Cardiac fibrosis(CF) is a cardiac pathological process characterized by excessive deposition of extracellular matrix(ECM). When the heart is damaged by adverse stimuli, cardiac fibroblasts are activated and secrete a large amount of ECM, leading to changes in cardiac fibrosis, myocardial stiffness, and cardiac function declines and accelerating the development of heart failure. There is a close relationship between heart yin deficiency and cardiac fibrosis, which have similar pathogenic mechanisms. Heart Yin deficiency, characterized by insufficient Yin fluids, causes the heart to lose its nourishing function, which acts as the initiating factor for myocardial dystrophy. The deficiency of body fluids leads to stagnation of blood flow, resulting in blood stasis and water retention. Blood stasis and water retention accumulate in the heart, which aligns with the pathological manifestation of excessive deposition of ECM, as a tangible pathogenic factor. This is an inevitable stage of the disease process. The lingering of blood stasis combined with water retention eventually leads to the generation of heat and toxins, triggering inflammatory responses similar to heat toxins, which continuously stimulate the heart and cause the ultimate outcome of CF. Considering the syndrome of heart Yin deficiency, traditional Chinese medicine capable of nourishing Yin, activating blood, and promoting urination can reduce myocardial cell apoptosis, inhibit fibroblast activation, and lower the inflammation level, showing significant advantages in combating CF.
Humans ; Fibrosis/drug therapy* ; Animals ; Yin Deficiency/metabolism* ; Myocardium/metabolism* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use*

A high-performance liquid chromatography method using pre-column derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate was developed to determine the content of 15 amino acids in the medicinal snakes Bungarus Parvus, Agkistrodon, and Zaocys. The results showed that the total amino acid(TAA) content ranged from 277.13 to 515.05 mg·g~(-1), with the top four amino acids in all three species being glutamic acid(Glu), glycine(Gly), aspartic acid(Asp), and lysine(Lys). The essential amino acid(EAA) content ranged from 74.56 to 203.94 mg·g~(-1), with Agkistrodon exhibiting the highest content. The non-essential amino acid(NEAA), semi-essential amino acid(semi-EAA), and medicinal amino acid(MAA) content ranged from 189.06 to 318.23, 12.89 to 33.53, and 179.83 to 342.33 mg·g~(-1), respectively, with Zaocys having the highest content in these categories. Amino acid nutritional value was evaluated using the amino acid ratio(RAA), amino acid ratio coefficient(RCAA), and amino acid ratio coefficient score(SRCAA), and the results indicated that all three medicinal snakes possessed good nutritional value. The amino acid composition was similar across the species, though significant differences in content were observed. Based on these differences, an orthogonal partial least squares-discriminant analysis(OPLS-DA) model was established, which could clearly distinguish between the three medicinal snake species. The key differences in amino acid content included Gly, tyrosine(Tyr), Glu, and serine(Ser), which may be related to the observed clinical application differences among the species. Further research into the mechanisms of these differential amino acids is expected to provide more insights into the clinical application disparities of these three medicinal snake species.
Amino Acids/chemistry* ; Animals ; Nutritive Value ; Chromatography, High Pressure Liquid ; Snakes/classification* ; Bungarus

Objective Vascular dementia(VD)is a common cognitive dysfunction associated with cerebrovascular disease.This study is aimed at investigating the therapeutic effect of anisodine hydromide(AH)on VD and the potential antioxidative stress mechanisms involved.Methods A VD model was established in Sprague-Dawley(SD)rats through permanent bilateral common carotid artery occlusion.The rats were divided into a sham group,a VD model group,and AH treatment groups receiving AH at low,medium,or high doses(n=4).The neurological function of the rats in each group was evaluated using the Bederson scale,and limb coordination ability was assessed using the pole climbing test.Superoxide dismutase(SOD)and malondialdehyde(MDA)levels in the serum and brain were measured by enzyme-linked immunosorbent assay(ELISA)to assess the level of oxidative stress.In addition,apoptosis was assessed by TUNEL assay,and reactive oxygen species(ROS)levels in neuronal cells were determined using dichloro-dihydro-fluorescein diacetate(DCFH-DA)probe.The potential mechanism of action of AH on M receptors was investigated using M1-M5 inhibitors.Results Compared with the sham group,the nerve function and limb coordination of rats in the VD model group were significantly impaired(P＜0.01),and the SOD levels were significantly decreased in the serum([100.70±18.95]U/mL vs.[44.22±7.11]U/mL,P＜0.001)and the brain([131.77±8.34]U/mg vs.[84.39±4.10]U/mg,P＜0.01),MDA levels were significantly increased in the serum([12.03±1.01]nmol/mL vs.[17.74±1.00]nmol/mL,P＜0.001)and the brain([4.41±0.30]nmol/mg vs.[6.17±0.70]nmol/mg,P＜0.05).AH treatment significantly improved the neurological function and limb coordination ability of VD rats.In comparison with the VD group,the high-dose AH treatment group,in particular,exhibited the most significant increase in SOD levels in the serum([44.22±7.11]U/mL vs.[98.67±0.86]U/mL,P＜0.001)and the brain([84.39±4.10]U/mg vs.[162.83±17.36]U/mg,P＜0.001),and the most significant decrease in MDA levels in the serum([17.74±1.00]nmol/mL vs.[6.68±0.06]nmol/mL,P＜0.001)and the brain([6.17±0.70]nmol/mg vs.[3.96±0.77]nmol/mg,P＜0.01).AH also reduced the number of TUNEL positive cells(P＜0.01)in a dose-dependent manner.The percentage of apoptotic cells was(36.10±9.07)％,(9.60±5.63)％,and(3.43±0.92)％,respectively,for AH treatment at low,medium,and high concentrations,indicating that AH had an inhibitory effect on apoptosis.According to findings from the in vitro experiments,AH treatment reduced the MDA content(P＜0.01),increased the SOD activity(P＜0.01),and decreased the ROS levels of HT22 and NSC-34 cells in a dose-dependent manner.M2 receptor inhibitors could reduce the ROS level in oxidative stress injury,suggesting that AH,as an M receptor antagonist,might exert its effect by inhibiting the M2 receptor.Conclusion AH modulates SOD and MDA levels and reduces oxidative stress injury,thereby improving neurological function and limb coordination and showing potential therapeutic effects in VD.The neuroprotective effects of AH may be related to its antioxidative stress and antiapoptotic mechanisms,and the M2 receptor may be a potential target of its actions.These findings provide an important theoretical basis for the development of new therapeutic strategies for VD.

Objective To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/-mice.Methods The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/-mice.Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers.Results Proteomic analysis showed that there were 43 significantly up-regulated and 58 sig-nificantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group.Among them,GBP2,TAOK3,TFR1 and UCP1 were biomarkers with great diagnostic potential.KEGG pathway enrichment analysis indicated that fer-roptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model.The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model.Conclusion Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferrop-tosis.Four potential biomarkers are selected for myocardial injury diagnosis,providing a new direction for sudden cardiac death(SCD)caused by hyperlipidemia combined with the restraint stress.

Objective: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m 2 ) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this phase I trial, a time-to-event Bayesian optimal interval design was used.Docetaxel was given at a starting dose of 60 mg/m2 and was increased in 5 mg/m2 increments until the MTD was determined or the maximum dose level of 75 mg/m2 was reached. The doselimiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. Results: From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m2 , no DLT was reported. DLTs were observed in one patient who received 70 mg/m2 docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m2 docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m2 in combination with cisplatin 75 mg/m2 had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. Conclusion Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m2), can be used safely at intraperitoneal doses of 75 mg/m2 in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery.

Objective: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m 2 ) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this phase I trial, a time-to-event Bayesian optimal interval design was used.Docetaxel was given at a starting dose of 60 mg/m2 and was increased in 5 mg/m2 increments until the MTD was determined or the maximum dose level of 75 mg/m2 was reached. The doselimiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. Results: From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m2 , no DLT was reported. DLTs were observed in one patient who received 70 mg/m2 docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m2 docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m2 in combination with cisplatin 75 mg/m2 had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. Conclusion Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m2), can be used safely at intraperitoneal doses of 75 mg/m2 in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery.

Objective: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m 2 ) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this phase I trial, a time-to-event Bayesian optimal interval design was used.Docetaxel was given at a starting dose of 60 mg/m2 and was increased in 5 mg/m2 increments until the MTD was determined or the maximum dose level of 75 mg/m2 was reached. The doselimiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. Results: From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m2 , no DLT was reported. DLTs were observed in one patient who received 70 mg/m2 docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m2 docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m2 in combination with cisplatin 75 mg/m2 had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. Conclusion Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m2), can be used safely at intraperitoneal doses of 75 mg/m2 in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery.

Objective To construct microscale rectangular hydrogel grooves and to investigate the morphology and alignment of human umbilical vein endothelial cells(HUVECs)under spatial constraints.Vascular endothelial cell morphology and alignment are important factors in vascular development and the maintenance of homeostasis.Methods A 4-arm polyethylene glycol-acrylate(PEG-acrylate)hydrogel was used to fabricate rectangular microgrooves of the widths of 60 μm,100 μm,and 140 μm.The sizes and the fibronectin(FN)adhesion of these hydrogel microgrooves were measured.HUVECs were seeded onto the FN-coated microgrooves,while the flat surface without micropatterns was used as the control.After 48 hours of incubation,the morphology and orientation of the cells were examined.The cytoskeleton was labelled with phalloidine and the orientation of the cytoskeleton in the hydrogel microgrooves was observed by laser confocal microscopy.Results The hydrogel microgrooves constructed exhibited uniform and well-defined morphology,a complete structure,and clear edges,with the width deviation being less than 3.5%.The depth differences between the hydrogel microgrooves of different widths were small and the FN adhesion is uniform,providing a micro-patterned growth interface for cells.In the control group,the cells were arranged haphazardly in random orientations and the cell orientation angle was(46.9±1.8)°.In contrast,the cell orientation angle in the hydrogel microgrooves was significantly reduced(P<0.001).However,the cell orientation angles increased with the increase in hydrogel microgroove width.For the 60 μm,100 μm,and 140 μm hydrogel microgrooves,the cell orientation angles were(16.4±2.8)°,(24.5±3.2)°,and(30.3±3.5)°,respectively.Compared to that of the control group(35.7%),the number of cells with orientation angles<30° increased significantly in the hydrogel microgrooves of different widths(P<0.001).However,as the width of the hydrogel microgrooves increased,the number of cells with orientation angles<30° gradually decreased(79.9%,62.3%,54.7%,respectively),while the number of cells with orientation angles between 60°-90° increased(P<0.001).The cell bodies in the microgrooves were smaller and more rounded in shape.The cells were aligned along the direction of the microgrooves and corresponding changes occurred in the arrangement of the cell cytoskeleton.In the control group,cytoskeletal filaments were aligned in random directions,presenting an orientation angle of(45.5±3.7)°.Cytoskeletal filaments were distributed evenly within various orientation angles.However,in the 60 μm,100 μm,and 140 μm hydrogel microgrooves,the orientation angles of the cytoskeletal filaments were significantly decreased,measuring(14.4±3.1)°,(24.7±3.5)°,and(31.9±3.3)°,respectively.The number of cytoskeletal filaments with orientation angles<30° significantly increased in hydrogel microgrooves of different widths(P<0.001).However,as the width of the hydrogel microgrooves increased,the number of cytoskeletal filaments with orientation angles<30° gradually decreased,while the number of cytoskeletal filaments with orientation angles between 60°-90° gradually increased(P<0.001).Conclusion Hydrogel microgrooves can regulate the morphology and orientation of HUVECs and mimic to a certain extent the in vivo microenvironment of vascular endothelial cells,providing an experimental model that bears better resemblance to human physiology for the study of the unique physiological functions of vascular endothelial cells.Nonetheless,the molecular mechanism of spatial constraints on the morphology and the assembly of vascular endothelial cell needs to be further investigated.

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

Organoids are three-dimensional structures formed by self-organizing growth of cells in vitro, which own many structures and functions similar with those of corresponding in vivo organs. Although the organoid culture technologies are rapidly developed and the original cells are abundant, the organoid cultured by current technologies are rather different with the real organs, which limits their application. The major challenges of organoid cultures are the immature tissue structure and restricted growth, both of which are caused by poor functional vasculature. Therefore, how to develop the vascularization of organoids has become an urgent problem. We presently reviewed the progresses on the original cells of organoids and the current methods to develop organoids vascularization, which provide clues to solve the above-mentioned problems.
Humans ; Organoids ; Neovascularization, Pathologic ; Technology