This study explored the potential therapeutic targets and mechanisms of Danggui Shaoyao San(DSS) in the prevention and treatment of Alzheimer's disease(AD) through transcriptomics and metabolomics, combined with animal experiments. Fifty male C57BL/6J mice, aged seven weeks, were randomly divided into the following five groups: control, model, positive drug, low-dose DSS, and high-dose DSS groups. After the intervention, the Morris water maze was used to assess learning and memory abilities of mice, and Nissl staining and hematoxylin-eosin(HE) staining were performed to observe pathological changes in the hippocampal tissue. Transcriptomics and metabolomics were employed to sequence brain tissue and identify differential metabolites, analyzing key genes and metabolites related to disease progression. Reverse transcription-quantitative polymerase chain reaction(RT-qPCR) was employed to validate the expression of key genes. The Morris water maze results indicated that DSS significantly improved learning and cognitive function in scopolamine(SCOP)-induced model mice, with the high-dose DSS group showing the best results. Pathological staining showed that DSS effectively reduced hippocampal neuronal damage, increased Nissl body numbers, and reduced nuclear pyknosis and neuronal loss. Transcriptomics identified seven key genes, including neurexin 1(Nrxn1) and sodium voltage-gated channel α subunit 1(Scn1a), and metabolomics revealed 113 differential metabolites, all of which were closely associated with synaptic function, oxidative stress, and metabolic regulation. RT-qPCR experiments confirmed that the expression of these seven key genes was consistent with the transcriptomics results. This study suggests that DSS significantly improves learning and memory in SCOP model mice and alleviates hippocampal neuronal pathological damage. The mechanisms likely involve the modulation of synaptic function, reduction of oxidative stress, and metabolic balance, with these seven key genes serving as important targets for DSS in the treatment of AD.
Animals ; Alzheimer Disease/genetics* ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Mice, Inbred C57BL ; Metabolomics ; Transcriptome/drug effects* ; Maze Learning/drug effects* ; Hippocampus/metabolism* ; Humans ; Disease Models, Animal ; Memory/drug effects*

Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

Background::Atopic dermatitis (AD) affects approximately 10% of adults worldwide. CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling. This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD.Methods::This multicenter, randomized, double-blind, placebo-controlled, phase 2b trial was conducted in 21 medical institutions in China from February to November 2021. Totally 120 eligible patients were enrolled and randomized (1:1:1) to receive subcutaneous injections of 300 mg CM310, 150 mg CM310, or placebo every 2 weeks for 16 weeks, followed by an 8-week follow-up period. The primary endpoint was the proportion of patients achieving ≥75% improvement in the Eczema Area and Severity Index (EASI-75) score from baseline at week 16. Safety and pharmacodynamics were also studied.Results::At week 16, the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups (70% [28/40] for high-dose and 65% [26/40] for low-dose) than that in the placebo group (20%[8/40]). The differences in EASI-75 response rate were 50% (high vs. placebo, 95% CI 31%–69%) and 45% (low vs. placebo, 95% CI 26%–64%), with both P values <0.0001. CM310 at both doses also significantly improved the EASI score, Investigator’s Global Assessment score, daily peak pruritus Numerical Rating Scale, AD-affected body surface area, and Dermatology Life Quality Index compared with placebo. CM310 treatment reduced levels of thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase, and blood eosinophils. The incidence of treatment-emergent adverse events (TEAEs) was similar among all three groups, with the most common TEAEs reported being upper respiratory tract infection, atopic dermatitis, hyperlipidemia, and hyperuricemia. No severe adverse events were deemed to be attributed to CM310. Conclusion::CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.Trial Registration::ClinicalTrials.gov, NCT04805411.

Objective To design a novel oxygenator to solve the existing problems of extracorporeal membrane oxygenation(ECMO)machine in high transmembrane pressure difference,low efficiency of blood oxygen exchange and susceptibility to thrombosis.Methods The main body of the oxygenator vascular access flow field was gifted with a flat cylindrical shape.The topology of the vascular access was modeled in three dimensions,and the whole flow field was cut into a blood inlet section,an inlet buffer,a heat exchange zone,a blood oxygen exchange zone,an outlet buffer and a blood outlet section.The oxygenator was compared with Quadrox oxygenator by means of ANSYS FLUENT-based simulation and prototype experiments.Results Simulation calculations showed the oxygenator designed was comparable to the clinically used ones in general,and gained advantages in transmembrane pressure difference,blood oxygen exchange and flow uniformity.Experimental results indicated that the oxygenator behaved better than Quadrox oxygenator in transmembrane pressure difference and blood oxygen exchange.Conclusion The oxygenator has advantages in transmem-brane pressure difference,temperature change,blood oxygen ex-change and low probability of thrombosis.[Chinese Medical Equipment Journal,2024,45(3):23-28]

Purpose To explore the value of contrast-enhanced ultrasound(CEUS)in the differential diagnosis of gallbladder polypoid lesions(GPLs)(diameter≥10 mm).Materials and Methods A prospective enrollment of 229 patients with GPLs who underwent cholecystectomy in 17 hospitals from December 1 2021 to June 30 2024 was conducted to analyze the relationship between general data,conventional ultrasound,CEUS characteristics and the nature of GPLs.Multivariate Logistic regression was employed to identify independent risk factors for neoplastic polyps,the differential diagnostic value of different indicators was compared.Results Among 229 patients with GPLs,there were 108 cases of cholesterol polyps,102 cases of adenoma and 19 cases of gallbladder cancer.Age(Z=-4.476,P<0.001),polyp number(χ2=15.561,P<0.001),diameter(Z=-8.149,P<0.001),echogenicity(χ2=9.241,P=0.010),vascularity(χ2=23.107,P<0.001),enhancement intensity(χ2=47.610,P<0.001),enhancement pattern(χ2=6.468,P=0.011),vascular type(χ2=84.470,P<0.001),integrity of gallbladder wall(χ2=7.662,P=0.006)and stalk width(Z=-9.831,P<0.001)between cholesterol polyps and neoplastic polyps were statistically significant.Age,location,diameter,echogenicity,enhancement pattern,vascular type and stalk width between adenoma and gallbladder cancer were statistically significant(Z=-4.333,-3.902,-5.042,all P<0.05).Multivariate Logistic regression analysis showed that hyper-enhancement,branched vascular type and stalk width were independent risk factors for neoplastic polyps(OR=4.563,5.770,3.075,all P<0.001).The combination of independent risk factors was better than single factor and diameter in the differential diagnosis of cholesterol polyps and neoplastic polyps(all P<0.01).Conclusion CEUS can effectively identify the nature of GPLs and provide a valuable imaging reference for the selection of treatment methods.

AIM To establish the quality standard of the zhujieshen Formula Granules based on standard decoction.METHODS The contents and transfer rates of ginsenoside Ro and chikusetsu saponin Ⅳa in standard decoction and formula granules were determined by HPLC,after which the transfer rates were calculated.The HPLC characteristic chromatograms of standard decoctions were established,after which cluster analysis and principal component analysis were adopted.Then the HPLC characteristic chromatograms of formula granules were established.RESULTS Nine common peaks were found in the HPLC characteristic chromatograms of seventeen batches of standard decoctions with the similarities of more than 0.9(except for S6,S12),which were clustered into two categories,and the accumulative variance contribution rate of three principal components reached 86.7％.The contents of ginsenoside Ro in three batches of formula granules were 83.1-88.6 mg/g,and the transfer rates were 53.1％-55.5％.The contents of chikusetsusaponin Ⅳa were 14.8-15.0 mg/g,and the transfer rates were 47.4％-48.1％.Nine common peaks were found in the HPLC characteristic chromatograms of three batches of formula granules with the similarities of 0.998,0.998 and 0.999,respectively.CONCLUSION This reasonable and reliable method can comprehensively evaluate the quality of Zhujieshen Formula Granules,and provide a reference for the quality control.

Objective: The effect on fat infiltration (FI) of paraspinal muscles in degenerative lumbar spinal diseases has been demonstrated except for spinopelvic parameters. The present study is to identify the effect of spinopelvic parameters on FI of paraspinal muscle (PSM) and psoas major muscle (PMM) in patients with degenerative lumbar spondylolisthesis. Methods: A single-center, retrospective cross-sectional study of 160 patients with degenerative lumbar spondylolisthesis (DLS) and lumbar stenosis (LSS) who had lateral full-spine x-ray and lumbar spine magnetic resonance imaging was conducted. PSM and PMM FIs were defined as the ratio of fat to its muscle cross-sectional area. The FIs were compared among patients with different pelvic tilt (PT) and pelvic incidence (PI), respectively. Results: The PSM FI correlated significantly with pelvic parameters in DLS patients, but not in LSS patients. The PSM FI in pelvic retroversion (PT > 25°) was 0.54 ± 0.13, which was significantly higher in DLS patients than in normal pelvis (0.41 ± 0.14) and pelvic anteversion (PT < 5°) (0.34 ± 0.12). The PSM FI of DLS patients with large PI ( > 60°) was 0.50 ± 0.13, which was higher than those with small ( < 45°) and normal PI (0.37 ± 0.11 and 0.36 ± 0.13). However, the PSM FI of LSS patients didn’t change significantly with PT or PI. Moreover, the PMM FI was about 0.10–0.15, which was significantly lower than the PSM FI, and changed with PT and PI in a similar way of PSM FI with much less in magnitude. Conclusion FI of the PSMs increased with greater pelvic retroversion or larger pelvic incidence in DLS patients, but not in LSS patients.

Objective: The effect on fat infiltration (FI) of paraspinal muscles in degenerative lumbar spinal diseases has been demonstrated except for spinopelvic parameters. The present study is to identify the effect of spinopelvic parameters on FI of paraspinal muscle (PSM) and psoas major muscle (PMM) in patients with degenerative lumbar spondylolisthesis. Methods: A single-center, retrospective cross-sectional study of 160 patients with degenerative lumbar spondylolisthesis (DLS) and lumbar stenosis (LSS) who had lateral full-spine x-ray and lumbar spine magnetic resonance imaging was conducted. PSM and PMM FIs were defined as the ratio of fat to its muscle cross-sectional area. The FIs were compared among patients with different pelvic tilt (PT) and pelvic incidence (PI), respectively. Results: The PSM FI correlated significantly with pelvic parameters in DLS patients, but not in LSS patients. The PSM FI in pelvic retroversion (PT > 25°) was 0.54 ± 0.13, which was significantly higher in DLS patients than in normal pelvis (0.41 ± 0.14) and pelvic anteversion (PT < 5°) (0.34 ± 0.12). The PSM FI of DLS patients with large PI ( > 60°) was 0.50 ± 0.13, which was higher than those with small ( < 45°) and normal PI (0.37 ± 0.11 and 0.36 ± 0.13). However, the PSM FI of LSS patients didn’t change significantly with PT or PI. Moreover, the PMM FI was about 0.10–0.15, which was significantly lower than the PSM FI, and changed with PT and PI in a similar way of PSM FI with much less in magnitude. Conclusion FI of the PSMs increased with greater pelvic retroversion or larger pelvic incidence in DLS patients, but not in LSS patients.

Objective: The effect on fat infiltration (FI) of paraspinal muscles in degenerative lumbar spinal diseases has been demonstrated except for spinopelvic parameters. The present study is to identify the effect of spinopelvic parameters on FI of paraspinal muscle (PSM) and psoas major muscle (PMM) in patients with degenerative lumbar spondylolisthesis. Methods: A single-center, retrospective cross-sectional study of 160 patients with degenerative lumbar spondylolisthesis (DLS) and lumbar stenosis (LSS) who had lateral full-spine x-ray and lumbar spine magnetic resonance imaging was conducted. PSM and PMM FIs were defined as the ratio of fat to its muscle cross-sectional area. The FIs were compared among patients with different pelvic tilt (PT) and pelvic incidence (PI), respectively. Results: The PSM FI correlated significantly with pelvic parameters in DLS patients, but not in LSS patients. The PSM FI in pelvic retroversion (PT > 25°) was 0.54 ± 0.13, which was significantly higher in DLS patients than in normal pelvis (0.41 ± 0.14) and pelvic anteversion (PT < 5°) (0.34 ± 0.12). The PSM FI of DLS patients with large PI ( > 60°) was 0.50 ± 0.13, which was higher than those with small ( < 45°) and normal PI (0.37 ± 0.11 and 0.36 ± 0.13). However, the PSM FI of LSS patients didn’t change significantly with PT or PI. Moreover, the PMM FI was about 0.10–0.15, which was significantly lower than the PSM FI, and changed with PT and PI in a similar way of PSM FI with much less in magnitude. Conclusion FI of the PSMs increased with greater pelvic retroversion or larger pelvic incidence in DLS patients, but not in LSS patients.

Objective: The effect on fat infiltration (FI) of paraspinal muscles in degenerative lumbar spinal diseases has been demonstrated except for spinopelvic parameters. The present study is to identify the effect of spinopelvic parameters on FI of paraspinal muscle (PSM) and psoas major muscle (PMM) in patients with degenerative lumbar spondylolisthesis. Methods: A single-center, retrospective cross-sectional study of 160 patients with degenerative lumbar spondylolisthesis (DLS) and lumbar stenosis (LSS) who had lateral full-spine x-ray and lumbar spine magnetic resonance imaging was conducted. PSM and PMM FIs were defined as the ratio of fat to its muscle cross-sectional area. The FIs were compared among patients with different pelvic tilt (PT) and pelvic incidence (PI), respectively. Results: The PSM FI correlated significantly with pelvic parameters in DLS patients, but not in LSS patients. The PSM FI in pelvic retroversion (PT > 25°) was 0.54 ± 0.13, which was significantly higher in DLS patients than in normal pelvis (0.41 ± 0.14) and pelvic anteversion (PT < 5°) (0.34 ± 0.12). The PSM FI of DLS patients with large PI ( > 60°) was 0.50 ± 0.13, which was higher than those with small ( < 45°) and normal PI (0.37 ± 0.11 and 0.36 ± 0.13). However, the PSM FI of LSS patients didn’t change significantly with PT or PI. Moreover, the PMM FI was about 0.10–0.15, which was significantly lower than the PSM FI, and changed with PT and PI in a similar way of PSM FI with much less in magnitude. Conclusion FI of the PSMs increased with greater pelvic retroversion or larger pelvic incidence in DLS patients, but not in LSS patients.