Biomolecules最新文献

Mammalian placentation represents one of the most striking evolutionary innovations among vertebrates, and accumulating evidence indicates that virus-derived genes-particularly the metavirus-derived PEG10 and PEG11/RTL1-have played indispensable but distinct roles: PEG10 in the emergence of therian viviparity and PEG11/RTL1 in the subsequent differentiation between marsupial and eutherian placental types. Notably, the metavirus-derived SIRH/RTL gene group, which includes PEG10 and PEG11/RTL1, exhibits unique and diverse functions not only in placenta development but also within microglia of the brain. Because microglia originate from yolk sac progenitors, these findings suggest that extraembryonic tissues such as the placenta and yolk sac provided permissive environments that enabled the retention, expression and functional domestication of virus-derived sequences. Once the placenta itself was established through viral gene integration, it may in turn have acted as a powerful driver of eutherian evolution through recurrent acquisition and co-option of additional virus-derived genes-a process we refer to as "placenta-driven evolution." This perspective offers a unified framework in which viral gene acquisition is viewed as a key driver of genomic innovation, tightly intertwined with the emergence of viviparity, subsequent divergence at the marsupial-eutherian split, and continued diversification of placental structure and function across eutherian lineages.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, resulting in cardinal motor symptoms such as tremor, rigidity, and bradykinesia. Neuroinflammation is increasingly recognized as a central driver of PD onset and progression in which oligodendrocytes, astrocytes, and microglia engage in complex bidirectional crosstalk that shapes the inflammatory milieu of the central nervous system. Pathological activation of glial cells triggers the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species, thereby exacerbating neuronal injury and contributing to sustained disease progression. Modulating maladaptive glial activation states and their intercellular communication represents a promising therapeutic avenue aimed at mitigating neuroinflammation and slowing PD pathology. This review synthesizes current knowledge on neuroinflammation in PD, focusing on the distinct roles of microglia, astrocytes, and oligodendrocytes, their interaction networks, and emerging therapeutic strategies.

Dental caries is a multifactorial chronic infectious disease that impacts healthcare costs globally, caused by alterations of the plaque microbiome and proliferation of cariogenic Streptococcus mutans. Treatments targeting S. mutans, such as alternative strategies using probiotics, might be effective in preventing the development of dental caries. In this study, the probiotic formulation of Lactobacillus reuteri SGL01, vitamin C, and acerola was tested against S. mutans DSM20523. Antimicrobial activity was assessed by deferred antagonism and spot-on-lawn assays for L. reuteri SGL01. MIC and MBC of L. reuteri SGL01 cell-free supernatant (CFS), vitamin C, and acerola were determined with the microdilution method. Time-kill assays determined the bactericidal kinetics for each compound. The checkerboard method was used to evaluate the potential synergistic activity of CFS-vitamin C or CFS-acerola at scalar dilutions from 1 to 8X MIC. Lastly, antibiofilm activity was tested for each compound. Antimicrobial activity of L. reuteri SGL01 was first assessed by classic methods. MIC and MBC values differed for one dilution for all compounds, with values of 25% and 50% for CFS, 9.3 mg/mL and 18.7 mg/mL for vitamin C, and 18.7 mg/mL and 37.5 mg/mL for acerola, respectively. Moreover, time-kill assays confirmed the bactericidal activity at different timepoints: 4 h for CFS, 6 h for vitamin C, and 24 h for acerola. The fractional inhibitory concentration index (FICI) showed indifference for all combinations, and for associations tested at 2, 4, and 8XMIC. S. mutans biofilm production was impaired for all components, with stronger activity by vitamin C and acerola at lower concentrations. The probiotic formulation containing L. reuteri SGl01, vitamin C, and acerola extract exerts a bactericidal effect, especially strong for the CFS, as well as antibiofilm activity. Thus, the combination of these three components could be advantageous for their complementary effects, with use as a novel treatment against the development of dental caries by S. mutans.

Blood-sucking organisms produce various anticoagulant proteins that prevent blood clotting in their prey. Even in well-studied species like Hirudo medicinalis, many such proteins remain unidentified. We previously described a novel cysteine-rich anticoagulant (CRA), a distant homolog of antistasin. Later, we discovered another, much larger homolog in the medicinal leech. Its amino acid sequence is also highly cysteine-rich. Analysis of cysteine patterns showed four antistasin-like domain motifs, with one of them strongly disrupted. Since both antistasin and CRA contain two such domains, the new protein represents a duplicated antistasin-like structure. We cloned its cDNA, expressed the recombinant protein in Escherichia coli, purified it by metal-chelate chromatography, refolded it, and tested its anticoagulant properties. Using standard clinical assays-activated partial thromboplastin time, prothrombin time, and thrombin time-we found that the protein inhibited coagulation in all tests, though to varying degrees. These findings suggest that different antistasin-like anticoagulants in the leech enable it to block both intrinsic and extrinsic coagulation pathways, while hirudin inhibits the final step of clot formation. The combination of different anticoagulant proteins allows the leech to effectively prevent the prey's blood from clotting during feeding.

Two series of tri(2-furyl)- and triphenylphosphine-gold(I) complexes, with pyridyl- and pyrimidine-thiolate ligands containing electron-donating (-CH₃) and electron-withdrawing (-CF₃) substituents were synthesized and investigated for cell viability inhibitions. Prior results indicate that several of the gold(I) complexes in these series have high antifungal properties. The observed link between antifungal and anticancer activity provided motivation to investigate their antiproliferative effects, reported here. The synthesized compounds from both series were characterized by ¹H, ¹³C, and ³¹P NMR spectroscopy, mass spectrometry (MS), infrared and UV-Vis spectroscopy, and solution stability studies. In addition, an X-ray crystallographic study was conducted on one of the gold(I) complexes. Analyte solubilities in McCoy's 5A cell media were evaluated by ICP-MS. Initial screening studies were conducted on the two series to evaluate cell viability using the SK-BR-3 cell line. All ten gold(I) complexes exhibited sub-µM cytotoxicity and the most potent representatives, one from each series, were selected for further evaluation in four additional cell lines. Half-maximal effective concentrations (EC₅₀) were determined for the MCF7 and MDA-MB-231 malignant mammary cell lines as well as the two control cell lines, HEK293T and MCF10A, to probe for specificity. Results indicate significant selectivity towards inhibition of cancer cells compared to non-transformed for tri(2-furyl)- and triphenylphosphine-gold(I) complexes with the 3,5-dimethylpyrimidine thiolate ligand when dissolved in cell media. Additional studies including 1% DMSO as a solubilizing agent revealed its significant impact on cellular responses.

The increasing demand for rapid identification of bacteria capable of degrading environmentally relevant organic compounds highlights the need for scalable and selective analytical tools. Cupriavidus necator catabolizes several hydroxybenzoic acids, including 2-hydroxybenzoate (salicylate, 2-HBA), 4-hydroxybenzoate (4-HBA), and 3-hydroxybenzoate (3-HBA), funneling them into central aromatic catabolism via monooxygenation to 2,5-dihydroxybenzoate (gentisate, 2,5-dHBA) and 3,4-dihydroxybenzoate (protocatechuate, 3,4-dHBA) followed by the oxidative cleavage reaction, enabling complete conversion to tricarboxylic acid (TCA) cycle intermediates. To quantify how readily C. necator is able to activate catabolic genes in response to hydroxybenzoic acid, an extracellular ligand, we applied an approach centered on a transcription-factor (TF)-based biosensor that combines ligand-bound regulator activity with a fluorescent reporter. This approach allowed to evaluate the ligand sensitivity by determining gene activation threshold AC_min and half-maximal effective concentration EC₅₀. Amongst studied hydroxybenzoic acids, 2-HBA and 4-HBA sensors from C. necator showed very low thresholds 4.8 and 2.4 μM and EC₅₀ values of 19.91 and 13.06 μM, indicating high sensitivity to these compounds and implicating a scavenging characteristic of associated catabolism. This study shows that the TF-based-biosensor approach applied for mapping functional sensing ranges of hydroxybenzoates combined with the research and informatics of catabolism can advance our understanding of how gene expression regulation systems have evolved to respond differentially to the availability and concentration of carbon sources. Furthermore, it can inform metabolic engineering strategies in the prevention of premature pathway activation or in predicting competitive substrate hierarchies in complex mixed environments.

A novel steviol glycoside, Rebaudioside D17, was identified from the leaf extract of Stevia rebaudiana Bertoni. This compound features a rare β-1→4 glycosidic linkage between two glucose units at the C19 position, distinguishing it from its structural isomer, Rebaudioside D. The aim of this study was to isolate and characterize Rebaudioside D17 and investigate its biosynthetic origin. The compound was isolated and structurally characterized using comprehensive NMR spectroscopy including ¹H, ¹³C, COSY, NOESY, Heteronuclear Single Quantum Coherence-Distortionless Enhancement by Polarization Transfer (HSQC-DEPT), Heteronuclear Multiple Bond Correlation (HMBC), Heteronuclear Single Quantum Coherence-Total Correlated Spectroscopy (HSQC-TOCSY), along with mass spectrometry analysis. A tentative biosynthetic pathway is proposed, involving Rebaudioside E19, a putative intermediate bearing the same β-1→4 glycosidic linkage at C19. Rebaudioside E19 may serve as a common precursor to both Rebaudioside D17 and Rebaudioside U3, a minor steviol glycoside previously reported in Stevia rebaudiana leaf extract, which also contains the same β-1→4 glycosidic linkage. The discovery of Rebaudioside D17 expands the known diversity of steviol glycosides and provides new insights into glycosylation patterns in Stevia rebaudiana, which may support the development and production of novel sweeteners with improved sensory and physicochemical properties.

Background: Mechanical loading is a fundamental regulator of bone remodelling; however, the mechanotransduction mechanisms governing alveolar bone adaptation under tensile-dominant orthodontic loading remain insufficiently defined. In particular, the molecular pathways associated with tension-driven cortical modelling in the periodontal ligament (PDL)-bone complex have not been systematically interpreted in the context of advanced biomechanical simulations. Methods: A nonlinear finite element model of the alveolar bone-PDL-tooth complex was developed using patient-specific CBCT data. Three loading configurations were analysed: (i) conventional orthodontic loading, (ii) loading combined with corticotomy alone, and (iii) a translation-dominant configuration generated by the Bone Protection System (BPS). Pressure distribution, displacement vectors, and stress polarity within the PDL and cortical plate were quantified across different bone density conditions. The mechanical outputs were subsequently interpreted in relation to established mechanotransductive molecular pathways involved in osteogenesis and angiogenesis. Results: Conventional loading generated compression-dominant stress fields within the marginal PDL, frequently exceeding physiological thresholds and producing moment-driven root displacement. Corticotomy alone reduced local stiffness but did not substantially alter stress polarity. The BPS configuration redirected loads toward a tensile-favourable mechanical environment characterised by reduced peak compressive pressures and parallel (translation-dominant) displacement vectors. The predicted tensile stress distribution is compatible with activation profiles of key mechanosensitive pathways, including integrin-FAK signalling, Wnt/β-catenin-mediated osteogenic differentiation and HIF-1α/VEGF-driven angiogenic coupling, suggesting a microenvironment that may be more conducive to cortical apposition than to resorption. Conclusions: This study presents a computational-molecular framework linking finite element-derived tensile stress patterns with osteogenic and angiogenic signalling pathways relevant to alveolar bone remodelling. The findings suggestthat controlled redirection of orthodontic loading toward tensile domains may shift the mechanical environment of the PDL-bone complex toward conditions associated with osteogenic than resorptive responses providing a mechanistic basis for tension-induced cortical modelling. This mechanobiological paradigm advances the understanding of load-guided alveolar bone adaptation at both the tissue and molecular levels.

Selective inhibition of CYP17A1 17,20-lyase is critical for treating hyperandrogenic disorders without the cortisol-depleting side effects of non-selective drugs like abiraterone. We evaluated tanshinones from Salvia miltiorrhiza as potential selective inhibitors using biochemical assays and computational modeling. Dihydrotanshinone (DT) emerged as the superior candidate; at 10 µM, it inhibited 17,20-lyase activity by 56.6% while preserving >93% of 17α-hydroxylase activity. This yields a selectivity index of 8.67, drastically outperforming abiraterone (0.73). Furthermore, DT displayed minimal off-target inhibition of CYP21A2 (14.9%) compared to abiraterone (29.8%). Molecular modeling suggests DT's efficacy arises from a unique, functionally disruptive binding pose rather than superior thermodynamic affinity. Consequently, DT is validated as a potent natural product lead. Its dual selectivity over 17α-hydroxylase and CYP21A2 establishes the tanshinone scaffold as a promising candidate for developing safer therapies that suppress androgens while sparing cortisol biosynthesis.

In today's world, unhealthy living habits have contributed to the rise in metabolic disorders like hyperlipidemia. Recognized as a popular edible and medicinal mushroom in China and various eastern nations, Ganoderma lucidum is a promising high-value functional and medicinal food with multiple biological activities. Our earlier research has demonstrated that G. lucidum polysaccharides (GLP) showed distinct lipid-lowering abilities by enhancing the response to oxidative stress and inflammation, adjusting bile acid production and lipid regulation factors, and facilitating reverse cholesterol transport through Nrf2-Keap1, NF-κB, LXRα-ABCA1/ABCG1, CYP7A1-CYP27A1, and FXR-FGF15 pathways, hence we delved deeper into the effects of GLP on hyperlipidemia, focusing on its structural characterization, gut microbiota, and fecal metabolites. Our findings showed that GLP changed the composition and structure of gut microbiota, and 10 key biomarker strains screened by LEfSe analysis markedly increased the abundance of energy metabolism, and cell growth and death pathways which were found by PICRUSt2. In addition, GLP intervention significantly altered the fecal metabolites, which enriched in amino acid metabolism and lipid metabolism pathways. The results of structural characterization showed that GLP, with the molecular weight of 12.53 kDa, consisted of pyranose rings and was linked by α-type and β-type glycosidic bonds, and its overall morphology appeared as an irregular flaky structure with some flecks and holes in the surface. Collectively, our study highlighted that the protective effects of GLP were closely associated with the modification of gut microbiota and the regulation of metabolites profiles, thus ameliorating dyslipidemia.