Global trends in Cryptococcus and its interactions with the host immune system: a bibliometric analysis.

Objectives: This manuscript undertakes a systematic examination of the research landscape concerning global Cryptococcus species and their dynamism with the host immune system spanning the past decade. It furnishes a detailed survey of leading knowledge institutions and critical focal points in this area, utilizing bibliometric analysis. Methods: VOSviewer and CiteSpace software platforms were employed to systematically analyze and graphically depict the relevant literature indexed in the WoSCC database over the preceding ten years. Results: In the interval between October 1, 2013, and October 1, 2023, a corpus of 795 publications was amassed. The primary research institutions involved in this study include Duke University, the University of Minnesota, and the University of Sydney. The leading trio of nations, in terms of publication volume, comprises the United States, China, and Brazil. Among the most prolific authors are Casadevall, Arturo; Wormley, Floyd L., Jr.; and Olszewski, Michal A., with the most highly cited author being Perfect, Jr. The most esteemed journal is Mbio, while Infection and Immunity commands the highest citation frequency, and the Journal of Clinical Microbiology boasts the most significant impact factor. Present research foci encompass the intricate interactions between Cryptococcus pathogenesis and host immunity, alongside immune mechanisms, complications, and immunotherapies. Conclusion: This represents the first exhaustive scholarly review and bibliometric scrutiny of the evolving landscapes in Cryptococcus research and its interactions with the host immune system. The analyses delineated herein provide insights into prevailing research foci and trajectories, thus furnishing critical directions for subsequent inquiries in this domain.

Exploring the mechanism of Huanglian ointment in alleviating wound healing after anal fistula surgery through metabolomics and proteomics.

Anal fistula is a common anal and intestinal disease. The wound of anal fistula surgery is open and polluting, which is the most difficult to heal among all surgical incisions. To investigate the mechanism of Huanglian ointment (HLO) on wound healing after anal fistula incision. The S. aureus infected wound in SD rats were used to imitate poor healing wound after anal fistula surgery. SD rats with wound sites (n = 24) were randomly divided into four groups (Control group, Model group, Potassium permanganate (PP) treatment group, and HLO treatment group). The wound healing rate was evaluated, HE staining was used to evaluate the pathological changes of each group, ELISA was used to detect the secretion of inflammatory factors in each group, and the mechanism was explored through metabolomics and proteomics in plasma rat. Compared to other groups, the rate of wound healing in the HLO group was higher on days 7 and 14. Histological analysis showed that collagen and fibroblast in HLO rats were significantly increased, inflammatory cells were reduced, and vascular endothelial permeability was increased. ELISA results showed that the secretion of inflammatory factors in HLO rats was significantly lower. Significant proteins and metabolites were identified in the wound tissues of the infected rats and HLO-treated rats, which were mainly attributed to Cdc42, Ctnnb1, Actr2, Actr3, Arpc1b, Itgam, Itgb2, Cttn, Linoleic acid metabolism, d-Glutamine and d-glutamate metabolism, Phenylalanine, tyrosine and tryptophan biosynthesis, Phenylalanine metabolism, alpha-Linolenic acid metabolism, and Ascorbate and aldarate metabolism. In conclusion, this study showed that HLO can promote S. aureus infected wound healing, and the data provide a theoretical basis for the treatment of wounds after anal fistula surgery with HLO.

[Expression and significance of hypoxia-inducible factor 1α and Bcl-2/adenovirus E1B19kDa-interacting protein 3 in children with traumatic brain injury]. / ç¼ºæ°§è¯±å¯¼å› å­1α、Bcl-2/è ºç— æ¯’E1B19kDa相互作用蛋白3在儿童创伤性脑损伤中的表达及意义.

OBJECTIVES: To dynamically observe the changes in hypoxia-inducible factor 1α (HIF-1α) and Bcl-2/adenovirus E1B19kDa-interacting protein 3 (BNIP3) in children with traumatic brain injury (TBI) and evaluate their clinical value in predicting the severity and prognosis of pediatric TBI. METHODS: A prospective study included 47 children with moderate to severe TBI from January 2021 to July 2023, categorized into moderate (scores 9-12) and severe (scores 3-8) subgroups based on the Glasgow Coma Scale. A control group consisted of 30 children diagnosed and treated for inguinal hernia during the same period, with no underlying diseases. The levels of HIF-1α, BNIP3, autophagy-related protein Beclin-1, and S100B were compared among groups. The predictive value of HIF-1α, BNIP3, Beclin-1, and S100B for the severity and prognosis of TBI was assessed using receiver operating characteristic (ROC) curves. RESULTS: Serum levels of HIF-1α, BNIP3, Beclin-1, and S100B in the TBI group were higher than those in the control group (P<0.05). Among the TBI patients, the severe subgroup had higher levels of HIF-1α, BNIP3, Beclin-1, and S100B than the moderate subgroup (P<0.05). Correlation analysis showed that the serum levels of HIF-1α, BNIP3, Beclin-1, and S100B were negatively correlated with the Glasgow Coma Scale scores (P<0.05). After 7 days of treatment, serum levels of HIF-1α, BNIP3, Beclin-1, and S100B in both non-surgical and surgical TBI patients decreased compared to before treatment (P<0.05). ROC curve analysis indicated that the areas under the curve for predicting severe TBI based on serum levels of HIF-1α, BNIP3, Beclin-1, and S100B were 0.782, 0.835, 0.872, and 0.880, respectively (P<0.05), and for predicting poor prognosis of TBI were 0.749, 0.775, 0.814, and 0.751, respectively (P<0.05). CONCLUSIONS: Serum levels of HIF-1α, BNIP3, and Beclin-1 are significantly elevated in children with TBI, and their measurement can aid in the clinical assessment of the severity and prognosis of pediatric TBI.

The Potential Mechanism of the Anti-Liver Fibrotic Effect of Curcumin in the Gut-Liver Axis.

This study aimed to explore the curative effect of curcumin on liver fibrosis and its correlation with the gut-liver axis in animal models. Histological staining was utilized to conduct histological analysis of the liver and intestine. An automatic biochemical analyzer or enzyme-linked immunosorbent assay system was utilized for analyzing the biochemical indexes in mice. Western blotting was employed to examine the level of relevant proteins. Furthermore, 16S rRNA high-throughput sequencing was performed to explore the impact of curcumin on intestinal microorganisms in rats with liver fibrosis. Ultrahigh-performance liquid chromatography with quadrupole-orbitrap mass spectrometry was utilized to analyze the effect of curcumin on rat feces metabolites. Our results showed that curcumin reduced the formation of collagen fibers caused by carbon tetrachloride in a dose-dependent manner. In addition, curcumin was able to restore intestinal permeability in rats with liver fibrosis. By adopting α diversity analysis (Chao 1 index, Shannon index, and Simpson index), we observed that both the diversity and the abundance of intestinal flora in rats with liver fibrosis were increased. The principal component analysis diagram demonstrated that curcumin could enhance the abundance and diversity of intestinal flora, and also restore the composition of model rat flora, which was similar to that in normal rats, thereby correcting the imbalance of flora in rats with liver fibrosis. In addition, curcumin regulated feces metabolites and their signaling pathways, including glycerophospholipid metabolism, pantothenate and CoA biosynthesis. Our findings suggest that curcumin exhibits antiliver fibrosis effects, and its antiliver fibrosis effects might correlate with gut-liver axis.

Development and application of the physiologically-based toxicokinetic (PBTK) model for ochratoxin A (OTA) in rats and humans.

Ochratoxin A (OTA) is a common fungal toxin frequently detected in food and human plasma samples. Currently, the physiologically based toxicokinetic (PBTK) model plays an active role in dose translation and can improve and enhance the risk assessment of toxins. In this study, the PBTK model of OTA in rats and humans was established based on knowledge of OTA-specific absorption, distribution, metabolism, and excretion (ADME) in order to better explain the disposition of OTA in humans and the discrepancies with other species. The models were calibrated and optimized using the available kinetic and toxicokinetic (TK) data, and independent test datasets were used for model evaluation. Subsequently, sensitivity analyses and population simulations were performed to characterize the extent to which variations in physiological and specific chemical parameters affected the model output. Finally, the constructed models were used for dose extrapolation of OTA, including the rat-to-human dose adjustment factor (DAF) and the human exposure conversion factor (ECF). The results showed that the unbound fraction (Fup) of OTA in plasma of rat and human was 0.02-0.04% and 0.13-4.21%, respectively. In vitro experiments, the maximum enzyme velocity (Vmax) and Michaelis-Menten constant (Km) of OTA in rat and human liver microsomes were 3.86 and 78.17 µg/g min-1, 0.46 and 4.108 µg/mL, respectively. The predicted results of the model were in good agreement with the observed data, and the models in rats and humans were verified. The PBTK model derived a DAF of 0.1081 between rats and humans, whereas the ECF was 2.03. The established PBTK model can be used to estimate short- or long-term OTA exposure levels in rats and humans, with the capacity for dose translation of OTA to provide the underlying data for risk assessment of OTA.

Rapid identification and determination of chemical components of huai yam based on UPLC-Q-Exactive-MS and fragmentation patterns.

Huai Yam (Dioscoreae Rhizoma) contains many active ingredients such as flavonoids, saponins, and amino acids. In this study, an efficient method for the classification and rapid identification of yam components was established based on UPLC-Q-Exactive-MS and data post-processing techniques. First, the mass spectrometry information including the characteristic fragmentations (CFs) and neutral losses (NLs) of yam reported in the literature were summarised and a database of compounds was established. Then, the mass spectrometry data detected by the yam sample are compared with those described in database for rapid identification of target compounds. Finally, 60 compounds were identified, including 18 flavones, 2 saponins, 10 amino acids, 7 organic acids, 3 carbohydrates, 8 fatty acids and 12 others. A new strategy for identifying target constituents based on CFs and NLs was successfully established, laying the foundation for further research on yam and promoting the development of composition analysis of Traditional Chinese Medicine (TCM).

A longitudinal study of blood pressure circadian rhythm from childhood to early adulthood.

Altered blood pressure (BP) circadian rhythmicity has been increasingly linked with cardiovascular risk. However, little is known about BP circadian rhythm change with age and its possible sociodemographic, anthropometric, and genetic moderators. Twenty-four-hour ambulatory BP was measured up to 16 times over a 23-year period in 339 European Americans (EAs) and 293 African Americans (AAs), with an average age of 15 years at the initial visit. BP circadian rhythms were indexed by amplitude and percent rhythm (a measure of rhythm integrity) and calculated using Fourier analysis. BP amplitude and percent rhythm increased with age and average BP (BP mesor). AAs were more likely to have lower BP amplitude and percent rhythm than their EA counterparts. BP amplitude and percent rhythm also decreased with adiposity (BMI and waist circumference). The summer season was associated with lower BP amplitude in AAs and lower percent rhythm in both AAs and EAs. Sex, height, socioeconomic status, physical activity, and family history of essential hypertension did not have an independent impact on BP amplitude or percent rhythm. The results of the present study suggest that BP circadian rhythm increases with age and BP mesor from childhood to young adulthood, decreases with adiposity, and that AAs are more likely to have lower circadian rhythm than EAs. Furthermore, we demonstrated that the summer season is associated with lower BP rhythmicity.

Studies of Mycotoxins in Medicinal Plants Conducted Worldwide over the Last Decade: A Systematic Review, Meta-Analysis, and Exposure Risk Assessment.

BACKGROUND: Mycotoxins have been reported to be present in medicinal plants. With the growing usage of medicinal plants, contamination of mycotoxins has emerged as one of the biggest threats to global food hygiene and ecological environment, posing a severe threat to human health. PURPOSE: This study aimed to determine the mycotoxin prevalence and levels in medicinal plants and conduct a risk assessment by conducting a systematic review and meta-analysis. METHODS: A thorough search on Web of Science and PubMed was conducted for the last decade, resulting in 54 studies (meeting the inclusion criteria) with 2829 data items that were included in the meta-analysis. RESULTS: The combined prevalence of mycotoxins in medicinal plants was 1.7% (95% confidence interval, CI = 1.1% - 2.4%), with a mean mycotoxin concentration in medicinal plants of 3.551 µg/kg (95% CI = 3.461 - 3.641 µg/kg). Risk assessment results indicated that aflatoxins and ochratoxin A found in several medicinal plants posed a health risk to humans; additionally, emerging enniatins exhibited possible health risks. CONCLUSION: Therefore, the study underlines the need for establishing stringent control measures to reduce the severity of mycotoxin contamination in medicinal plants.

A low bleeding risk thrombolytic agent: citPA5.

AIMS: Alteplase is a cornerstone thrombolytic agent in clinical practice, but presents a potential bleeding risk. Stroke patients need pre-screening to exclude hemorrhagic stroke before using Alteplase. In this study, we develop a new thrombolytic agent citPA5, characterized by an enhanced safety profile and minimal bleeding tendency. METHODS AND RESULTS: A clot lysis agent, named citPA5, is developed based on rtPA with point mutations to completely suppress its proteolytic activity in the absence of fibrin. In the presence of fibrin, citPA5 exhibited significantly higher fibrinolytic activity (a 15.8-fold increase of kcat/Km). Furthermore, citPA5 showed resistance to endogenous fibrinolysis inhibitor, PAI-1, resulting in enhanced potency. In a series of safety evaluation experiments, including thrombelastography (TEG) assay, mice tail bleeding assay, and a murine intracerebral hemorrhage (ICH) model, citPA5 did not cause systemic bleeding or worsen intracerebral hemorrhage compared to Alteplase. This highlights the low risk of bleeding associated with citPA5. Finally, we found that citPA5 effectively improved cerebral blood flow and reduced infarct volume in a carotid embolism-induced stroke (CES) model. CONCLUSIONS: This clot lysis agent, citPA5, not only exhibits a low risk of bleeding but also demonstrates highly effective thrombolysis capabilities. As a result, citPA5 shows great potential for administration prior to the classification of stroke types, making it possible for use in ambulances at the onset of stroke when symptoms are identified. The findings presented in this study also suggest that this strategy could be applied to develop a new generation of fibrinolytic drugs that offer greater safety and specificity in targeting fibrin.

GPIbα CAAR-T cells function like a Trojan horse to eliminate autoreactive B cells to treat immune thrombocytopenia.

Breakthrough treatment for refractory and relapsed immune thrombocytopenia (ITP) patients is urgently needed. Autoantibody-mediated platelet clearance and megakaryocyte dysfunction are important pathogenic mediators of ITP. Glycoprotein (GP) Ibα is a significant autoantigen found in ITP patients and is associated with poor response to standard immunosuppressive treatments. Here, we engineered human T cells to express a chimeric autoantibody receptor (CAAR) with GPIbα constructed into the ligand-binding domain fused to the CD8 transmembrane domain and CD3ζ-4-1BB signaling domains. We performed cytotoxicity assays to assess GPIbα CAAR-T-cell selective cytolysis of cells expressing anti-GPIbα B-cell receptors (BCRs) in vitro. Furthermore, we demonstrated the potential of GPIbα CAAR-T cells to persist and precisely eliminate GPIbα-specific B cells in vivo. In summary, we present a proof of concept for CAAR-T-cell therapy to eradicate autoimmune B cells while sparing healthy B cells with GPIbα CAAR-T cells that function like a Trojan horse. GPIbα CAAR-Tcell therapy is a promising treatment for refractory and relapsed ITP patients.

Association of metformin and statin uses with the prognosis of colon cancer: a meta-analysis.

BACKGROUND: Metformin and statins are commonly used globally for the treatment of type 2 diabetes mellitus and dyslipidemia, respectively. Recently, multiple novel pathways have been discovered, which may contribute to the treatment of various types of cancer. Several meta-analysis studies have reported that the use of metformin or statins is associated with a lower risk of colon cancer compared to nonusers. In this study, our aim was to perform a meta-analysis and investigate the prognostic roles of these two medications in colon cancer. METHODS: To identify relevant articles, literature searches were performed in the PubMed and Web of Science databases using a combination of keywords related to metformin, statins and colon cancer prognosis until August 2023. The study utilized STATA 12.0 software (Stata Corporation, College Station, Texas, USA) to compute all the hazard ratios (HRs) and 95% confidence intervals (CIs) regarding the association between metformin or statin uses and prognostic-related outcomes. RESULTS: Our analysis revealed that the use of metformin was associated with a significantly lower overall mortality of colon cancer (HR = 0.63; 95% CI = 0.51-0.77; I2 = 94.9%; P < 0.001), as well as lower cancer-specific mortality of colon cancer (HR = 0.68; 95% CI = 0.50-0.94; I2 = 91.9%; P < 0.001). Similarly, the use of statins was also associated with a lower overall mortality of colon cancer (HR = 0.68; 95% CI = 0.60-0.78; I2 = 93.8%; P < 0.001), as well as a lower cancer-specific mortality of colon cancer (HR = 0.74; 95% CI = 0.67-0.81; I2 = 82.2%; P < 0.001). CONCLUSION: Our meta-analysis study suggests that statins and metformin may have potential as adjuvant agents with significant benefits in the prognosis of colon cancer.

Honokiol targeting ankyrin repeat domain of TRPV4 ameliorates endothelial permeability in mice inflammatory bowel disease induced by DSS.

ETHNOPHARMACOLOGICAL RELEVANCE: As a classic traditional Chinese medicine, Magnolia officinalis (M. officinalis) is widely used in digestive diseases. It has rich gastrointestinal activity including inflammatory bowel disease (IBD) treatment, but the mechanism is not clear. AIM OF THE STUDY: In recent years, there has been a growing interest in investigating the regulatory effects of herbal compounds on transient receptor potential (TRP) channel proteins. Transient receptor potential vanilloid 4 (TRPV4), a subtype involved in endothelial permeability regulation, was discussed as the target of M. officinalis in the treatment of IBD in the study. Based on the targeting effect of TRPV4, this study investigated the active ingredients and mechanism of M. officinalis extract in treating IBD. MATERIALS AND METHODS: To reveal the connection between the active ingredients in M. officinalis and TRPV4, a bioactivity-guided high performance liquid chromatography system coupled with mass spectrometry identification was utilized to screen for TRPV4 antagonists. TRPV4 siRNA knockdown experiment was employed to validate the significance of TRPV4 as a crucial target in regulating endothelial permeability by honokiol (HON). The interaction of the active ingredient representing HON with TRPV4 was confirmed by molecular docking, fluorescence-based thermal shift and live cell calcium imaging experiments. The potential binding sites and inhibitory mechanisms of HON in TRPV4 were analyzed by molecular dynamics simulation and microscale thermophoresis. The therapeutic effect of HON based on TRPV4 was discussed in DSS-IBD mice. RESULTS: Our finding elucidated that the inhibitory activity of M. officinalis against TRPV4 is primarily attributed to HON analogues. The knockdown of TRPV4 expression significantly impaired the calcium regulation and permeability protection in endothelial cells. The mechanism study revealed that HON specifically targets the Q239 residue located in the ankyrin repeat domain of TRPV4, and competitively inhibits channel opening with adenosine triphosphate (ATP) binding. The immunofluorescence assay demonstrated that the administration of HON enhances the expression and location of VE-Cadherin to protect the endothelial barrier and attenuates immune cell infiltration. CONCLUSIONS: The finding suggested that HON alleviates IBD by improving endothelial permeability through TRPV4. The discovery provides valuable insights into the potential therapeutic strategy of active natural products for alleviating IBD.

Specific inhibition on PAI-1 reduces the dose of Alteplase for ischemic stroke treatment.

Administration of recombinant tPA (rtPA, or trade name Alteplase®) is an FDA-approved therapy for acute ischemic stroke (AIS), but poses the risk of hemorrhagic complications. Recombinant tPA can be rapidly inactivated by the endogenous inhibitor, plasminogen activator inhibitor 1 (PAI-1). In this work, we study a novel treatment approach that combines a PAI-1 inhibitor, PAItrap4, with a reduced dose of rtPA to address the hemorrhagic concern of rtPA. PAItrap4 is a highly specific and very potent protein-based inhibitor of PAI-1, comprising of a variant of uPA serine protease domain, human serum albumin, and a cyclic RGD peptide. PAItrap4 efficiently targets and inhibits PAI-1 on activated platelets, and also possesses a long half-life in vivo. Our results demonstrate that PAItrap4 effectively counteracts the inhibitory effects of PAI-1 on rtPA, preserving rtPA activity based on amidolytic and clot lysis assays. In an in vivo murine stroke model, PAItrap4, together with low-dose rtPA, enhances the blood perfusion in the stroke-affected areas, reduces infarct size, and promotes neurological recovery in mice. Importantly, such treatment does not increase the amount of cerebral hemorrhage, thus reducing the risk of cerebral hemorrhage. In addition, PAItrap4 does not compromise the normal blood coagulation function in mice, demonstrating its safety as a therapeutic agent. These findings highlight this combination therapy as a promising alternative for the treatment of ischemic stroke, offering improved safety and efficacy.

Zanubrutinib-lenalidomide-rituximab (ZR2) in unfit diffuse large B-cell lymphoma: efficient and tolerant.

The objective of this study is to examine the effectiveness and safety of zanubrutinib, rituximab, and lenalidomide (ZR2) in unfit patients with diffuse large B-cell lymphoma (DLBCL). Thrombosis or bleeding risk of ZR2 regimen, especially when antiplatelet agents were co-prescribed, was also evaluated. We retrospectively reviewed unfit newly diagnosed (ND) and refractory or relapsed (R/R) patients with DLBCL who were administered with ZR2 regimen in two medical centers between December 2019 and February 2022. Response rates, progression-free survival (PFS), overall survival (OS), bleeding adverse events (AEs), and thrombosis episodes were analyzed. Furthermore, we investigated the effects of zanubrutinib alone or in combination with lenalidomide on platelet functions in vitro and in vivo. A total of 30 unfit patients (13 ND DLBCL and 17 R/R DLBCL patients) who received ZR2 regimen were enrolled in the study (median age: 69.5 years). The ultimate ORRs for the ND DLBCL and R/R DLBCL were 77.0% and 50.1%, respectively. The median follow-up was 16.6 months. The median PFS and OS were not achieved during the follow-up time. Subcutaneous hemorrhage AEs occurred in four cases, three cases suffered severe bleeding events, and thrombosis events were observed in two patients. ZR2 regimen inhibited platelet functions (aggregation, clot retraction, spreading and activation) in vitro and in vivo function testing especially in response to collagen. ZR2 is an efficient treatment option for unfit patients with DLBCL and could be well tolerated. Notably, this regimen inhibited platelet functions. Antiplatelet agents should be used with caution in patients treated with this regimen.

Exploring quality evaluation markers of Fructus Psoraleae based on chemometric analysis integrated with network pharmacology.

INTRODUCTION: Fructus Psoraleae (FP) is a well-known traditional Chinese medicine for the treatment of osteoporosis. However, major quality differences were witnessed owing to its various origins, thus influencing its safety and efficacy. OBJECTIVES: The study aimed to evaluate the quality of FP from different origins and predict its quality evaluation markers. METHODS: Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was employed for tentative characterisation of the constituents in 10 batches of FP, followed by the utilisation of multivariate statistical analysis methods including principal component analysis and orthogonal partial least squares discriminant analysis for quality evaluation. Network pharmacology approaches were utilised to explore the underlying mechanism of the screened chemotaxonomic markers in treating osteoporosis. RESULTS: Forty-one components in FP including, chalcones, coumarins, coumestans, flavonoids, iso-flavonoids, and phenolics, were characterised based on their fragmentation pathways. Ten batches of FP were basically divided into three categories, and eight chemotaxonomic markers including isopsoralen, calamenene, bakuchiol, psoralen, bavachinin, isoneobavaisoflavone, corylifol C, and neobavaisoflavone were screened. Network pharmacology revealed that the chemotaxonomic markers can act on targets such as AKT1, HSP90AA1, and EGFR and possess effects mainly through glycolysis and wnt/ß-catenin signalling to alleviate osteoporosis. Molecular docking and molecular dynamic simulation confirmed the good binding affinity and stability between proteins and selected markers. So, eight chemotaxonomic markers were all preferentially recommended as quality evaluation markers. CONCLUSION: The study not only provides a reference for the improvement of quality control of FP but also offers a theoretical basis for its further in-depth research in osteoporosis.

Serum Cell Division Cycle 42 before and after Programmed Death-1 Inhibitor Therapy in Advanced Melanoma Patients: Correlation with Tumor Features, Clinical Response, and Survival.

Cell division cycle 42 (CDC42) mediates immune escape in cancers. This study aimed to investigate linkages of CDC42 with tumor features, treatment response, and survival in advanced melanoma patients receiving programmed death-1 (PD-1) inhibitors. Pre-treatment and post-treatment (after 2 cycles) serum CDC42 of 35 advanced melanoma patients receiving PD-1 inhibitor was assessed by enzyme-linked immunosorbent assay. Patients with tumor-node-metastasis (TNM) stage IV (vs. III) (P = 0.050) and abnormal (vs. normal) lactate dehydrogenase (LDH) (P = 0.022) had higher pre-treatment CDC42. After 2-cycle therapy, CDC42 was declined (P < 0.001). Objective response and disease control rates were 34.3% and 62.9%, respectively. Additionally, pre-treatment and post-treatment CDC42 was reduced in patients with objective response and disease control than those without (all P < 0.050). Concerning survival, pre-treatment with CDC42 > 700 pg/mL was associated with shorter progression-free survival (PFS) (P = 0.013), but not overall survival (OS) (P = 0.060). Specifically, the 12-month PFS rate was 26.7% and 66.2%, and the 12-month OS rate was 61.1% and 82.5% in patients with pre-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, respectively. Post-treatment with CDC42 > 700 pg/mL was correlated with shortened PFS (P = 0.010) and OS (P = 0.006). The 12-month PFS rate was 12.5% and 62.0%, and the 12-month OS rate was 42.3% and 88.0% in patients with post-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, accordingly. Furthermore, post-treatment with CDC42 > 700 pg/mL was independently related to PFS [hazard ratio (HR): 2.704, P = 0.029 and OS (HR: 7.749, P = 0.005)]. Elevated CDC42 correlates with advanced TNM, abnormal LDH, worse clinical response, and dismal survival in advanced melanoma patients receiving PD-1 inhibitors.

Near-infrared-responsive GE11-CuS@Gal nanoparticles as an intelligent drug release system for targeting therapy against oral squamous cell carcinoma.

Galangin (Gal) is a natural plant flavonoid. More and more evidence shows that Gal can achieve anti-tumor effects by regulating various mechanisms. However, its poor water solubility, low bioavailability, and insufficient lesion targeting limit its clinical application. To overcome these shortcomings, we designed and developed a mesoporous nanosystem (GE11-CuS) that actively located the target area and photo-controlled drug release, which promoted the rapid accumulation of drugs in tumor tissues under NIR irradiation, thus achieving positive effects against cancer. In this study, we explored the application of the Gal-loaded nanometer system (GE11-CuS@Gal) in the treatment of oral squamous cell carcinoma (OSCC) both in vitro and in vivo. The results exhibited that GE11-CuS@Gal had excellent targeting ability and could accumulate efficiently in tumor cells (HSC-3). Meanwhile, the temperature of GE11-CuS@Gal increasing rapidly under NIR illumination damaged the integrity of the carrier and allowed Gal molecules to escape from the pores of the nanoparticles. When the accumulation of Gal in the nidus reached a certain level, the intracellular ROS level could be significantly increased and the antioxidative stress pathway mediated by Nrf2/OH-1 was effectively blocked, to inhibit the growth and migration of tumors. In conclusion, the GE11-CuS improved the antitumor activity of Gal in the body, which laid a foundation for the treatment of OSCC with traditional Chinese medicine ingredients.

Systematic characterization of the chemical constituents in vitro and in vivo of Qianghuo by UPLC-Q-TOF-MS/MS.

The Chinese herb Qianghuo is an antiphlogistic herb with many effects and complex components. In this study, the chemical composition of Qianghuo and its components in rat plasma after oral administration were investigated using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). The extracts, blank plasma, and plasma containing the drug were analyzed by mass spectrometry, and data collected in both positive and negative ion modes were analyzed using Masslynx software, and the structures were confirmed by combining the compound fragment ions and mass spectrometry cleavage pathways. A total of 62 in vitro chemical components were identified, including 27 coumarins, 18 organic acids, 5 amino acids, 5 glycosides, 2 flavonoids, 4 nucleotides, and 1 ester, which were summarized from the obtained compounds in terms of their possible cleavage patterns. Among the identified 31 compounds in rat plasma, 21 were prototypes, mostly coumarins, organic acids, and flavonoids, and 10 were metabolites, which were mainly generated via hydroxylation and methylation pathways. Based on these, this study provides a theoretical foundation for quality control and basic research on Qianghuo medicinal substances.

Age, sex and race distribution of accelerometer-derived sleep variability in US school-aged children and adults.

Sleep variability (e.g. intra-individual variabilities in sleep duration or sleep timing, social jetlag, and catch-up sleep) is an important factor impacting health and mortality. However, limited information is available on the distribution of these sleep parameters across the human life span. We aimed to provide distribution of sleep variability related parameters across lifespan by sex and race in a national representative sample from the U.S. population. The study included 9981 participants 6 years and older from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, who had 4-7 days of valid 24-h accelerometer recording with at least one day obtained during weekend (Friday or Saturday night). Of the study participants, 43% showed ≥ 60 min sleep duration standard deviation (SD), 51% experienced ≥ 60 min catch-up sleep, 20% showed ≥ 60 min sleep midpoint SD, and 43% experienced ≥ 60 min social jetlag. American youth and young adults averaged greater sleep variability compared to other age groups. Non-Hispanic Blacks showed greater sleep variability in all parameters compared to other racial groups. There was a main effect of sex on sleep midpoint SD and social jetlag with males averaging slightly more than females. Our study provides important observations on sleep variability parameters of residents of the United States by using objectively measured sleep patterns and will provide unique insights for personalized advice on sleep hygiene.

Causal relationship between gut microbiota with subcutaneous and visceral adipose tissue: a bidirectional two-sample Mendelian Randomization study.

Background: Numerous studies have revealed associations between gut microbiota and adipose tissue. However, the specific functional bacterial taxa and their causal relationships with adipose tissue production in different regions of the body remain unclear. Methods: We conducted a bidirectional two-sample Mendelian Randomization (MR) study using aggregated data from genome-wide association studies (GWAS) for gut microbiota and adipose tissue. We employed methods such as inverse variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode to assess the causal relationships between gut microbiota and subcutaneous adipose tissue (SAT) as well as visceral adipose tissue (VAT). Cochran's Q test, MR-Egger regression intercept analysis, and MR-PRESSO were used to test for heterogeneity, pleiotropy, and outliers of the instrumental variables, respectively. Reverse MR was employed to evaluate the reverse causal relationships between SAT, VAT, and gut microbiota with significant associations. Results: IVW results demonstrated that Betaproteobacteria were protective factors for SAT production (OR = 0.88, 95% CI: 0.80-0.96, p = 0.005) and VAT production (OR = 0.91, 95% CI: 0.83-0.99, p = 0.030). Various bacterial taxa including Ruminococcaceae UCG002 (OR = 0.94, 95% CI: 0.89-0.99, p = 0.017), Methanobacteria class (OR = 0.96, 95% CI: 0.92-1.00, p = 0.029), and Burkholderiales (OR = 0.90, 95% CI: 0.83-0.98, p = 0.012) were associated only with decreased SAT production. Rikenellaceae RC9 gut group (OR = 1.05, 95% CI: 1.02-1.10, p = 0.005), Eubacterium hallii group (OR = 1.08, 95% CI: 1.01-1.15, p = 0.028), Peptococcaceae (OR = 1.08, 95% CI: 1.01-1.17, p = 0.034), and Peptococcus (OR = 1.05, 95% CI: 1.00-1.10, p = 0.047) were risk factors for SAT production. Meanwhile, Eubacterium fissicatena group (OR = 0.95, 95% CI: 0.91-0.99, p = 0.019), Turicibacter (OR = 0.93, 95% CI: 0.88-0.99, p = 0.022), and Defluviitaleaceae UCG011 (OR = 0.94, 95% CI: 0.89-0.99, p = 0.024) were protective factors for VAT production. Furthermore, Bacteroidetes (OR = 1.09, 95% CI: 1.01-1.17, p = 0.018), Eubacterium eligens group (OR = 1.09, 95% CI: 1.01-1.19, p = 0.037), Alloprevotella (OR = 1.05, 95% CI: 1.00-1.10, p = 0.038), and Phascolarctobacterium (OR = 1.07, 95% CI: 1.00-1.15, p = 0.042) were associated with VAT accumulation. Additionally, reverse MR revealed significant associations between SAT, VAT, and Rikenellaceae RC9 gut group (IVW: OR = 1.57, 95% CI: 1.18-2.09, p = 0.002) as well as Betaproteobacteria (IVW: OR = 1.14, 95% CI: 1.01-1.29, p = 0.029), both acting as risk factors. Sensitivity analyzes during bidirectional MR did not identify heterogeneity or pleiotropy. Conclusion: This study unveils complex causal relationships between gut microbiota and SAT/VAT, providing novel insights into the diagnostic and therapeutic potential of gut microbiota in obesity and related metabolic disorders.