Systematic studies on the kinetic process of 20(S)-protopanaxadiol in rats and dogs: absorption, distribution, metabolism and excretion.

Background and Objective: Ginseng has been regarded as a precious medicinal herb with miraculous effects in Eastern culture. The primary chemical constituents of ginseng are saponins, and the physiological activities of ginsenosides determine their edible and medicinal value. The aim of this study is to comprehensively and systematically investigate the kinetic processes of 20(S)-protopanaxadiol (PPD) in rats and dogs, in order to promote the rational combination of ginseng as a drug and dietary ingredient. Methods: PPD was administered, and drug concentration in different biological samples were detected by liquid chromatography tandem mass spectrometry (LC/MS/MS) and radioactive tracer methods. Pharmacokinetic parameters such as absorption, bioavailability, tissue distribution, plasma protein binding rate, excretion rate, and cumulative excretion were calculated, along with inference of major metabolites. Results: This study systematically investigated the absorption, distribution, metabolism, excretion (ADME) of PPD in rats and dogs for the first time. The bioavailabilities of PPD were relatively low, with oral absorption nearly complete, and the majority underwent first-pass metabolism. PPD had a high plasma protein binding rate and was relatively evenly distributed in the body. Following oral administration, PPD underwent extensive metabolism, potentially involving one structural transformation and three hydroxylation reactions. The metabolites were primarily excreted through feces and urine, indicating the presence of enterohepatic circulation. The pharmacokinetic processes of PPD following intravenous administration aligned well with a three-compartment model. In contrast, after gastric administration, it fitted better with a two-compartment model, conforming to linear pharmacokinetics and proportional elimination. There were evident interspecies differences between rats and dogs regarding PPD, but individual variations of this drug were minimal within the same species. Conclusion: This study systematically studied the kinetic process of PPD in rats and also investigated the kinetic characteristics of PPD in dogs for the first time. These findings lay the foundation for further research on the dietary nutrition and pharmacological effects of PPD.

Theoretical insights into the reduction of Azurin metal site with unnatural amino acid substitutions.

Copper-containing proteins play crucial roles in biological systems. Azurin is a copper-containing protein which has a Type 1 copper site that facilitates electron transfer in the cytochrome chain. Previous research has highlighted the significant impact of mutations in the axial Met121 of the copper site on the reduction potential. However, the mechanism of this regulation has not been fully established. In this study, we employed theoretical modeling to investigate the reduction of the Type 1 copper site, focusing on how unnatural amino acid substitutions at Met121 influence its behavior. Our findings demonstrated a strong linear correlation between electrostatic interactions and the reduction potential of the copper site, which indicates that the perturbation of the reduction potential is primarily influenced by electrostatic interactions between the metal ion and the ligating atom. Furthermore, we found that CF/π and CF…H interactions could induce subtle changes in geometry and hence impact the electronic properties of the systems under study. In addition, our calculations suggest the coordination mode and ion-ligand distance could significantly impact the reduction potential of a copper site. Overall, this study offers valuable insights into the structural and electronic properties of the Type 1 copper site, which could potentially guide the design of future artificial catalysts.

Global burden and trends of leukemia attributable to high body mass index risk in adults over the past 30 years.

Background: High BMI (Body Mass Index) is a significant factor impacting health, with a clear link to an increased risk of leukemia. Research on this topic is limited. Understanding the epidemiological trends of leukemia attributable to high BMI risk is crucial for disease prevention and patient support. Methods: We obtained the data from the Global Burden of Disease Study, analyzing the ASR (age-standardized rates), including ASDR (age-standardized death rate) and age-standardized disability-adjusted life years (DALYs) rate, and estimated annual percentage change (EAPC) by gender, age, country, and region from 1990 to 2019. Results: In 2019, deaths and DALYs have significantly increased to 21.73 thousand and 584.09 thousand. The global age-standardized death and DALYs rates have slightly increased over the past 30 years (EAPCs: 0.34 and 0.29). Among four common leukemia subtypes, only CML (Chronic Myeloid Leukemia) exhibited a significant decrease in ASDR and age-standardized DALYs rate, with EAPC of -1.74 and -1.52. AML (Acute Myeloid Leukemia) showed the most pronounced upward trend in ASDR, with an EAPC of 1.34. These trends vary by gender, age, region, and national economic status. Older people have been at a significantly greater risk. Females globally have borne a higher burden. While males have shown an increasing trend. The regions experiencing the greatest growth in ASR were South Asia. The countries with the largest increases were Equatorial Guinea. However, It is worth noting that there may be variations among specific subtypes of leukemia. Regions with high Socio-demographic Index (SDI) have had the highest ASR, while low-middle SDI regions have shown the greatest increase in these rates. All ASRs values have been positively correlated with SDI, but there has been a turning point in medium to high SDI regions. Conclusions: Leukemia attributable to high BMI risk is gradually becoming a heavier burden globally. Different subtypes of leukemia have distinct temporal and regional patterns. This study's findings will provide information for analyzing the worldwide disease burden patterns and serve as a basis for disease prevention, developing suitable strategies for the modifiable risk factor.

Biodegradable Ferroelectric Molecular Plastic Crystal HOCH2(CF2)7CH2OH Structurally Inspired by Polyvinylidene Fluoride.

Ferroelectric materials, traditionally comprising inorganic ceramics and polymers, are commonly used in medical implantable devices. However, their nondegradable nature often necessitates secondary surgeries for removal. In contrast, ferroelectric molecular crystals have the advantages of easy solution processing, lightweight, and good biocompatibility, which are promising candidates for transient (short-term) implantable devices. Despite these benefits, the discovered biodegradable ferroelectric materials remain limited due to the absence of efficient design strategies. Here, inspired by the polar structure of polyvinylidene fluoride (PVDF), a ferroelectric molecular crystal 1H,1H,9H,9H-perfluoro-1,9-nonanediol (PFND), which undergoes a cubic-to-monoclinic ferroelectric plastic phase transition at 339 K, is discovered. This transition is facilitated by a 2D hydrogen bond network formed through O-H···O interactions among the oriented PFND molecules, which is crucial for the manifestation of ferroelectric properties. In this sense, by reducing the number of -CF2- groups from ≈5 000 in PVDF to seven in PFND, it is demonstrated that this ferroelectric compound only needs simple solution processing while maintaining excellent biosafety, biocompatibility, and biodegradability. This work illuminates the path toward the development of new biodegradable ferroelectric molecular crystals, offering promising avenues for biomedical applications.

Suboptimal diet quality is associated with the incidence of type 2 diabetes mellitus in middle-aged and older populations in China: evidence from a population-based cross-sectional study.

The association between dietary quality and type 2 diabetes mellitus (T2DM) based on the Chinese Dietary Balance Index (DBI-16) is seldom reported. We hypothesized that poor dietary quality might increase the risk of T2DM in the middle-aged and older populations. A total of 1816 individuals (≥50 years) were included in the study. Demographic characteristics and dietary intake data were collected. Logistic regression and restricted cubic spline (RCS) analyses were conducted to explore the association between DBI-16 indexes and the risk of T2DM. The insufficient intake of vegetables and dairy might decrease the risk of T2DM (ORVegetable = 0.77, 95% CI = 0.60-0.97; ORDairy = 0.58, 95% CI = 0.35-0.96), but the individuals with insufficient intake of fruit were more likely to have a higher risk of T2DM (ORfruit = 2.26, 95% CI = 1.69-3.06). Compared with the subjects with the lowest quartile of Low Bound Score (LBS) or Diet Quality Distance (DQD), the individuals with Q2 and Q3 level of LBS (ORQ2 = 1.40, 95% CI = 1.03-1.90, P = .033; ORQ3 = 1.52, 95% CI = 1.11-2.08, P < .01) or DQD (ORQ2 = 1.45, 95% CI = 1.06-1.99, P = .021; ORQ3 = 1.64, 95% CI = 1.20-2.24, P < .01) showed increased risk of T2DM with a nonlinear association observed by RCS analysis. We concluded that imbalanced dietary intake, especially insufficient daily fruit intake, might predict an increased risk of T2DM in the middle-aged and elderly Chinese.

Identification of a conserved G-quadruplex within the E165R of African swine fever virus (ASFV) as a potential antiviral target.

Identification of a conserved G-quadruplex in E165R of ASFVAfrican swine fever virus (ASFV) is a double-stranded DNA arbovirus with high transmissibility and mortality rates. It has caused immense economic losses to the global pig industry. Currently, no effective vaccines or medications are to combat ASFV infection. G-quadruplex (G4) structures have attracted increasing interest because of their regulatory role in vital biological processes. In this study, we identified a conserved G-rich sequence within the E165R gene of ASFV. Subsequently, using various methods, we verified that this sequence could fold into a parallel G4. In addition, the G4-stabilizers pyridostatin and 5,10,15,20-tetrakis-(N-methyl-4-pyridyl) porphin (TMPyP4) can bind and stabilize this G4 structure, thereby inhibiting E165R gene expression, and the inhibitory effect is associated with G4 formation. Moreover, the G4 ligand pyridostatin substantially impeded ASFV proliferation in Vero cells by reducing gene copy number and viral protein expression. These compelling findings suggest that G4 structures may represent a promising and novel antiviral target against ASFV.

Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy. / å”¾æ¶²é ¸ç³–åŸºè½¬ç§»é ¶ST3GAL6的沉默可通过减少α2,3-å”¾æ¶²é ¸åŒ–èšç³–é™ä½ŽHSPB8-BAG3è¡¨è¾¾ä»Žè€Œè°ƒæŽ§è‚æ€§è„‘ç— å°é¼ å¤§è„‘ä¸­çš„è‡ªå™¬.

End-stage liver diseases, such as cirrhosis and liver cancer caused by hepatitis B, are often combined with hepatic encephalopathy (HE); ammonia poisoning is posited as one of its main pathogenesis mechanisms. Ammonia is closely related to autophagy, but the molecular mechanism of ammonia's regulatory effect on autophagy in HE remains unclear. Sialylation is an essential form of glycosylation. In the nervous system, abnormal sialylation affects various physiological processes, such as neural development and synapse formation. ST3 ß|-galactoside α2,|3-sialyltransferase 6 (ST3GAL6) is one of the significant glycosyltransferases responsible for adding α2,3-linked sialic acid to substrates and generating glycan structures. We found that the expression of ST3GAL6 was upregulated in the brains of mice with HE and in astrocytes after ammonia induction, and the expression levels of α2,3-sialylated glycans and autophagy-related proteins microtubule-associated protein light chain 3 (LC3) and Beclin-1 were upregulated in ammonia-induced astrocytes. These findings suggest that ST3GAL6 is related to autophagy in HE. Therefore, we aimed to determine the regulatory relationship between ST3GAL6 and autophagy. We found that silencing ST3GAL6 and blocking or degrading α2,3-sialylated glycans by way of Maackia amurensis lectin-II (MAL-II) and neuraminidase can inhibit autophagy. In addition, silencing the expression of ST3GAL6 can downregulate the expression of heat shock protein ß8 (HSPB8) and Bcl2-associated athanogene 3 (BAG3). Notably, the overexpression of HSPB8 partially restored the reduced autophagy levels caused by silencing ST3GAL6 expression. Our results indicate that ST3GAL6 regulates autophagy through the HSPB8-BAG3 complex.

Study on the influence of water saturation on radon exhalation rates of rocks.

The radon exhalation characteristics of rocks will change significantly during water saturation treatment, and radon, as an important tracer, is of great significance in predicting rock activities. In this paper, the radon exhalation characteristics of rocks after saturated with different water contents were studied by centrifugal test, radon measurement test and other indoor tests. The results show that the radon exhalation rate of rocks shows a rising and then decreasing trend with the increase of rock water saturation. The radon precipitation rate peaked at 0.7 Sw âˆ¼ 0.8 Sw, and the high water saturation had an obvious inhibiting effect on the radon exhalation rate of rocks. The research results are of great significance in predicting the rock-water-based geological processes.

Purification and Structural Analyses of Sulfated Polysaccharides from Low-Value Sea Cucumber Stichopus naso and Anticoagulant Activities of Its Oligosaccharides.

Three polysaccharides (SnNG, SnFS and SnFG) were purified from the body wall of Stichopus naso. The physicochemical properties, including monosaccharide composition, molecular weight, sulfate content, and optical rotation, were analyzed, confirming that SnFS and SnFG are sulfated polysaccharides commonly found in sea cucumbers. The highly regular structure {3)-L-Fuc2S-(α1,}n of SnFS was determined via a detailed NMR analysis of its oxidative degradation product. By employing ß-elimination depolymerization of SnFG, tri-, penta-, octa-, hendeca-, tetradeca-, and heptadeca-saccharides were obtained from the low-molecular-weight product. Their well-defined structures confirmed that SnFG possessed the backbone of {D-GalNAc4S6S-ß(1,4)-D-GlcA}, and each GlcA residue was branched with Fuc2S4S. SnFS and SnFG are both structurally the simplest version of natural fucan sulfate and fucosylated glycosaminoglycan, facilitating the application of low-value sea cucumbers S. naso. Bioactivity assays showed that SnFG and its derived oligosaccharides exhibited potent anticoagulation and intrinsic factor Xase (iXase) inhibition. Moreover, a comparative analysis with the series of oligosaccharides solely branched with Fuc3S4S showed that in oligosaccharides with lower degrees of polymerization, such as octasaccharides, Fuc2S4S led to a greater increase in APTT prolongation and iXase inhibition. As the degree of polymerization increases, the influence from the sulfation pattern diminishes, until it is overshadowed by the effects of molecular weight.

Vinylcyclopropane-Cyclopentene (VCP-CP) Rearrangement Enabled by Pyridine-Assisted Boronyl Radical Catalysis.

An unprecedented VCP-CP (vinylcyclopropane-cyclopentene) rearrangement approach has been established herein by virtue of the pyridine-boronyl radical catalyzed intramolecular ring expansions. This metal-free radical pathway harnesses readily available catalysts and unactivated vinylcyclopropane starting materials, providing an array of cyclopentene derivatives chemoselectively under relatively mild conditions. Mechanistic studies support the idea that the boronyl radical engages in the generation of allylic/ketyl radical species, thus inducing the ring opening of cyclopropanes and the following intramolecular cyclization processes.

Rhodococcus equi and Brucella pulmonary mass in immunocompetent: A case report and literature review.

Rhodococcus equi, predominantly recognized as an opportunistic pathogen affecting immunocompromised hosts, and Brucella, a widespread zoonotic bacterium, infrequently co-infect immunocompetent adults, thereby posing a distinctive diagnostic challenge. Here, we describe a case involving a 53-year-old male with a history of goat farming, who presented with persistent chest tightness, cough, and notable weight loss, absent fever. Radiological and bronchoscopic assessments showed a right hilar mass, extensive vertebral destruction, and bronchial lesions, deviating from the typical symptoms associated with either pathogen. Laboratory analyses confirmed a co-infection involving R. equi and Brucella. Initial therapy with levofloxacin and vancomycin proved ineffective; however, a subsequent treatment regimen comprising azithromycin, etimicin, minocycline, and moxifloxacin resulted in substantial clinical improvement. This case accentuates the intricacies involved in diagnosing and managing atypical co-infections in immunocompetent individuals and underscores the importance of careful microbiological testing to inform effective therapeutic strategies.

Catalyst-free reaction of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates: synthesis of 1,2-dihydroquinolines and 2,3-dihydropyrroles.

Catalyst-free annulations of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates have been successfully achieved under mild conditions. Specifically, the reaction of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates with sulfur ylides furnished various 1,2-dihydroquinolines in generally high yields. Furthermore, [3+2]-annulations of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates with α,ß-unsaturated imines afforded a broad scope of polysubstituted 2,3-dihydropyrroles with high efficiency.

RUNX1 regulates MCM2/CDC20 to promote COAD progression modified by deubiquitination of USP31.

Colon adenocarcinoma (COAD) is the second leading cause of cancer death, and there is still a lack of diagnostic biomarkers and therapeutic targets. In this study, bioinformatics analysis of the TCGA database was used to obtain RUNX1, a gene with prognostic value in COAD. RUNX1 plays an important role in many malignancies, and its molecular regulatory mechanisms in COAD remain to be fully understood. To explore the physiological role of RUNX1, we performed functional analyses, such as CCK-8, colony formation and migration assays. In addition, we investigated the underlying mechanisms using transcriptome sequencing and chromatin immunoprecipitation assays. RUNX1 is highly expressed in COAD patients and significantly correlates with survival. Silencing of RUNX1 significantly slowed down the proliferation and migratory capacity of COAD cells. Furthermore, we demonstrate that CDC20 and MCM2 may be target genes of RUNX1, and that RUNX1 may be physically linked to the deubiquitinating enzyme USP31, which mediates the upregulation of RUNX1 protein to promote transcriptional function. Our results may provide new insights into the mechanism of action of RUNX1 in COAD and reveal potential therapeutic targets for this disease.

Lewis Acid-Catalyzed Formal [2π+2σ] Cycloaddition of Bicyclobutanes with Quinoxalin-2(1H)-ones: Access to Quinoxaline-Fused Aza-Bicyclo[2.1.1]hexanes.

An efficient synthesis of quinoxaline-fused aza-bicyclo[2.1.1]hexanes bearing multiple quaternary carbon centers via the intermolecular [2π+2σ] cycloaddition of bicyclo[1.1.0]butanes and quinoxalin-2(1H)-ones, facilitated by Lewis acid catalysis, is presented. This reaction is carried out under mild conditions and exhibits a broad substrate scope and excellent functional group tolerance.

Catechol compounds as dual-targeting agents for fish protection against Ichthyophthirius multifiliis infections.

Aquaculture is one of the fastest growing sectors in global food production, recognized as a significant contributor to poverty alleviation, food security, and income generation. However, the frequent occurrence of diseases caused by pathogen infections result in reduced yields and economic losses, posing a substantial constraint to the sustainable development of aquaculture. Here, our study identified that four catechol compounds, quercetin, luteolin, caffeic acid, and chlorogenic acid, exhibited potent antiparasitic effects against Ichthyophthirius multifiliis in both, in vitro and in vivo. The parasite is recognized as one of the most pathogenic to fish worldwide. Using a combination of in silico methods, the dipeptidyl peptidase (DPP) was identified as a critical target for catechol compounds. The two hydroxyl radicals of the catechol group were essential for its binding to and interacting with the DPP protein. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that catechol compounds disrupt pathways associated with the metabolism and growth of I. multifiliis, thereby exerting antiparasitic effects. Furthermore, these compounds attenuated the expression of proinflammatory cytokines in vivo in fish and promoted macrophage polarization toward M2 phenotype by inhibiting the STAT1 signaling pathway. The dual activity of catechol compounds, acting as both direct antiparasitic and anti-inflammatory agents in fish, offers a promising therapeutic approach for combating I. multifiliis infections in aquaculture.

High-elevation-induced decrease in soil pH weakens ecosystem multifunctionality by influencing soil microbiomes.

Plant environmental stress response has become a global research hotspot, yet there is a lack of clear understanding regarding the mechanisms that maintain microbial diversity and their ecosystem services under environmental stress. In our research, we examined the effects of moderate elevation on the rhizosphere soil characteristics, microbial community composition, and ecosystem multifunctionality (EMF) within agricultural systems. Our findings revealed a notable negative correlation between EMF and elevation, indicating a decline in multifunctionality at higher elevations. Additionally, our analysis across bacterial and protistan communities showed a general decrease in microbial richness with increasing elevation. Using random forest models, pH was identified as the key environmental stressor influencing microbial communities. Furthermore, we found that microbial community diversity is negatively correlated with stability by mediating complexity. Interestingly, while pH was found to affect the complexity within bacterial networks, it did not significantly impact the ecosystem stability along the elevation gradients. Using a Binary-State Speciation and Extinction (BiSSE) model to explore the evolutionary dynamics, we found that Generalists had higher speciation rates and lower extinction rates compared to specialists, resulting in a skewed distribution towards higher net diversification for generalists under increasing environmental stress. Moreover, structural equation modeling (SEM) analysis highlighted a negative correlation between environmental stress and community diversity, but showed a positive correlation between environmental stress and degree of cooperation & competition. These interactions under environmental stress indirectly increased community stability and decreased multifunctionality. Our comprehensive study offers valuable insights into the intricate relationship among environmental factors, microbial communities, and ecosystem functions, especially in the context of varying elevation gradients. These findings contribute significantly to our understanding of how environmental stressors affect microbial diversity and ecosystem services, providing a foundation for future ecological research and management strategies in similar contexts.

Benchmarking State-of-the-Art Large Language Models for Migraine Patient Education: A Comparison of Performances on the Responses to Common Queries.

UNSTRUCTURED: Migraine, a frequent and highly disabling disorder, necessitates enhanced education of individuals with migraine to mitigate this global burden. The rapidly evolving field of large language models (LLMs) presents a promising avenue for assisting in migraine patient education. This study aims to assess the potential of LLMs in this context by evaluating the accuracy of responses from five leading LLMs, including OpenAI's ChatGPT 3.5 and 4.0, Google Bard, Meta Llama2, and Anthropic Claude2, in addressing 30 commonly asked migraine-related queries. We found that LLMs demonstrated varied levels of accuracy. ChatGPT-4.0 provided 96.7% appropriate responses, while other chatbots provided 83.3% to 90% appropriate responses (Pearson's chi-squared test, P=0.481). Additionally, Google Bard had a 'poor' rating proportion of 6.7%, other LLMs had 3.3% (Pearson's chi-squared test, P=0.961). This study underscores the potential of LLMs to accurately address common migraine-related queries. Such findings could advance AI-assisted education for individuals with migraine, providing insights for a holistic approach to migraine management.

Mutations in nonstructural proteins essential for pathogenicity in SARS-CoV-2-infected mice.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has resulted in substantial morbidity and mortality. The basis of severe disease in humans is difficult to determine without the use of experimental animal models. Mice are resistant to infection with ancestral strains of SARS-CoV-2, although many variants that arose later in the pandemic were able to directly infect mice. In almost all cases, viruses that naturally infected mice or were engineered to enable mouse infection required mouse passage to become virulent. In most cases, changes in structural and nonstructural changes occurred during mouse adaptation. However, the mechanism of increased virulence in mice is not understood. Here, using a recently described strain of mouse-adapted SARS-CoV-2 (rSARS2-MA30N501Y), we engineered a series of recombinant viruses that expressed a subset of the mutations present in rSARS2-MA30N501Y. Mutations were detected in the spike protein and in three nonstructural proteins (nsp4, nsp8, and nsp9). We found that infection of mice with recombinant SARS-CoV-2 expressing only the S protein mutations caused very mild infection. Addition of the mutations in nsp4 and nsp8 was required for complete virulence. Of note, all these recombinant viruses replicated equivalently in cultured cells. The innate immune response was delayed after infection with virulent compared to attenuated viruses. Further, using a lineage tracking system, we found that attenuated virus was highly inhibited in the ability to infect the parenchyma, but not the airway after infection. Together, these results indicate that mutations in both the S protein and nonstructural proteins are required for maximal virulence during mouse adaptation.IMPORTANCEUnderstanding the pathogenesis of coronavirus disease 2019 (COVID-19) requires the study of experimental animals after infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). For this purpose, several mouse-adapted SARS-CoV-2 strains have been developed. Here, using a strain of mouse-adapted virus that causes a range of diseases ranging from mild to severe, we show that mutations in both a structural protein [spike (S) protein] and nonstructural proteins are required for maximal virulence. Thus, changes in the S protein, the most widely studied viral protein, while required for mouse adaptation, are not sufficient to result in a virulent virus.