This article discusses the key pathogenesis of atherosclerosis （AS） based on the physiological characteristics and pathological changes of lipids and introduces the therapeutic effect of Zhuyuwan on AS， aiming to provide a theoretical basis for the treatment of cardiovascular diseases from the spleen. As essential substances， lipids have the same essence but different forms. They circulate throughout the body with body fluids under the action of Yang Qi to nourish the nutrient Qi and support the defensive Qi. Lipid metabolism disorder often leads to the obstruction of Qi movement， the accumulation of dampness and turbidity， and the generation of phlegm and blood stasis. It has been proven that the formation of vulnerable plaques in AS is attributed to the interaction of three pathogenic factors： deficiency of healthy Qi， phlegm-turbidity， and collateral stasis. Their pathological essence is closely related to abnormal lipid metabolism. As lipids constitute the thick and dense components of body fluids， their impaired dispersion may lead to phlegm-turbidity and blood stasis， the pathological process of which is predominantly ascribed to the dysfunction of the spleen in distributing essence. Therefore， AS is rooted in spleen-stomach disorder， manifests as plaques formed by pathological product accumulation in vessels， with lipid transport disorder as its core pathogenesis. Specifically speaking， the dysfunction of spleen in transportation with accumulation of dampness-turbidity marks the initial stage， and blood turbidity and coagulation and phlegm-nodules accumulating in vessels represent the intermediate phase. Cold accumulation and stagnated heat transforming into toxins represent the terminal stage. Zhuyuwan， first recorded in Taiping Holy Prescriptions for Universal Relief， contains equal proportions of Coptidis Rhizoma and Evodiae Fructus. Coptidis Rhizoma， bitter and cold， exerts descending and purging actions to assist stomach Qi in lowering turbidity. Evodiae Fructus， pungent-bitter and hot， disperses obstruction and promotes free flow to support spleen Qi in ascending the clear. The compatibility of Coptidis Rhizoma and Evodiae Fructus ascends the clear and descends the turbid to harmonize Yin and Yang， assisting the spleen in distributing essence and resolving lipid accumulation to reduce lipid levels. In terms of the therapeutic mechanism， Zhuyuwan modulates lipid metabolism by correcting immune-inflammation network imbalance， improving gut microbiota composition and metabolism， and enhancing reverse cholesterol transport. By analyzing the pathological characteristics of lipid transport disorder in AS， this study delves into the intrinsic connections between cardiovascular disease and lipid transport disorder， giving novel insights into the prevention and treatment of AS.

This article discusses the key pathogenesis of atherosclerosis （AS） based on the physiological characteristics and pathological changes of lipids and introduces the therapeutic effect of Zhuyuwan on AS， aiming to provide a theoretical basis for the treatment of cardiovascular diseases from the spleen. As essential substances， lipids have the same essence but different forms. They circulate throughout the body with body fluids under the action of Yang Qi to nourish the nutrient Qi and support the defensive Qi. Lipid metabolism disorder often leads to the obstruction of Qi movement， the accumulation of dampness and turbidity， and the generation of phlegm and blood stasis. It has been proven that the formation of vulnerable plaques in AS is attributed to the interaction of three pathogenic factors： deficiency of healthy Qi， phlegm-turbidity， and collateral stasis. Their pathological essence is closely related to abnormal lipid metabolism. As lipids constitute the thick and dense components of body fluids， their impaired dispersion may lead to phlegm-turbidity and blood stasis， the pathological process of which is predominantly ascribed to the dysfunction of the spleen in distributing essence. Therefore， AS is rooted in spleen-stomach disorder， manifests as plaques formed by pathological product accumulation in vessels， with lipid transport disorder as its core pathogenesis. Specifically speaking， the dysfunction of spleen in transportation with accumulation of dampness-turbidity marks the initial stage， and blood turbidity and coagulation and phlegm-nodules accumulating in vessels represent the intermediate phase. Cold accumulation and stagnated heat transforming into toxins represent the terminal stage. Zhuyuwan， first recorded in Taiping Holy Prescriptions for Universal Relief， contains equal proportions of Coptidis Rhizoma and Evodiae Fructus. Coptidis Rhizoma， bitter and cold， exerts descending and purging actions to assist stomach Qi in lowering turbidity. Evodiae Fructus， pungent-bitter and hot， disperses obstruction and promotes free flow to support spleen Qi in ascending the clear. The compatibility of Coptidis Rhizoma and Evodiae Fructus ascends the clear and descends the turbid to harmonize Yin and Yang， assisting the spleen in distributing essence and resolving lipid accumulation to reduce lipid levels. In terms of the therapeutic mechanism， Zhuyuwan modulates lipid metabolism by correcting immune-inflammation network imbalance， improving gut microbiota composition and metabolism， and enhancing reverse cholesterol transport. By analyzing the pathological characteristics of lipid transport disorder in AS， this study delves into the intrinsic connections between cardiovascular disease and lipid transport disorder， giving novel insights into the prevention and treatment of AS.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Abstract Child abuse is a global public health problem, which has emerged as a neglected yet pressing issue in global development. Early and accurate identification of abuse at a lower-age group is of great significance for treatment, which might reduce the risk of re-maltreatment and promote children s physical and mental health development. Therefore, by reviewing the clinical characteristics, risk factors and existing abuse identification and screening tools of child abuse, the study aims at providing basic evidence for the development of child abuse risk identification tools and the establishment of child maltreatment system in China, so as to take timely intervention measures to prevent adverse outcomes or reduce their severity.

Objective: To compare the clinical value of total gastrectomy and proximal gastrectomy in the treatment of gastric fundus carcinoma. Methods: 80 patients with gastric fundus cancer were divided into observation group and control group according to the random number method.The observation group was treated with total gastrectomy, and the control group was treated by proximal gastrectomy.The operation-related conditions, such as operation time, intraoperative bleeding and postoperative anal exhaust time of the two groups were compared.After surgery R0 resection rate and 2-year survival rate were analyzed. Results: The operative time in the observation group was (86.3±1.9)min, which was shorter than (102.3±2.6)min in the control group (t=31.424, P<0.05). The intraoperative blood loss of the observation group was (180.5±15.0)mL, which was less than (230.0±25.0)mL of the control group (t=10.738, P<0.05). The anal exhaust time of the observation group was (41.5±2.1)h, which was shorter than (56.9±3.3)h of the control group (t=24.900, P<0.05). The percentage of pathologic R0 resection of the observation group was 32.5%(13/40), which was higher than 5.0%(2/40) of the control group (χ²=8.205, P<0.05). The 1-year survival rate and 2-year survival rate in the observation group were 92.5%, 67.5%, respectively, which were significantly higher than those in the control group(60.0%, 42.5%, χ²=4.943, 5.051, all P<0.05). Conclusion Compared with the proximal gastrectomy, the total gastrectomy in the treatment of gastric fundus carcinoma has shorter operation time, less intraoperative blood loss, quicker postoperative recovery, higher pathologic resection rate and survival rate.

Objective To investigate the toxic reaction,toxic organs or target tissues of protamine recombinant human insulin (Insulin NPH),and provide basis for clinical trials by single dose toxicity test in mice,repeated toxicity and immunogenicity of Beagle's dogs,and systemic active allergy in guinea pig.Methods ① Using maximum dose method,mice in single dose toxicity test were sc injected with normal saline (NS),vehicle,and Insulin NPH (2092-2488 IU/kg),the toxic reactions after injection were monitored.② In repeated toxicity study,Beagle's dogs were sc administrated with vehicle,the original (Humulin NPH,1.5 IU/kg)and different doses of Insulin NPH (0.5,1.0 and 1.5 IU/kg) for 30 d continuously,followed by a 14-d recovery.During the administration and recovery period,general observation,local irritation,body weight,anus temperature,blood glucose,and electrocardiogram (ECG) were checked,moreover,hematology,serum biochemistry and urine were detected.Also,organic weights and histopathological examination were conducted.Binding antibodies in dog serum were measured by indirect ELISA method in immunogenicity test.③ In systemic active allergy study,cavies were sc injected with low-and high-dose (4 and 12 IU/kg) Insulin NPH,normal saline and vehicle.Besides,ova as positive control was also included.After five times of sensitization test with above doses,the excitation reactions of iv injection with tripled sensitizing doses were observed.Results No obvious toxicity was observed in mice after injected with 165 times of usual clinical dose of Insulin NPH.Repeated toxicity study of Beagle's dogs revealed that 1.0 IU/kg was the no-toxic-effect dose (NOAEL) for Insulin NPH,which was equivalent to 2 times of clinical dose.No bindingantibodies were found in immunogenicity test.There was no obvious allergic symptom in the active systemic allergy study of guinea pig.Conclusion Under the experimental conditions,no serious toxicity of Insulin NPH is found.

Objective To investigate the expression of the vascular endothelial growth factor (VEGF) and mucin MUC5AC in nasal mucosa before and after chronic rhinitis - sinusitis and nasal polyps - endoscopic sinus surgery.Methods 75 cases chronic rhinitis - sinusitis and nasal polyps - endoscopic sinus surgery patients were selected as nasal polyps group and 75 cases of nasal bone fracture or epistaxis patients as the control group from January 2012 to January 2015. Took the samples of nasal polyps before surgery and the maxillary sinus mucosa specimens after surgery six weeks of nasal polyps’ patients and on the edge of the inferior turbinate mucosa specimens of the control group to detect eosinophil count by HE staining, and detect the expression of VEGF and mucin MUC5AC by immunohistochemical staining.Results The specimens eosinophils of preoperative nasal polyp group and postoperative nasal polyp group were higher than that of control group (P < 0.05), the nasal eosinophils of postoperative nasal polyp group was lower than that of preoperative nasal polyp group (P < 0.05). The expression of specimens VEGF and mucin MUC5AC area percentages in preoperative nasal polyp group and postoperative nasal polyp group were higher than that in control group (P < 0.05), the expression of nasal VEGF and mucin MUC5AC area percentages in the postoperative nasal polyp group was lower than that of preoperative nasal polyp group (P< 0.05).Conclusion Eosinophil count and the expression levels of VEGF and mucin MUC5AC of nasal mucosa in chronic rhinitis - sinusitis and nasal polyps - endoscopic sinus surgery preoperative are higher, and reduce at postoperative six weeks, VEGF and mucin MUC5AC may be involved nasal repair.

Objective To study the effects of TRβ△ on apoptosis and proliferation of liver cancer cell line RH-35 from rat in vitro. Methods RH-35 cells were transfected by empty vector pcDNA3. 1 and expression plasmid pcDNA3. 1-TRβ△, then exposure to 10 nmol/ L T3 . RH-35 cells apoptosis and proliferation were observed by flow cytometry and MTT colorimetric assay; Levels of catenin β-1(CTNNB1), senescence marker protein-30(SMP-30) and BCL2-antagonist/ killer ( BAK ) mRNA evaluation were detected by quantitative real-time RT-PCR (RT-qPCR). Results In the presence of T3 , overexpression of TRβ△ significantly inhibited the proliferation, increased the percentage of apoptotic, down-regulated CTNNB1and SMP-30 expression, up-regulated BAK expression in RH-35 cells( P < 0. 05). Conclusion TRβ△ could inhibit the proliferation of RH-35 cells and promote their apoptosis, which may be related to upregulation of BAK genes expression and downregulation of CTNNB1 and SMP-30 gene expression, and these effects could be regulated by T3 .