Critical factors in soil organic carbon mineralization induced by drying, wetting and wet-dry cycles in a typical watershed of Loess Plateau.

As global climate change progresses, soil will experience prolonged periods of both drought and heavy rainfall, leading to a more frequent drought-re-wetting process that may impact the ecosystem's carbon (C) cycle. However, understanding the extent to which different water conditions and wet-dry cycles alter the process of soil organic carbon (SOC) mineralization remains limited. Therefore, our study focused on the dammed land unique to the Loess Plateau, silted by check dams constructed for erosion control. We implemented three water gradients-drought (30% WHC), water stress (100% WHC), and wet-dry cycling (30-100%)-indoors to observe the SOC mineralization process five times. We identified a transient excitation effect of the wet-dry cycles on SOC mineralization. Soil mineralization decreased gradually with the alternation of wet-dry cycles. The wet-dry cycles not only significantly impacted the contents of SOC and TN but also stimulated the activities of enzymes related to C and N cycles. As the cycle frequency increased, the utilization of C sources by soil microorganisms gradually decreased, and the dominance of carbohydrates, amines, and acids evolved into a single acid, esters, or alcohols. Phosphatase and Chloroflexi were the main factors influencing SOC mineralization under drought stress, while TN and Ascomycota were the primary factors under water stress. SOC and Gemmatimonadetes were the main limiting factors for SOC mineralization under the wet-dry cycles. Additionally, we quantified the direct and interactive contributions of each factor to SOC mineralization. The direct contributions of drought stress, water stress, and the wet-dry cycles to SOC mineralization were 0.961, 0.736, and 0.942, respectively. This study contributes to a more comprehensive understanding of the mechanisms underlying SOC mineralization in the Loess Plateau under changing conditions.

ROS-responsive celastrol-nanomedicine alleviates inflammation for dry eye disease.

Dry eye disease (DED) is a major global eye disease leading to severe eye discomfort and even vision impairment. The incidence of DED has been gradually increasing with the high frequency of use of electronic devices. It has been demonstrated that celastrol (Cel) has excellent therapeutic efficacy in ocular disorders. However, the poor water solubility and short half-life of Cel limit its further therapeutic applications. In this work, a reactive oxygen species (ROS) sensitive polymeric micelle was fabricated for Cel delivery. The micelles improve the solubility of Cel, and the resulting Cel loaded micelles exhibit an enhanced intervention effect for DED. Thein vitroresults demonstrated that Cel-nanomedicine had a marked ROS responsive release behavior. The results ofin vitroandin vivoexperiments demonstrated that Cel has excellent biological activities to alleviate inflammation in DED by inhibiting TLR4 signaling activation and reducing pro-inflammatory cytokine expression. Therefore, the Cel nanomedicine can effectively eliminate ocular inflammation, promote corneal epithelial repair, and restore the number of goblet cells and tear secretion, providing a new option for the treatment of DED.

The moderating effect of physical activity on the relationship between neutrophil count and depressive symptoms.

Variations in immune cell counts can trigger depressive symptoms, while physical activity effectively reduces the risk and severity of depressive symptoms. This study, based on the NHANES database, analyzes the relationship between neutrophil count and depressive symptoms and explores the moderating effect of physical activity on this relationship. Cross-sectional data from the NHANES database were extracted, including immune cell counts, PHQ-9 scores for self-assessment of depressive symptoms, and Global Physical Activity Questionnaire (GPAQ) scores (PA). The interrelations among physical activity, neutrophil count, and depressive symptoms were analyzed. After controlling for confounding factors, neutrophil count was found to have a significant role in identifying depressive symptoms with an odds ratio (OR) [95% Confidence Interval (CI)] = 1.13 [1.02, 1.251]; the moderating effect of physical activity on the impact of neutrophil count on depressive symptoms was statistically significant (coefficient = -0.0028, P < 0.05). Neutrophil count may be a significant factor in identifying depressive symptoms in adults. As an effective moderating factor, physical activity can mitigate the impact of neutrophil count on depressive symptoms to a certain extent.

Raddeanin A Protects the BRB Through Inhibiting Inflammation and Apoptosis in the Retina of Alzheimer's Disease.

Neuroinflammation and endothelial cell apoptosis are prominent features of blood-brain barrier (BBB) disruption, which have been described in Alzheimer's disease (AD) and can predict cognitive decline. Recent reports revealed vascular ß-amyloid (Aß) deposits, Muller cell degeneration and microglial dysfunction in the retina of AD patients. However, there has been no in-depth research on the roles of inflammation, retinal endothelial cell apoptosis, and blood-retinal barrier (BRB) damage in AD retinopathy. We found that Raddeanin A (RDA) could improve pathological and cognitive deficits in a mouse model of Alzheimer's disease by targeting ß-amyloidosis, However, the effects of RDA on AD retinal function require further study. To clarify whether RDA inhibits inflammation and apoptosis and thus improves BRB function in AD-related retinopathy. In vitro we used Aß-treated HRECs and MIO-M1 cells, and in vivo we used 3×Tg-AD mice to investigate the effect of RDA on BRB in AD-related retinopathy. We found that RDA could improve BRB function in AD-related retinopathy by inhibiting NLRP3-mediated inflammation and suppressing Wnt/ß-catenin pathway-mediated apoptosis, which is expected to improve the pathological changes in AD-related retinopathy and the quality of life of AD patients.

3D-printed porous zinc scaffold combined with bioactive serum exosomes promotes bone defect repair in rabbit radius.

Currently, the repair of large bone defects still faces numerous challenges, with the most crucial being the lack of large bone grafts with good osteogenic properties. In this study, a novel bone repair implant (degradable porous zinc scaffold/BF Exo composite implant) was developed by utilizing laser melting rapid prototyping 3D printing technology to fabricate a porous zinc scaffold, combining it under vacuum conditions with highly bioactive serum exosomes (BF EXO) and Poloxamer 407 thermosensitive hydrogel. The electron microscope revealed the presence of tea saucer-shaped exosomes with a double-layered membrane structure, ranging in diameter from 30-150 nm, with an average size of 86.3 nm and a concentration of 3.28E+09 particles/mL. In vitro experiments demonstrated that the zinc scaffold displayed no significant cytotoxicity, and loading exosomes enhanced the zinc scaffold's ability to promote osteogenic cell activity while inhibiting osteoclast activity. In vivo experiments on rabbits indicated that the hepatic and renal toxicity of the zinc scaffold decreased over time, and the loading of exosomes alleviated the hepatic and renal toxic effects of the zinc scaffold. Throughout various stages of repairing radial bone defects in rabbits, loading exosomes reinforced the zinc scaffold's capacity to enhance osteogenic cell activity, suppress osteoclast activity, and promote angiogenesis. This effect may be attributed to BF Exo's regulation of p38/STAT1 signaling. This study signifies that the combined treatment of degradable porous zinc scaffolds and BF Exo is an effective and biocompatible strategy for bone defect repair therapy.

Organocatalytic Enantioselective 1,12-Addition of Alkynyl Biphenyl Quinone Methides Formed In Situ.

The chemistry of quinone methides formed in situ has been flourishing in recent years. In sharp contrast, the development and utilization of biphenyl quinone methides are rare. Herein, we achieved a remote stereocontrolled 1,12-conjugate addition of biphenyl quinone methides formed in situ for the first time. In the presence of a suitable chiral phosphoric acid, alkynyl biphenyl quinone methides were generated from α-[4-(4-hydroxyphenyl)phenyl]propargyl alcohols, followed by enantioselective 1,12-conjugate addition with indole-2-carboxylates. The strategy enabled the additional alcohols to serve as efficient allenylation reagents, providing a practical access to a broad range of axially chiral allenes bearing (1,1'-biphenyl)-4-ol unit that are previously less accessible. Combined with control experiments, density functional theory calculations shed light on the reaction mechanism, indicating that enantioselectivity originates from the nucleophilic addition of alkynyl biphenyl quinone methides. Notably, not only the presence of biphenyl quinone methides as versatile intermediates was confirmed but also organocatalytic enantioselective 1,12-addition was established for the first time. This work enriched the family of quinone methides and provided a new platform for the remote stereocontrolled transformation of such versatile intermediates.

Peripheral blood transcriptomic profiling of molecular mechanisms commonly regulated by binge drinking and placebo effects.

Molecular responses to alcohol consumption are dynamic, context-dependent, and arise from a complex interplay of biological and external factors. While many have studied genetic risk associated with drinking patterns, comprehensive studies identifying dynamic responses to pharmacologic and psychological/placebo effects underlying binge drinking are lacking. We investigated transcriptome-wide response to binge, medium, and placebo alcohol consumption by 17 healthy heavy social drinkers enrolled in a controlled, in-house, longitudinal study of up to 12 days. Using RNA-seq, we identified 251 and 13 differentially expressed genes (DEGs) in response to binge drinking and placebo, respectively. Eleven protein-coding DEGs had very large effect sizes in response to binge drinking (Cohen's d > 1). Furthermore, binge dose significantly impacted the Cytokine-cytokine receptor interaction pathway (KEGG: hsa04060) across all experimental sequences. Placebo also impacted hsa04060, but only when administered following regular alcohol drinking sessions. Similarly, medium-dose and placebo commonly impacted KEGG pathways of Systemic lupus erythematosus, Neutrophil extracellular trap formation, and Alcoholism based on the sequence of drinking sessions. These findings together indicate the "dose-extending effects" of placebo at a molecular level. Furthermore, besides supporting alcohol dose-specific molecular changes, results suggest that the placebo effects may induce molecular responses within the same pathways regulated by alcohol.

Hematocrit drift and outcomes in surgical patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: There is a paucity of conclusive evidence regarding the impact of downward drift in hematocrit levels among patients who have undergone surgical clipping for aneurysmal subarachnoid hemorrhage (aSAH). This study endeavors to explore the potential association between hematocrit drift and mortality in this specific patient population. METHODS: A cohort study was conducted, encompassing adult patients diagnosed with aSAH at a university hospital. The primary endpoint was follow-up mortality. Propensity score matching was employed to align patients based on their baseline characteristics. Discrimination capacity across various models was assessed and compared using net reclassification improvement (NRI). RESULTS: Among the 671 patients with aSAH in the study period, 118 patients (17.6%) experienced an in-hospital hematocrit drift of more than 25%. Following adjustment with multivariate regression analysis, patients with elevated hematocrit drift demonstrated significantly increased odds of mortality (aOR: 2.12, 95% CI: 1.14 to 3.97; P = 0.019). Matching analysis yielded similar results (aOR: 2.07, 95% CI: 1.05 to 4.10; P = 0.036). The inclusion of hematocrit drift significantly improved the NRI (P < 0.0001) for mortality prediction. When in-hospital hematocrit drift was served as a continuous variable, each 10% increase in hematocrit drift corresponded to an adjusted odds ratio of 1.31 (95% CI 1.08-1.61; P = 0.008) for mortality. CONCLUSIONS: In conclusion, the findings from this comprehensive cohort study indicate that a downward hematocrit drift exceeding 25% independently predicts mortality in surgical patients with aSAH. These findings underscore the significance of monitoring hematocrit and managing anemia in this patient population.

Unveiling the Selectivity of Ru(II)-Catalyzed C-H Activation for Defluorinative Cyclization of 2-Arylbenzimidazole and Trifluoromethyl Diazo: A DFT Study.

The synthesis of monofluorinated heterocyclic compounds by C-H activation combined with defluorination is useful. Studies on the reaction mechanism and selectivity have shown that these processes play a positive role in promoting the development of monofluorinated reactions. Density functional theory (DFT) calculations were performed to investigate the mechanism and selectivity of Ru(II)-catalyzed 2-arylbenzimidazole with trifluoromethyl diazo. DFT calculations showed that C-H activation occurs through a concerted metalation/deprotonation (CMD) mechanism. After that, deprotonation and defluorinative cyclization are assisted by acetate and trifluoroethanol (TFE). Further mechanistic insights through noncovalent interaction (NCI) analysis were also obtained to elucidate the origin of the selectivity in the defluorination process.

Infertility risk assessment with ultrasound in congenital adrenal hyperplasia male patients.

Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (rs = - 0.83, P < 0.001) and progressive motility (rs = - 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.

Comparative study on the efficacy of Conbercept and Aflibercept in the treatment of neovascular age-related macular degeneration.

This study compares the effectiveness of Conbercept and Aflibercept in treating neovascular age-related macular degeneration (nAMD). Conducted at the First Affiliated Hospital of Chongqing Medical University's Ophthalmology Department (May 2020-May 2023), this prospective study enrolled 159 nAMD patients. Participants were randomly divided into two groups: one receiving 0.5 mg Conbercept and the other 2 mg Aflibercept intravitreal injections. Over 12 months, the study, employing a Treat-and-Extend (T&E) regimen, assessed Best-Corrected Visual Acuity (BCVA), Central Retinal Thickness (CRT) changes and injection frequency. Of the 159 patients, 137 (149 eyes) completed the study. No significant age difference was found between the groups (P = 0.331). After 12 months, BCVA improved similarly in both groups (Conbercept: 52.8 ± 18.9, Aflibercept: 52.0 ± 19.7 letters; P = 0.820). CRT reduction was also comparable (Conbercept: 246.3 ± 82.8 µm, Aflibercept: 275.9 ± 114.3 µm; P = 0.079). Injection frequencies averaged 6.9 ± 0.7 (Conbercept) and 6.7 ± 0.7 (Aflibercept; P = 0.255). Subtype analysis revealed Type 1 MNV had higher baseline BCVA and lower CRT, with more frequent injections compared to other types. Both Conbercept and Aflibercept are clinically similar in efficacy for nAMD, with the T&E regimen proving therapeutically effective and potentially reducing patient costs. Anti-VEGF treatment efficacy varies across nAMD subtypes, indicating a potential benefit in tailored treatments for specific subtypes.Clinical trial registration number NCT05539235 (Protocol Registration and Results System).

Enhanced rock weathering increased soil phosphorus availability and altered root phosphorus-acquisition strategies.

Enhanced rock weathering (ERW) has been proposed as a measure to enhance the carbon (C)-sequestration potential and fertility of soils. The effects of this practice on the soil phosphorus (P) pools and the general mechanisms affecting microbial P cycling, as well as plant P uptake are not well understood. Here, the impact of ERW on soil P availability and microbial P cycling functional groups and root P-acquisition traits were explored through a 2-year wollastonite field addition experiment in a tropical rubber plantation. The results show that ERW significantly increased soil microbial carbon-use efficiency and total P concentrations and indirectly increased soil P availability by enhancing organic P mobilization and mineralization of rhizosheath carboxylates and phosphatase, respectively. Also, ERW stimulated the activities of P-solubilizing (gcd, ppa and ppx) and mineralizing enzymes (phoADN and phnAPHLFXIM), thus contributing to the inorganic P solubilization and organic P mineralization. Accompanying the increase in soil P availability, the P-acquisition strategy of the rubber fine roots changed from do-it-yourself acquisition by roots to dependence on mycorrhizal collaboration and the release of root exudates. In addition, the direct effects of ERW on root P-acquisition traits (such as root diameter, specific root length, and mycorrhizal colonization rate) may also be related to changes in the pattern of belowground carbon investments in plants. Our study provides a new insight that ERW increases carbon-sequestration potential and P availability in tropical forests and profoundly affects belowground plant resource-use strategies.

Atomic layer deposited TiO2 nanofilm on titanium implant for reduced the release of particles.

Objective: Titanium implants are widely used in surgeries for their biocompatibility and mechanical properties. However, excessive titanium particle release can cause implant failure. This study explores Atomic Layer Deposition (ALD) to coat commercially pure titanium (Cp-Ti) with TiO2, aiming to improve its frictional and corrosion resistance while reducing particle release. By comparing TiO2 films with varying ALD cycle numbers, we assess surface properties, particle release, friction, and corrosion performance, providing insights into mitigating particle release from implants. Methods: Cp-Ti surfaces were prepared and coated with TiO2 films of 100, 300, and 500 ALD cycles. Surface characterization involved SEM, EDX, and XRD. Friction was tested using SEM, nanoindentation, and ICP-MS. Corrosion resistance was evaluated through immersion tests and electrochemical analysis. Cytotoxicity was assessed using BMSCs. Results: Surface characterization revealed smoother surfaces with increased ALD cycles, confirming successful TiO2 deposition. Friction testing showed reduced friction coefficients with higher ALD cycles, supported by nanoindentation results. Corrosion resistance improved with increasing ALD cycles, as evidenced by electrochemical tests and reduced titanium release. Cytotoxicity studies showed no significant cytotoxic effects. Conclusion: ALD-coated TiO2 films significantly enhance frictional and corrosion resistance of titanium implants while reducing particle release. The study underscores the importance of ALD cycle numbers in optimizing film performance, offering insights for designing implants with improved properties.

High levels of blood glycemic indicators are associated with chronic kidney disease prevalence in non-diabetic adults: Cross-sectional data from the national health and nutrition examination survey 2005-2016.

Objective: Hyperglycemia in individuals with diabetes is associated with chronic kidney disease (CKD); however, little is known about its association with those without diabetes. Our goal was to investigate the association between glycemic indicators and CKD in individuals without diabetes. Methods: This cross-sectional study included 9610 participants without diabetes who participated in the Health and Nutrition Examination Survey between 2005 and 2016. Exposures included postprandial glucose dip (PGD), fasting blood glucose (FBG), oral glucose tolerance test two-hour blood glucose (OGTT-2HBG), and glycated hemoglobin (HbA1C) levels. Moreover, CKD was defined as an estimated glomerular filtration rate below 60 mL/min per 1.73 m2 or a urinary albumin-creatinine ratio of ≥ 30 mg/g. Two multivariate models were constructed. Interaction effects were also explored. Results: The mean age of the participants was 46.0 years, with 50.3 % being females. The prevalence of CKD was 12.6 %. In the final multivariable models, the odds ratios (ORs) for CKD were 1.51 (95 % confidence interval [CI]: 1.22,1.88, p < 0.001) for participants in the highest quartile of PGD,1.46 (95 %CI: 1.13,1.87, p = 0.004) for OGTT-2HBG, and 1.33 (95 %CI: 1.04,1.70, p = 0.020) for HbA1C, when compared with the quartile 1. No significant association was observed between FBG levels and CKD in the final model. Additionally, interactions were observed between PGD and body mass index, as well as between PGD and alcohol consumption in relation to CKD. Conclusion: The study identified that high levels of PGD, OGTT-2HBG, and HBA1C were significantly associated with a high prevalence of CKD in individuals without diabetes.

Identification and analysis of immunogenicity and immunotherapy efficacy by fatty acid genes: a novel prognostic features of lumbar disc herniation and Mendelian randomization analysis.

BACKGROUND: Sciatica is a phrase used to describe radiating leg discomfort. The most common cause is lumbar disc herniation (LDH), which is considered to start in the nucleus pulposus. Advancements in lipidomics and metabolomics have unveiled the complex role of fatty acid metabolism (FAM) in both healthy and pathological states. However, the specific roles of fatty acid metabolism-related genes (FAMGs) in shaping therapeutic approaches, especially in LDH, remain largely unexplored and are a subject of ongoing research. METHODS: The junction of the weighted correlation network analysis (WGCNA) test with 6 FAMGs enabled the finding of FAMGs. Gene set variation analysis (GSVA) was used to identify the possible biological activities and pathways of FAMGs. LASSO was used to determine diagnostic effectiveness of the four FAMGs in diagnosing LDH. GSE124272, GSE147383, GSE150408, and GSE153761 were utilized to confirm the levels of expression of four FAMGs. RESULTS: Four FAMGs were discovered [Acyl-CoA Thioesterase 4 (ACOT4), Cytochrome P450 Family 4 Subfamily A Member 11 (CYP4A11), Acyl-CoA Dehydrogenase Long Chain (ACADL), Enoyl-CoA Hydratase and 3-Hydroxyacyl CoA Dehydrogenase (EHHADH)] For biological function analysis, mhc class ib receptor activity, response to thyroxine, response to l phenylalanine derivative were emphasized. CONCLUSIONS: FAMGs can help with prognosis and immunology, and provide evidence for fatty acid metabolism-related targeted therapeutics. In LDH, FAMGs and their interactions with immune cells might be therapeutic targets.

Anticoagulation therapy in non-valvular atrial fibrillation after intracerebral hemorrhage: A propensity score-matched study.

BACKGROUND: The effect of antithrombotic therapy on patients with atrial fibrillation who sustained previous intracerebral hemorrhage (ICH) remains uncertain. Data regarding antithrombotic therapy use in these patients are limited. This study aims to compare the clinical and overall outcomes of antithrombotic therapy and usual care in patients with atrial fibrillation who sustained ICH. METHODS: We assembled consecutive patients with atrial fibrillation sustaining an ICH from our institution. Multivariable regression analysis and propensity-matched analysis were applied to assess associations of different antithrombotic therapies and outcomes. The primary outcome was mortality within the longest follow-up. Kaplan-Meier curves and log-rank tests of the time-to-event data were used to assess differences in survival. RESULTS: In total, 296 consecutive patients with atrial fibrillation who survived an ICH were included in this study. Our analysis demonstrated that antithrombotic therapy was associated with reduced mortality up to a 4-year duration of follow-up (OR, 0.49, 95 % CI 0.30-0.81). Similar results were obtained from the propensity-matched analysis (OR, 0.58, 95 % CI 0.34-0.98). Subgroup analysis showed that compared with usual care, direct oral anticoagulant (DOAC) with or without antiplatelet was associated with a lower risk of long-term mortality (OR, 0.34, 95 % CI 0.17-0.69). In addition, our analysis observed a significant interaction between cardiac insufficiency and treatment effect (P = 0.04). CONCLUSIONS: In patients with atrial fibrillation who have a history of ICH, administration of antithrombotic therapy, especially DOAC, was associated with lower mortality. Future randomized trials are warranted to test the positive net clinical benefit of DOAC therapy.

An observational study on the safety of teprotumumab based on FAERS database.

OBJECTIVE: Teprotumumab plays an important role in thyroid eye disease pathogenesis and progression. We intend to mine the adverse event (AE) signals from a relevant database, thereby contributing to the safe use of teprotumumab. METHODS: The data obtained from the ASCII data packages in the FAERS database from January 2020 to the second quarter of 2023 were imported into the SAS software (version 9.4) for data cleaning and analysis. Disproportionality analysis was performed using the reporting odds ratio (ROR) in conjunction with the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) omnibus standard method to detect positive signals. PARTICIPANTS: This retrospective observational study relied on adverse drug reactions reported to the FDA through FAERS, which is a standard public system for spontaneous reporting. RESULTS: Collectively, 2171 AE reports for teprotumumab were collected, among which 108 significant signals were identified involving 17 system organ classes. The SOC of ear and labyrinth disorders included the most AE signals and reports. Muscle spasms, fatigue, headache, nausea, diarrhea, alopecia, blood glucose increased, hypoacusis, tinnitus, and diabetes mellitus were the top ten PTs ranked by the frequency of reporting, meanwhile, the two high-strength signals of thyroid-stimulating immunoglobulin increase (ROR 662.89, 95% CI 182.40-2409.19) and gingival recession (ROR 125.13, 95% CI 79.70-196.45) were not documented in the drug instruction. Meanwhile, we found a higher risk of increased blood glucose, deafness, and decreased appetite for male patients, and headache for female patients. CONCLUSIONS: Clinical application of teprotumumab should be closely monitored for ototoxicity, nail abnormalities, and menstrual changes, as well as for AEs not mentioned in the drug instruction, including gingival recession, thyroid-stimulating immunoglobulin increase, and so on.

Discovery of Nine Dipeptidyl Peptidase-4 Inhibitors from Coptis chinensis Using Virtual Screening, Bioactivity Evaluation, and Binding Studies.

The objective of this study was to identify multiple alkaloids in Coptis chinensis that demonstrate inhibitory activity against DPP-4 and systematically evaluate their activity and binding characteristics. A combined strategy that included molecular docking, a DPP-4 inhibition assay, surface plasmon resonance (SPR), and a molecular dynamics simulation technique was employed. The results showed that nine alkaloids in Coptis chinensis directly inhibited DPP-4, with IC50 values of 3.44-53.73 µM. SPR-based binding studies revealed that these alkaloids display rapid binding and dissociation characteristics when interacting with DPP-4, with KD values ranging from 8.11 to 29.97 µM. A molecular dynamics analysis revealed that equilibrium was rapidly reached by nine DPP-4-ligand systems with minimal fluctuations, while binding free energy calculations showed that the ∆Gbind values for the nine test compounds ranged from -31.84 to -16.06 kcal/mol. The most important forces for the binding of these alkaloids with DPP-4 are electrostatic interactions and van der Waals forces. Various important amino acid residues, such as Arg125, His126, Phe357, Arg358, and Tyr547, were involved in the inhibition of DPP-4 by the compounds, revealing a mechanistic basis for the further optimization of these alkaloids as DPP-4 inhibitors. This study confirmed nine alkaloids as direct inhibitors of DPP-4 and characterized their binding features, thereby providing a basis for further research and development on novel DPP-4 inhibitors.

SCF/C-kit drives spermatogenesis disorder induced by abscopal effects of cranial irradiation in mice.

Cranial radiotherapy is a major treatment for leukemia and brain tumors. Our previous study found abscopal effects of cranial irradiation could cause spermatogenesis disorder in mice. However, the exact mechanisms are not yet fully understood. In the study, adult male C57BL/6 mice were administrated with 20 Gy X-ray cranial irradiation (5 Gy per day for 4 days consecutively) and sacrificed at 1, 2 and 4 weeks. Tandem Mass Tag (TMT) quantitative proteomics of testis was combined with bioinformatics analysis to identify key molecules and signal pathways related to spermatogenesis at 4 weeks after cranial irradiation. GO analysis showed that spermatogenesis was closely related to oxidative stress and inflammation. Severe oxidative stress occurred in testis, serum and brain, while serious inflammation also occurred in testis and serum. Additionally, the sex hormones related to hypothalamic-pituitary-gonadal (HPG) axis were disrupted. PI3K/Akt pathway was activated in testis, which upstream molecule SCF/C-Kit was significantly elevated. Furthermore, the proliferation and differentiation ability of spermatogonial stem cells (SSCs) were altered. These findings suggest that cranial irradiation can cause spermatogenesis disorder through brain-blood-testicular cascade oxidative stress, inflammation and the secretory dysfunction of HPG axis, and SCF/C-kit drive this process through activating PI3K/Akt pathway.

AntDAS-GCMS: A New Comprehensive Data Analysis Platform for GC-MS-Based Untargeted Metabolomics with the Advantage of Addressing the Time Shift Problem.

Over the years, a number of state-of-the-art data analysis tools have been developed to provide a comprehensive analysis of data collected from gas chromatography-mass spectrometry (GC-MS). Unfortunately, the time shift problem remains unsolved in these tools. Here, we developed a novel comprehensive data analysis strategy for GC-MS-based untargeted metabolomics (AntDAS-GCMS) to perform total ion chromatogram peak detection, peak resolution, time shift correction, component registration, statistical analysis, and compound identification. Time shift correction was specifically optimized in this work. The information on mass spectra and elution profiles of compounds was used to search for inherent landmarks within analyzed samples to resolve the time shift problem across samples efficiently and accurately. The performance of our AntDAS-GCMS was comprehensively investigated by using four complex GC-MS data sets with various types of time shift problems. Meanwhile, AntDAS-GCMS was compared with advanced GC-MS data analysis tools and classic time shift correction methods. Results indicated that AntDAS-GCMS could achieve the best performance compared to the other methods.