Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation.

Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing's anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing's pharmacologically significant constituents supports the medicine's anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.

Effective degradation of phenol by activating PMS with bimetallic Mo and Ni Co-doped g C3N4 composite catalyst: A Fenton-like degradation process promoted by non-free radical 1O2.

The application of bimetal supported graphite phase carbon nitride in activated peroxymonosulfate (PMS) process has become a research hotspot in recent years. In this study, 8-g C3N4/Mo/Ni composite catalyst material was successfully prepared by doping Mo and Ni in graphite phase carbon nitride. The bimetallic active sites were formed in the catalyst, and PMS was activated by the metal valence Mo6+/Mo4+ and Ni2+/Ni(0) through redox double cycle to effectively degrade phenol. When pH was neutral, the degradation rate of 20 mg/L phenol solution with 8-g C3N4/Mo/Ni (0.35 g/L) and PMS (0.6 mM) could reach 95% within 20 min. The degradation rate of 8-g C3N4/Mo/Ni/PMS catalytic system could reach more than 90% within 20min under the condition of pH range of 3-11 and different anions. Meanwhile, the degradation effects of RhB, MB and OFX on different pollutants within 30min were 99%, 100% and 82%, respectively. Electron spin resonance and quenching experiments showed that in 8-g C3N4/Mo/Ni/PMS system, the degradation mechanism was mainly non-free radicals, and the main active species in the degradation process was 1O2. This study provides a new idea for the study of bimetal supported graphite phase carbon nitride activation of PMS and the theoretical study of degradation mechanism.

Abnormal interhemispheric functional cooperation in schizophrenia follows the neurotransmitter profiles.

BACKGROUND: Interhemispheric cooperation is one of the most prominent functional architectures of the human brain. In patients with schizophrenia, interhemispheric cooperation deficits have been reported using increasingly powerful neurobehavioural and neuroimaging measures. However, these methods rely in part on the assumption of anatomic symmetry between hemispheres. In the present study, we explored interhemispheric cooperation deficits in schizophrenia using a newly developed index, connectivity between functionally homotopic voxels (CFH), which is unbiased by hemispheric asymmetry. METHODS: Patients with schizophrenia and age- and sexmatched healthy controls underwent multimodal MRI, and whole-brain CFH maps were constructed for comparison between groups. We examined the correlations of differing CFH values between the schizophrenia and control groups using various neurotransmitter receptor and transporter densities. RESULTS: We included 86 patients with schizophrenia and 86 matched controls in our analysis. Patients with schizophrenia showed significantly lower CFH values in the frontal lobes, left postcentral gyrus and right inferior temporal gyrus, and significantly greater CFH values in the right caudate nucleus than healthy controls. Moreover, the differing CFH values in patients with schizophrenia were significantly correlated with positive symptom score and illness duration. Functional connectivity within frontal lobes was significantly reduced at the voxel cluster level compared with healthy controls. Finally, the abnormal CFH map of patients with schizophrenia was spatially associated with the densities of the dopamine D1 and D2 receptors, fluorodopa, dopamine transporter, serotonin transporter and acetylcholine transporter. CONCLUSION: Regional abnormalities in interhemispheric cooperation may contribute to the clinical symptoms of schizophrenia. These CFH abnormalities may be associated with dysfunction in neurotransmitter systems strongly implicated in schizophrenia.

Transcriptomic Profiling Highlights the ABA Response Role of BnSIP1-1 in Brassica napus.

BnSIP1-1 is the first identified SIP1 (6b Interacting Protein1) subfamily gene of the trihelix transcription factor family from Brassica napus (B. napus). We previously used a reverse genetic method to reveal its abiotic stress response function in endowing plants resistance to drought and salinity, as well as ABA (Abscisic acid). However, the molecular mechanisms of BnSIP1-1 are unclear. In this study, the global transcriptome files of BnSIP1-1-overexpressing transgenic and wildtype B. napus seedlings under ABA treatment were constructed using RNA-seq. A total of 1823 and 5512 DEGs (Differentially Expressed Genes) were identified in OE vs. WT and OE_ABA vs. WT_ABA comparison groups, which included 751 and 2567 up-regulated DEGs, and 1072 and 2945 down-regulated DEGs, separately. The impact of overexpressed BnSIP1-1 on plants was amplified by ABA, indicating BnSIP1-1 was an ABA-conditioned responsive gene. More interestingly, we found the reasons for BnSIP1-1 increasing plants' insensitivity to ABA were not by regulating ABA synthesis and catabolism, but by manipulating ABA transportation, ABA signal perception and transduction, inositol phosphate metabolism, as well as endomembrane trafficking, indirectly suggesting this gene may play roles upstream of the core ABA response pathway. Our results provided new insights into improving the knowledge about the function of BnSIP1-1 and the ABA signaling mechanism in B. napus.

The Epidemiology of Sepsis in Chinese ICUs: A National Cross-Sectional Survey.

OBJECTIVES: We performed a national cross-sectional survey to determine the epidemiologic characteristics of patients with sepsis in ICU in China. DESIGN: A cross-section survey study. SETTING: Forty-four hospitals in mainland China from December 1, 2015, to January 31, 2016. PATIENTS: All septic patients diagnosed according sepsis-1 criteria admitted to participating ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We recorded demographic, physiologic, and microbiological data with follow-up for 90 days or death, if sooner. The frequency of sepsis and 90-day mortality rate were computed, and the relationship with gross domestic product determined. Multivariate logistic regression analysis was used to determine risk factors for 90-day mortality in patients with sepsis. Two-thousand three-hundred twenty-two patients with sepsis were included in the analysis, of whom 786 patients (33.9%) had hospital-acquired sepsis. The most common infection site was the lung (68.2%), followed by abdomen (26.6%) and bloodstream (7.8%). The frequency of sepsis in the ICU was 20.6 cases per 100 ICU admissions (95% CI, 15.8-25.4) with a 90-day mortality of 35.5%. The proportion of sepsis, severe sepsis, and septic shock were 3.10%, 43.6%, and 53.3% with a 90-day mortality of 2.78%, 17.69%, and 51.94%, respectively. Older age, low body weight, higher Sequential Organ Failure Assessment score, the number of systemic inflammatory response syndrome criteria, comorbid with heart failure, hematologic cancer, immunosuppression, higher level of lactate, infection site (pneumonia and bloodstream) were associated with 90-day mortality. CONCLUSIONS: Sepsis affects a fifth of patients admitted to ICUs in mainland China with a 90-day mortality rate of 35.5%. Our findings indicate that a large burden of sepsis, and we need to focus on sepsis as a quality improvement target in China given the high mortality. In addition, further studies are needed to delineate the epidemiology of sepsis outside the ICU.

Experimental evidence for cancer resistance in a bat species.

Mammals exhibit different rates of cancer, with long-lived species generally showing greater resistance. Although bats have been suggested to be resistant to cancer due to their longevity, this has yet to be systematically examined. Here, we investigate cancer resistance across seven bat species by activating oncogenic genes in their primary cells. Both in vitro and in vivo experiments suggest that Myotis pilosus (MPI) is particularly resistant to cancer. The transcriptomic and functional analyses reveal that the downregulation of three genes (HIF1A, COPS5, and RPS3) largely contributes to cancer resistance in MPI. Further, we identify the loss of a potential enhancer containing the HIF1A binding site upstream of COPS5 in MPI, resulting in the downregulation of COPS5. These findings not only provide direct experimental evidence for cancer resistance in a bat species but also offer insights into the natural mechanisms of cancer resistance in mammals.

Differential symptom cluster responses and predictors to repetitive transcranial magnetic stimulation treatment in Parkinson's disease: A retrospective study.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective noninvasive neuromodulation technique for Parkinson's disease (PD). However, the efficacy of rTMS varies widely between individuals. This study aimed to investigate the factors related to the response to rTMS in PD patients. Methods: We retrospectively analyzed the response of 70 idiopathic PD patients who underwent rTMS for 14 consecutive days targeting the supplementary motor area (SMA) in either an open-label trail (n = 31) or a randomized, double-blind, placebo-controlled trial (RCT) (n = 39). The motor symptoms of PD patients were assessed by the United Parkinson's Disease Rating Scale Part III (UPDRSIII). Based on previous studies, the UPDRSIII were divided into six symptom clusters: axial dysfunction, resting tremor, rigidity, bradykinesia affecting right and left extremities, and postural tremor. Subsequently, the efficacy of rTMS to different motor symptom clusters and clinical predictors were analyzed in these two trails. Results: After 14 days of treatment, only the total UPDRSIII scores and rigidity scores improved in both the open-label trial and the RCT. The results of multiple linear regression analysis indicated that baseline rigidity scores (ß = 0.37, p = 0.047) and RMT (ß = 0.30, P = 0.02) positively predicted the improvement of UPDRSIII. The baseline rigidity score (ß = 0.55, P < 0.0001) was identified as an independent factor to predict the improvement of rigidity. Conclusion: This study demonstrated significant improvements in total UPDRSIII scores and rigidity after 14-day treatment, with baseline rigidity scores and RMT identified as predictors of treatment response, underscoring the need for individualized therapy.

Heterogeneous Brain Abnormalities in Schizophrenia Converge on a Common Network Associated With Symptom Remission.

BACKGROUND AND HYPOTHESIS: There is a huge heterogeneity of magnetic resonance imaging findings in schizophrenia studies. Here, we hypothesized that brain regions identified by structural and functional imaging studies of schizophrenia could be reconciled in a common network. STUDY DESIGN: We systematically reviewed the case-control studies that estimated the brain morphology or resting-state local function for schizophrenia patients in the literature. Using the healthy human connectome (n = 652) and a validated technique "coordinate network mapping" to identify a common brain network affected in schizophrenia. Then, the specificity of this schizophrenia network was examined by independent data collected from 13 meta-analyses. The clinical relevance of this schizophrenia network was tested on independent data of medication, neuromodulation, and brain lesions. STUDY RESULTS: We identified 83 morphological and 60 functional studies comprising 7389 patients with schizophrenia and 7408 control subjects. The "coordinate network mapping" showed that the atrophy and dysfunction coordinates were functionally connected to a common network although they were spatially distant from each other. Taking all 143 studies together, we identified the schizophrenia network with hub regions in the bilateral anterior cingulate cortex, insula, temporal lobe, and subcortical structures. Based on independent data from 13 meta-analyses, we showed that these hub regions were specifically connected with regions of cortical thickness changes in schizophrenia. More importantly, this schizophrenia network was remarkably aligned with regions involving psychotic symptom remission. CONCLUSIONS: Neuroimaging abnormalities in cross-sectional schizophrenia studies converged into a common brain network that provided testable targets for developing precise therapies.

Decreased inter-hemispheric cooperation in major depressive disorder and its association with neurotransmitter profiles.

BACKGROUND: Inter-hemispheric cooperation is a prominent feature of the human brain, and previous neuroimaging studies have revealed aberrant inter-hemispheric cooperation patterns in patients with major depressive disorder (MDD). Typically, inter-hemispheric cooperation is examined by calculating the functional connectivity (FC) between each voxel in one hemisphere and its anatomical (structurally homotopic) counterpart in the opposite hemisphere. However, bilateral hemispheres are actually asymmetric in anatomy. METHODS: In the present study, we utilized connectivity between functionally homotopic voxels (CFH) to investigate abnormal inter-hemispheric cooperation in 96 MDD patients compared to 173 age- and sex-matched healthy controls (HCs). In addition, we analyzed the spatial correlations between abnormal CFH and the density maps of 13 neurotransmitter receptors and transporters. RESULTS: The CFH values in bilateral orbital frontal gyri and bilateral postcentral gyri were abnormally decreased in patients with MDD. Furthermore, these CFH abnormalities were correlated with clinical symptoms. In addition, the abnormal CFH pattern in MDD patients was spatially correlated with the distribution pattern of 5-HT1AR. LIMITATIONS: drug effect; the cross-sectional research design precludes causal inferences; the neurotransmitter atlases selected were constructed from healthy individuals rather than MDD patients. CONCLUSION: These findings characterized the abnormal inter-hemispheric cooperation in MDD using a novel method and the underlying neurotransmitter mechanism, which promotes our understanding of the pathophysiology of depression.

An Efficient Electrochemical Biosensor to Determine 1,5-Anhydroglucitol with Persimmon-Tannin-Reduced Graphene Oxide-PtPd Nanocomposites.

1,5-Anhydroglucitol (1,5-AG) is a sensitive biomarker for real-time detection of diabetes mellitus. In this study, an electrochemical biosensor to specifically detect 1,5-AG levels based on persimmon-tannin-reduced graphene oxide-PtPd nanocomposites (PT-rGO-PtPd NCs), which were modified onto the surface of a screen-printed carbon electrode (SPCE), was designed. The PT-rGO-PtPd NCs were prepared by using PT as the film-forming material and ascorbic acid as the reducing agent. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), ultraviolet-visible spectroscopy (UV-vis), and X-ray diffraction (XRD) spectroscopy analysis were used to characterise the newly synthesised materials. PT-rGO-PtPd NCs present a synergistic effect not only to increase the active surface area to bio-capture more targets, but also to exhibit electrocatalytic efficiency to catalyze the decomposition of hydrogen peroxide (H2O2). A sensitive layer is formed by pyranose oxidase (PROD) attached to the surface of PT-rGO-PtPd NC/SPCE. In the presence of 1,5-AG, PROD catalyzes the oxidization of 1,5-AG to generate 1,5-anhydrofuctose (1,5-AF) and H2O2 which can be decomposed into H2O under the synergistic catalysis of PT-rGO-PtPd NCs. The redox reaction between PT and its oxidative product (quinones, PTox) can be enhanced simultaneously by PT-rGO-PtPd NCs, and the current signal was recorded by the differential pulse voltammetry (DPV) method. Under optimal conditions, our biosensor shows a wide range (0.1-2.0 mg/mL) for 1,5-AG detection with a detection limit of 30 µg/mL (S/N = 3). Moreover, our electrochemical biosensor exhibits acceptable applicability with recoveries from 99.80 to 106.80%. In summary, our study provides an electrochemical method for the determination of 1,5-AG with simple procedures, lower costs, good reproducibility, and acceptable stability.

Diazepam promotes active avoidance extinction associating with increased dorsal CA3 and amygdala activity.

Active avoidance (AA) is an adaptive response to potentially harmful situations while maladapted avoidance that does not extinguish is one of the core symptoms of anxiety and post-traumatic stress disorder. However, the neural mechanisms of AA extinction and its relationship to anxiety remain unclear. We examined AA extinction during three extinction training sessions in two-way active avoidance paradigm and tested the effect of anxiolytic on AA extinction. Then we performed a meta-analysis of rodent studies, identified anxiolytic diazepam facilitates AA acquisition, and tested the same treatment in AA extinction. Diazepam-treated rats significantly reduced avoidance in the first two extinction training, compared with the saline-treated rats, and the reduction in avoidance remained in the third drug-free session. Then we explored extinction associated hippocampal and amygdala activity in saline-and diazepam-treated rats using c-Fos immunostaining following the last extinction session. The density of c-Fos positive cells was higher in dorsal CA3 of the diazepam group than in that of saline-treated animals, and was also higher in the central and basolateral amygdala regions of diazepam-treated rats than in that of saline-treated animals. Combined, these results suggest anxiolytics promotes AA extinction associated with dorsal CA3 and amygdala activity changes.

A novel fluorescent strategy for Golgi protein 73 determination based on aptamer/nitrogen-doped graphene quantum dots/molybdenum disulfide @ reduced graphene oxide nanosheets.

The effective detection of biomarkers associated with hepatocellular carcinoma (HCC) is of great importance. Golgi protein 73 (GP73), a serum biomarker of HCC, has better diagnostic value than Alpha-fetoprotein (AFP) has been reported. In this paper, highly accurate fluorescence sensing platform for detecting GP73 was constructed based on fluorescence resonance energy transfer (FRET), in which nitrogen-doped graphene quantum dots (NGQDs) labelling with GP73 aptamer (GP73Apt) was used as fluorescence probe, and molybdenum disulfide @ reduced graphene oxide (MoS2@RGO) nanosheets was used as fluorescent receptors. MoS2@RGO nanosheets can quench the fluorescence of NGQDs-GP73Apt owing to FRET mechanisms. In the presence of GP73, the NGQDs-GP73Apt specifically bound with GP73 to from the deployable structures, making NGQDs-GP73Apt far away from MoS2@RGO nanosheets, blocking the FRET process, resulting in fluorescence recovery of NGQDs-GP73Apt. Under optimal conditions, the recovery intensity of fluorescence in the detection system is linearly related to the concentration of GP73 in the range of 5 ng/mL - 100 ng/mL and the limit of detection is 4.54 ng/mL (S/N = 3). Moreover, detection of GP73 was performed in human serum samples with good recovery (97.21-100.83%). This platform provides a feasible method for the early diagnosis of HCC, and can be easily extended to the detection of other biomarkers.

Erratum: Author correction to "YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer" [Acta Pharmaceutica Sinica B 12 (2022) 2845-2858].

[This corrects the article DOI: 10.1016/j.apsb.2022.02.031.].

Safety, tolerability, pharmacokinetics, and efficacy of kukoamine B in patients with sepsis: A randomized phase IIa trial.

PURPOSE: To evaluate the safety, tolerability, pharmacokinetics, and efficacy of kukoamine B (KB), an alkaloid compound with high affinity for both lipopolysaccharide (LPS) and oligodeoxynucle-otides containing CpG motifs (CpG DNA), in patients with sepsis-induced organ failure. MATERIALS AND METHODS: This was a multicenter, randomized, double-blind, placebo-controlled phase IIa trial. Patients with sepsis-induced organ failure were randomized to receive either KB (0.06, 0.12, or 0.24 mg/kg) or placebo, every 8 h for 7 days. Primary endpoint was safety, and secondary endpoints included pharmacokinetic (PK) parameters, changes in inflammatory mediators' level, and prognostic parameters. RESULTS: Of 44 patients enrolled, adverse events occurred in 28 patients [n = 20, 66.7% (KB pooled); n = 8, 57.1% (placebo)], while treatment emergent adverse events were reported in 14 patients [n = 10, 33.3% (KB pooled); n = 4, 28.6% (placebo)]. Seven patients died at 28-day follow-up [n = 4, 13.3% (KB pooled); n = 3, 21.4% (placebo)], none was related to study drug. PK parameters suggested dose-dependent drug exposure and no drug accumulation. KB did not affect clinical outcomes such as ΔSOFA score, vasopressor-free days or ventilator-free days. CONCLUSIONS: In patients with sepsis-induced organ failure, KB was safe and well tolerated. Further investigation is warranted. TRIAL REGISTRATION: http://ClinicalTrials.gov, NCT03237728.

Pollution Characteristics, Source Apportionment, and Health Risk Assessment of Potentially Toxic Elements (PTEs) in Road Dust Samples in Jiayuguan, Hexi Corridor, China.

The sources of potentially toxic elements (PTEs) in road dust are complex and potentially harmful to humans, especially in industrial cities. Jiayuguan is the largest steel-producing city in Northwest China, and this study was the first to conduct a related study on PTEs in road dust in this city, including the pollution characteristics, source apportionment, and health risk assessment of PTEs in road dust. The results showed that the highest concentration of PTEs in the local road dust samples were Mn, Ba, Zn, and Cr. The enrichment factor (EF) of Se was the highest, and it was "Very high enrichment" in areas other than the background area, indicating that the local Se was more affected by human activities. The geoaccumulation index (Igeo) of Se was also the highest, and the pollution level was 5 in all areas except the background area, indicating that the local Se was more polluted and related to coal combustion. The sources of PTEs in local road dust samples mainly included geogenic-industrial sources, coal combustion, traffic sources, and oil combustion. For the non-carcinogenic risk, the hazard index (HI) of each element of children was higher than that of adults, and the sum of the HI of each element was greater than 1, indicating that there was a non-carcinogenic risk under the combined influence of multiple elements, which was especially obvious in industrial areas. For the carcinogenic risk, the cancer risk (CR) of Cr at a certain point in the industrial area exceeded 10-4, which was a carcinogenic risk, and the Cr in this area may be related to the topsoil of the local abandoned chromate plant.

YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer.

PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients, and their indications are expanding incessantly. Currently, most PD-1/PD-L1 agents are administered intravenously, which may be uncomfortable for some cancer patients. Herein, we develop a novel oral-delivered small molecular, YPD-29B, which specifically targets human PD-L1. Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. YDP-29B was modified as the YPD-30 prodrug to improve druggability. Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells, we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo. Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.

A label-free electrochemical aptasensor based on platinum@palladium nanoparticles decorated with hemin-reduced graphene oxide as a signal amplifier for glypican-3 determination.

Glypican-3 (GPC3) is a membrane-associated proteoglycan that is specifically upregulated in hepatocellular carcinoma (HCC) and has become one of the most promising biomarkers closely related to the occurrence and development of HCC. In this work, platinum@palladium nanoparticles decorated with hemin-reduced graphene oxide (H-rGO-Pt@Pd NPs) were used not only as a support for GPC3 aptamer (GPC3Apt) immobilization, but also as a new redox nanoprobe in electrochemical analysis for the determination of GPC3. The electrochemical aptasensor involved a reaction cell with a three-electrode system, and the differential pulse voltammetry (DPV) technique was adopted. In the presence of GPC3, the formed GPC3Apt-GPC3 complexes had stable structures and were cleaved from the electrode surface, leading to more electroactive H-rGO-Pt@Pd NPs repelling freely from the GPC3Apt/H-rGO-Pt@Pd NPs and thus to the increase of the oxidation peak current of hemin in H-rGO-Pt@Pd NPs. Under optimal conditions and a working voltage of +700 mV (vs. Ag/AgCl), the label-free electrochemical GPC3 aptasensor showed superior performance with a wider concentration linear range (0.001-10.0 µg mL-1), a lower limit of detection (LOD) (0.181 ng mL-1, S/N = 3), a higher sensitivity (0.0446 µA µM-1 cm-2) and good selectivity. Furthermore, the fabricated aptasensor was applied to GPC3 determination in human serum samples with satisfactory recoveries of 94.3%-119% and RSDs of 0.15%-5.78%. The current work provides a flexible approach for the rapid and sensitive analysis of GPC3 and has a broad application prospect in the diagnosis of HCC.

RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma.

BACKGROUND: Severe hypoxia is a prominent character of pancreatic ductal adenocarcinoma (PDAC) microenvironment. In the process of gemcitabine based chemotherapy, PDAC cells are insulted from replication stresses co-induced by hypoxia and gemcitabine. However, PDAC cells get outstanding abilities to resist to such harsh conditions and keep proliferating, causing a major obstacle for current therapy. RETSAT (Retinol Saturase) is defined as a hypoxia convergent gene recently, with high expression in PDAC hypoxic sectors. This study aimed to explore the roles of RETSAT in replication stress resistance and hypoxia adaptation in PDAC cells, and decipher the underlying mechanism. METHODS: The expression of RETSAT was examined in TCGA (The Cancer Genome Atlas), human pancreatic cancer microarray, clinical specimens and cell lines. Functions of RETSAT were studied by means of DNA fiber assay and comet assay in monolayer cultured PDAC cell lines, three dimensional spheroids, patient derived organoids and cell derived xenograft mouse models. Mechanism was investigated by using iPOND (isolate proteins on nascent DNA) combined with mass spectrometry, immunoprecipitation and immunoblotting. RESULTS: First, we found the converse relationship of RETSAT expression and PDAC chemotherapy. That is, PDAC patients with high RETSAT expression correlated with poor survival, while ones holding low RETSAT expression were benefitted more in Gemcitabine based chemotherapy. Second, we identified RETSAT as a novel replication fork associated protein. HIF-1α signaling promotes RETSAT expression under hypoxia. Functionally, RETSAT promoted fork restarting under replication stress and maintained genomic stability. Third, we uncovered the interaction of RETSAT and R-loop unwinding helicase DDX39B. RETSAT detained DDX39B on forks to resolve R-loops, through which avoided fork damage and CHK1 initiated apoptosis. Targeting DDX39B using chemical CCT018159 sensitized PDAC cells and organoids to gemcitabine induced apoptosis, highlighting the synergetic application of CCT018159 and gemcitabine in PDAC chemotherapy. CONCLUSIONS: This study identified RETSAT as a novel replication fork protein, which functions through interacting with DDX39B mediated R-loop clearance to promote fork restarting, leading to cellular resistance to replication stresses co-induced by tumor environmental hypoxia and gemcitabine in pancreatic ductal adenocarcinoma.

Network pharmacology to explore the anti-inflammatory mechanism of Xuebijing in the treatment of sepsis.

BACKGROUND: Xuebijing (XBJ) is a traditional Chinese patent medicine for sepsis. However, the mechanism of action (MoA) of XBJ on sepsis remain unclear. PURPOSE: Elucidate the MoA of XBJ for treating sepsis based on network pharmacology. STUDY DESIGN: Integrate computational prediction, experimental validation and literature reported clinical results analysis based on network pharmacology. METHODS: Computationally, representative compounds of XBJ were characterized by LC-MS/MS and the target profiles of each compound were identified using network-based method. Compounds from XBJ were compared with FDA approved drugs or experimental agents for sepsis by hierarchical clustering of target profile. Key biological functional modules of XBJ for treating sepsis were identified by enrichment analysis. Differential expressed analysis for each biological functional module was conducted from sepsis related public omics datasets. Herb-biological functional module network was constructed to reveal part of the traditional combinatorial rules of herbs for modules. Experimentally, the action of XBJ compounds on genes in biological functional module was validated by detecting quantitative transcriptional profiling and sepsis animal model. Clinically, combined with the clinical results recorded in literature, computational and experimental results were used to interpret the anti-inflammatory effect of XBJ for treating sepsis. RESULTS: The target profiles of compound cover most of the compound's related biomolecules reported in literature, which can characterize the comprehensive function of compound. XBJ has similar pharmacological effect as FDA approved drugs or experimental agents. Four key biological functional modules including inflammation, immune, cell apoptosis and coagulation of XBJ for treating sepsis were identified. Cell line experimental results show that part of ingredients in XBJ regulate the expression of genes in inflammation modules as predicted. Animal experiments show that compounds from XBJ could reduce the expression level of IL-1ß. Combined with literature reported clinical results, XBJ was found to exert anti-inflammatory effect through regulating the NF-kappa B signaling pathway. CONCLUSION: The network pharmacology framework integrating computational prediction, experimental validation and literature reported clinical results analysis provides a novel approach for analyzing MoA of XBJ for treating sepsis.

Simultaneous Determination of a Novel PD-L1 Inhibitor, IMMH-010, and Its Active Metabolite, YPD-29B, in Rat Biological Matrices by Polarity-Switching Liquid Chromatography-Tandem Mass Spectrometry: Application to ADME Studies.

IMMH-010 is a prodrug of YPD-29B, which is a novel PD-L1 inhibitor. A specific and sensitive LC-MS/MS method with polarity switching was developed and validated for the simultaneous determination of IMMH-010 and YPD-29B in rat plasma, liver, brain, urine and fecal samples. Method validation was investigated to demonstrate the lower limit of quantification linearity, precision and accuracy, matrix effect and recovery, stability and dilution reliability for IMMH-010 and YPD-29B. This validated method was successfully applied to investigate the pharmacokinetics, tissue distribution, and excretion of IMMH-010 and YPD-29B in rats. After oral administration of IMMH-010 maleate to rats, IMMH-010 was rapidly and extensively converted to the active metabolite YPD-29B. The areas under the plasma concentration-time curve (AUC) of IMMH-010 and YPD-29B were proportional to the dose in the range of 10-100 mg/kg. IMMH-010 was primarily distributed in the adrenal gland, lymph nodes, heart, liver and spleen. YPD-29B was mainly observed in the liver, lymph, kidney, and lung. Approximately 28.81% of the IMMH-010 dose was recovered in the urine and feces within 72 h, including unchanged IMMH-010 (7.99%) and YPD-29B (20.82%). The results of this study may be useful as a reference for further development of IMMH-010 and PD-L1 inhibitors. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT04343859?term=IMMH-010&draw=2&rank=1], identifier [NCT04343859]."