ObjectiveTo elucidate the chemical composition of Danshenyin and its blood components in rats after oral administration. MethodsUltra performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry（UPLC-Q-TOF-MS/MS） coupled with PeakView 1.2 software was used to systematically characterize and identify the components of Danshenyin aqueous extract and its migratory components in rat blood after oral administration based on the retention time， quasi-molecular ion peaks， secondary fragmentation ions， and literature reports， and a preliminary compounds identification of Salviae Miltiorrhizae Radix et Rhizoma aqueous extract， the co-decoction of Santali Albi Lignum and Amomi Fructus was carried out to attribute the chemical constituents of the aqueous extract of Danshenyin. ResultsA total of 73 compounds， including 21 phenolic acids， 23 diterpenes， 6 flavonoids， 7 organic acids， 3 volatile oils and 13 others， were identified from the aqueous extract of Danshenyin. And 36 prototypes and 15 metabolites were identified in rat plasma， the major metabolic pathways included reduction， hydration， hydroxylation， demethylation， methylation， sulfation and others， these metabolites were mainly derived from tanshinones and salvianolic acids. ConclusionThe main blood components of the aqueous extract of Danshenyin are salvianolic acids and tanshinones， which may be the material basis of the efficacy. This study can provide reference for pharmacological research， quality control， and clinical application of Danshenyin.

BACKGROUND: The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 1683 ALL patients from Peking University People's Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariable analysis was performed to determine independent influencing factors from the univariable analysis. RESULTS: Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity ( P  <0.001 for all). Disease status (complete remission 1 [CR1] vs . ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups ( P  = 0.027; P  = 0.003; P  = 0.035; P  = 0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively ( P  <0.001). Multivariable analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival. CONCLUSION Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.
Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology* ; Neoplasm, Residual ; Hematopoietic Stem Cell Transplantation/methods* ; Male ; Female ; Risk Factors ; Adolescent ; Adult ; Child ; Child, Preschool ; Young Adult ; Middle Aged ; Infant ; Transplantation, Homologous ; Proportional Hazards Models ; Retrospective Studies

HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

Environmental toxicants have been linked to aging and age-related diseases. The emerging evidence has shown that the enhancement of detoxification gene expression is a common transcriptome marker of long-lived mice, Drosophila melanogaster, and Caenorhabditis elegans. Meanwhile, the resistance to toxicants was increased in long-lived animals. Here, we show that farnesoid X receptor (FXR) agonist obeticholic acid (OCA), a marketed drug for the treatment of cholestasis, may extend the lifespan and healthspan both in C. elegans and chemical-induced early senescent mice. Furthermore, OCA increased the resistance of worms to toxicants and activated the expression of detoxification genes in both mice and C. elegans. The longevity effects of OCA were attenuated in Fxr ^-/- mice and Fxr homologous nhr-8 and daf-12 mutant C. elegans. In addition, metabolome analysis revealed that OCA increased the endogenous agonist levels of the pregnane X receptor (PXR), a major nuclear receptor for detoxification regulation, in the liver of mice. Together, our findings suggest that OCA has the potential to lengthen lifespan and healthspan by activating nuclear receptor-mediated detoxification functions, thus, targeting FXR may offer to promote longevity.

Background::Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants.Methods::A total of 3053 healthy Han Chinese adults (1922 women) aged 18-79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere-Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance.Results::All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction <0.05). The blood pressures, body mass index (BMI), and triglyceride levels were identified as major clinical determinants of carotid properties with adjustment of age and sex. Conclusions::The age- and sex-specific reference values of carotid properties measured by RF ultrasound for healthy Chinese adults were established. The blood pressures, BMI, and triglyceride levels should be considered for clinical application of corresponding reference values.

Background Long-term exposure to noise during sleep may has adverse effects on metabolic system, and liver lipid metabolism is closely related to circadian clock genes. Objective To investigate the effects of long-term noise exposure during sleep on liver circadian clock and lipid metabolism in mice and its related mechanism. Methods Twenty C57BL/6J male mice were randomly divided into two groups: a noise exposure group and a control group with 10 mice in each group. The mice in the noise exposure group were exposed to white noise at 90 dB sound pressure level (SPL) for 30 consecutive days, 8 h a day, from 9:00 to 17:00. The mice in the control group were exposed to background noise ≤40 dB SPL. After noise exposure, the animals were neutralized at 14:00 (ZT6) and 2:00 (ZT18), 5 animals at each time spot, and the liver tissues were collected. Total cholesterol and triglyceride in liver were determined by cholesterol oxidase method and glycerol phosphate oxidase method respectively. The expressions of circadian clock genes (Clock, Bmal1, Rev-erbα, and Rev-erbβ) and lipid metabolism genes (Srebp1c, Hmgcr, Fasn, Lxrα, Acc1, and Chrebp) in liver were detected by quantitative real-time PCR. Results Compared with the control group, the content of total cholesterol in liver in the noise exposure group increased by 48% (P<0.05) and the content of liver triglyceride increased by 61% (P<0.05) at ZT18. The mRNA expression levels of circadian clock genes Clock and Bmal1 in the noise exposure group was significantly increased at ZT18 and decreased at ZT6 (P<0.05). The mRNA expression level of Rev-erbα decreased at both ZT6 and ZT18 (P<0.05). The mRNA expression level of Rev-erbβ had no significant change at ZT6 and ZT18. The mRNA expression levels of liver lipid metabolism related genes Srebp1c, Hmgcr, Chrebp, and Lxrα in the noise exposure group were higher than those in the control group at ZT18 (P<0.05). The mRNA expression levels of Acc1 and Fasn showed no significant change at ZT6, then an upward trend at ZT18, but no significant difference between the two time spots (P>0.05). Conclusion Long-term noise exposure during sleep can cause circadian clock and lipid metabolism disorders in mice. Among them, suppression of key circadian clock genes may be associated with Rev-erbα-mediated upregulation of the nuclear receptors Srebp1c and Chrebp for lipid synthesis and deposition in the liver, resulting in lipid metabolism disorder.

Humans ; Nephrotic Syndrome ; Hematopoietic Stem Cell Transplantation ; Tissue Donors ; Transplantation Conditioning ; Graft vs Host Disease

AIM:To investigate the inhibitory ef-fect of Zushima ointment on inflammation and bone destruction in CIA mice.METHODS:SPF grade male DBA/1 mice were used,6 were random-ly selected as the normal group,and 18 CIA mice that were successfully modelled were randomly di-vided into the model group,the plaster group(1.0 g/kg),and the fuselage group(0.12 g per time)ac-cording to the random number table method,6 mice in each group,and each administered group was given medication according to the body mass,and saline was given to both the normal and model groups.The normal group and the model group were given saline,and breathable adhesive paper was applied once a day for 4 h/session for 4 consec-utive weeks.The arthritis scoring index was used to observe the changes of arthritis symptoms and ar-thritis index scores of mice in each group.Micro-CT was used to observe the damage of hind paw of mice,real-time fluorescence PCR was used to de-tect the mRNA expression of IL-17,IL-1β and TNF-αin ankle joint tissues,and immunohistochemistry was used to detect the expression of OPG and RANKL proteins in ankle joint tissues,and hematox-ylin-eosin(HE)staining was used to observe the pathological changes of synovial tissues after the treatment.The pathological changes of synovial tis-sue were observed after hematoxylin-eosin(HE)staining,and the changes of osteoclasts in ankle joint tissue were observed by anti-tartaric acid phosphatase(TRAP)method.RESULTS:Compared with the normal group,the arthritis index score of the model mice was significantly higher(P＜0.05).Micro-CT showed severe bone erosion in the hind paws of the mice,destruction of the bone surface and reduction of bone volume.The expression of IL-17,IL-1β and TNF-α mRNA(PCR)in the ankle joint tissues was significantly higher(P＜0.05).Im-munohistochemistry showed that the relative ex-pression of OPG protein in the ankle joint tissues was reduced(P＜0.05).Immunohistochemistry showed a decrease in the relative expression of OPG protein(P＜0.01)and an increase in the rela-tive expression of RANKL protein(P＜0.01).HE re-sults showed moderate inflammatory cell infiltra-tion,swelling of synovial cells,massive formation of vascular opacities and synovial hyperplasia;an increase in the number of osteoclasts,roughness of the surface of articular cartilage tissue,severe bone destruction and thinning of the cartilage lay-er.Compared with the model group,the arthritic symptoms of mice in the cream group and the futa-lin group were relieved and the arthritis index score was reduced;the bone density of the mice's hind paws improved,effectively relieving osteopo-rosis;the expression of IL-17,IL-1β and TNF-αmRNA(PCR)in the ankle joint tissue was signifi-cantly reduced(P＜0.05);the immunohistochemical results showed that the relative expression of OPG protein was increased(P＜0.05),the relative expres-sion of RANKL protein decreased(P＜0.01).HE re-sults showed that synovial cell enlargement was significantly improved,mild inflammatory cell infil-tration,synovial hyperplasia was not obvious;the number of broken bone was reduced,articular car-tilage destruction was significantly improved and relieved,and the thickness of cartilage layer was significantly increased.CONCLUSION:Ancestral hemp poultice relieves local symptoms of RA,re-duces the expression of inflammatory factors and attenuates the inflammatory response,possibly by inhibiting osteoclast differentiation and activation through modulation of the OPG/RANKL signalling axis,which further ameliorates the biological ef-fects of articular bone and cartilage destruction.