-18 production in vivo. These results suggest the potential use of therapies targeting ASC as beneficial in the treatment of tendinopathies.

Inositol pyrophosphates (PP-InsPs) are a sub-family of water soluble inositol phosphates that possess one or more diphosphate groups. PP-InsPs can transfer their β-phosphate group to a phosphorylated Ser residue to generate pyrophosphorylated Ser. This unique post-translational modification occurs on Ser residues that lie in acidic stretches within an intrinsically disordered protein sequence. Serine pyrophosphorylation is dependent on the presence of Mg2+ ions, but does not require an enzyme for catalysis. The mechanisms by which cells regulate PP-InsP-mediated pyrophosphorylation are still unknown. We performed mass spectrometry to identify interactors of IP6K1, an enzyme responsible for the synthesis of the PP-InsP 5-InsP7. Interestingly, IP6K1 interacted with several proteins that are known to undergo 5-InsP7-mediated pyrophosphorylation, including the nucleolar proteins NOLC1, TCOF and UBF1, and AP3B1, the β subunit of the AP3 adaptor protein complex. The IP6K1 interactome also included CK2, a protein kinase that phosphorylates Ser residues prior to pyrophosphorylation. We observe the formation of a protein complex between IP6K1, AP3B1, and the catalytic α-subunit of CK2, and show that disrupting IP6K1 binding to AP3B1 lowers its in vivo pyrophosphorylation. We propose that assembly of a substrate-CK2-IP6K complex would allow for coordinated pre-phosphorylation and pyrophosphorylation of the target serine residue, and provide a mechanism to regulate this enzyme-independent modification.

Rising temperatures due to the current climate crisis will soon have devastating impacts on crop performance and resilience. In particular, CO2 assimilation is dramatically limited at high temperatures. CO2 assimilation is accomplished by rubisco, which is inhibited by the binding of inhibitory sugar phosphates to its active site. Plants therefore utilize the essential chaperone rubisco activase (RCA) to remove these inhibitors and enable continued CO2 fixation. However, RCA does not function at moderately high temperatures (42°C), resulting in impaired rubisco activity and reduced CO2 assimilation. We set out to understand temperature-dependent RCA regulation in four different C4 plants, with a focus on the crop plants maize (two cultivars) and sorghum, as well as the model grass Setaria viridis (setaria) using gas exchange measurements, which confirm that CO2 assimilation is limited by carboxylation in these organisms at high temperatures (42°C). All three species express distinct complements of RCA isoforms and each species alters the isoform and proteoform abundances in response to heat; however, the changes are species-specific. We also examine whether the heat-mediated inactivation of RCA is due to biochemical regulation rather than simple thermal denaturation. We reveal that biochemical regulation affects RCA function differently in different C4 species, and differences are apparent even between different cultivars of the same species. Our results suggest that each grass evolved different strategies to maintain RCA function during stress and we conclude that a successful engineering approach aimed at improving carbon capture in C4 grasses will need to accommodate these individual regulatory mechanisms.