OBJECTIVE: To investigate the effect of Tongmai Hypoglycemic Capsule (THC) on myocardium injury in diabetic cardiomyopathy (DCM) rats. METHODS: A total of 24 Sprague Dawley rats were fed for 4 weeks with high-fat and high-sugar food and then injected with streptozotocin intraperitoneally for the establishment of the DCM model. In addition, 6 rats with normal diets were used as the control group. After modeling, 24 DCM rats were randomly divided into the model, L-THC, M-THC, and H-THC groups by computer generated random numbers, and 0, 0.16, 0.32, 0.64 g/kg of THC were adopted respectively by gavage, with 6 rats in each group. After 12 weeks of THC administration, echocardiography, histopathological staining, biochemical analysis, and Western blot were used to detect the changes in myocardial structure, oxidative stress (OS), biochemical indexes, protein expressions of myocardial fibrosis, and nuclear factor erythroid 2-related faactor 2 (Nrf2) element, respectively. RESULTS: Treatment with THC significantly decreased cardiac markers such as creatine kinase, lactate dehydrogenase, and creatine kinase-MB, etc., (P<0.01); enhanced cardiac function indicators including heart rate, ejection fraction, cardiac output, interventricular septal thickness at diastole, and others (P<0.05 or P<0.01); decreased levels of biochemical indicators such as fasting blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate transaminase, (P<0.05 or P<0.01); and decreased the levels of myocardial fibrosis markers α-smooth muscle actin (α-SMA), and collagen I (Col-1) protein (P<0.01), improved myocardial morphology and the status of myocardial interstitial fibrosis. THC significantly reduced malondialdehyde levels in model rats (P<0.01), increased levels of catalase, superoxide dismutase, and glutathione (P<0.01), and significantly increased the expression of Nrf2, NAD(P)H:quinone oxidoreductase 1, heme oxygenase-1, and superoxide dismutase 2 proteins in the left ventricle of rats (P<0.01). CONCLUSION THC activates the Nrf2 signaling pathway and plays a protective role in reducing OS injury and cardiac fibrosis in DCM rats.
Animals ; Diabetic Cardiomyopathies/physiopathology* ; Oxidative Stress/drug effects* ; Drugs, Chinese Herbal/therapeutic use* ; Rats, Sprague-Dawley ; Myocardium/metabolism* ; Fibrosis ; Male ; Capsules ; Hypoglycemic Agents/therapeutic use* ; NF-E2-Related Factor 2/metabolism* ; Rats ; Diabetes Mellitus, Experimental/drug therapy*

Objective : To investigate the selective activation of 5-hydroxytryptamine neurons in the dorsal raphe nucleus(DRN5-HT) of rats with insomnia induced by p-chlorophenylalanine(PCPA) using chemical genetics techniques, and to explore whether it has a regulatory effect on comorbidities of insomnia and anxiety. Methods : 32 male SD rats were randomly divided into control group, PCPA model group(PCPA group), chemical activation group(hM3Dq+CNO group), and chemical control group(hM3Dq+Saline group). The anxiety level of experimental rats was evaluated through open field experiments and elevated cross maze experiments.In vivoelectroencephalography(EEG) was used to record propofol induced sleep and cortical EEG changes, and immunofluorescence staining was used to observe changes in c-Fos positive protein expression in 5-HT neurons. Results : The behavioral results showed that compared with the chemical control group, the anxiety level of the chemical activation group was significantly lower(P<0.05), and sleep duration was significantly prolonged(P<0.05). The expression level of c-Fos positive protein in DRN5-HT neurons in the chemical activation group was higher(P<0.05). The EEG results showed that the percentage of δ-band power between the chemical activation group and the chemical control group was higher(P<0.05), the power percentage in the α-band was relatively low(P<0.05). Conclusion Chemical activation of 5-HT neurons in the DRN region can improve anxiety levels and increase sleep duration in PCPA induced insomnia rats.

Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.
Male ; Humans ; Prostate-Specific Antigen ; Treatment Outcome ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Immune Checkpoint Inhibitors/therapeutic use* ; Retrospective Studies

Humans ; Adult ; Lymphoma, Mantle-Cell/drug therapy* ; Rituximab/therapeutic use* ; Bendamustine Hydrochloride/therapeutic use* ; Lymphoma, B-Cell/pathology* ; Lymphoma, Non-Hodgkin/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use*

This study aims to establish a method for determination of paeonol(Pae), eugenol(Eug), and piperine(Pip) content in receptor liquid and research on the permeability and pharmacokinetics of Huoxue Zhitong gel patch and microemulsion gel. The Franz diffusion experiment was conducted to assess the percutaneous permeability, and the microdialysis method was employed to assess pharmacokinetics of Huoxue Zhitong gel patch and microemulsion gel. The content of Pae, Eug, and Pip in receptor liquid in vitro and in vivo was determined by HPLC and UPLC-MS. The Q_n and J_(ss) of Pae, Eug, and Pip in the gel patch were significantly higher than those in the microemulsion gel, indicating that the drug release was faster in the gel patch. The C_(max), AUC_(0-760), and MRT of Pae, Eug, and Pip in the gel patch were higher than those in the microemulsion gel, indicating that the gel patch can promote the penetration and prolong the skin residence of the drug. The results of this study provide reference for improving the dosage form of Huoxue Zhitong patch.
Administration, Cutaneous ; Chromatography, Liquid ; Emulsions ; Permeability ; Skin/metabolism* ; Skin Absorption ; Tandem Mass Spectrometry

Objective:To dynamically investigate the iodine nutritional status of residents in water source high iodine areas in Hebei Province, so as to provide basis for taking targeted prevention and control measures and accurate intervention strategies.Methods:According to the "National Monitoring Program for Water Source High Iodine Areas (2018 Edition)", water source high iodine monitoring was carried out in 5 cities and 35 counties (cities, districts, hereinafter referred to as counties) of Hebei Province. According to the survey results of drinking water iodine of residents of Hebei Province in 2017, the administrative villages with a median water iodine above 100 μg/L were sorted according to the water iodine value. The systematic sampling method was adopted. Five administrative villages were selected in each county, if there were less than 5 administrative villages, all of them were selected (if the median water iodine was > 300 μg/L, at least one village shall be selected). The iodine content in drinking water of residents among the monitoring sites, salt iodine, urinary iodine and thyroid volume of children aged 8 - 10, as well as salt iodine and urinary iodine of pregnant women were tested. Water iodine was detected by the "Method Suitable for the Detection of Water Iodine in Iodine Deficient and High Iodine Areas" recommended by the National Iodine Deficiency Reference Laboratory of the Chinese Center for Disease Control and Prevention. Salt iodine was detected by semi quantitative method. Urinary iodine was detected by "Arsenic Cerium Catalytic Spectrophotometry Method" (WS/T 107-2006). Children's thyroid volume was detected by B-ultrasound.Results:A total of 239 water samples were collected in 167 villages, 35 counties, the median water iodine was 163.95 μg/L, ranging from 5.53 - 930.82 μg/L. A total of 6 772 edible salt samples were monitored, including 3 495 non-iodine salt samples and the rate of non-iodine salt was 51.61% (3 495/6 772). A total of 6 101 urine samples of children were tested, the median urinary iodine was 328.00 μg/L. A total of 6 103 children aged 8 - 10 were carried out B-ultrasound detection of thyroid volume in 35 counties. The goiter rate of children was 5.01% (306/6 103), and the rate of nodules was 0.56% (34/6 103). A total of 713 urine samples of pregnant women were tested, and the median urinary iodine was 221.70 μg/L.Conclusions:The iodine nutrition of children in water source high iodine areas of Hebei Province is at an excess level, and the iodine nutrition of pregnant women is at an appropriate level. In addition to stopping the supply of iodized salt, we should further expand the coverage of water improvement and iodine reduction projects in high iodine areas, and strengthen the monitoring of iodine nutrition status of key populations.

Objective: To investigate the effect of berberine on programmed necrosis of hepatocytes induced by metabolic-associated fatty liver disease (MAFLD) in mice and its related molecular mechanism. Methods: Twenty male C57BL/6N mice were randomly divided into four groups (n=5 in each group): control group (S), fatty liver group (H), berberine group(B), nuclear factor erythroid 2-related factor 2 inhibitor group (Nrf2), and all-trans-retinoic acid (ATRA) group (A). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), triglycerides (TG), total cholesterol (TC), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) concentrations were detected at the end of week 12 to calculate fatty liver index (liver mass/body mass ratio). Liver tissue was stained with HE, Masson and Oil Red O, and SAF score was used to evaluate the degree of liver injury. The expression levels of hepatic programmed necrosis-related proteins, namely receptor-interacting protein kinase 3 (RIPK3), phosphorylated mixed series protease-like domain (p-MLKL) and Nrf2 were detected by Western blot method. One-way ANOVA was used for intragroup comparisons and LSD-t tests were used for intergroup comparisons. Results: Compared with S group, H group serum ALT, AST, LDH, TG, TC, TNF-α, IL-1β levels and fatty liver index were significantly increased. The liver tissue was filled with vacuolar-like changes and inflammatory cell infiltration. Numerous red lipid droplets were observed with oil red O staining. Collagen fiber hyperplasia was evident with Masson staining. SAF scores (6.60 ± 0.55 and 0.80 ± 0.45) were significantly increased. The expressions of RIPK3 and p-MLKL were up-regulated. Nrf2 level was relatively increased, and the differences were statistically significant (P < 0.05). Compared with H group, berberine intervention group liver biochemical indexes, lipid levels, pro-inflammatory mediator expression, fatty liver index, and SAF score were significantly reduced, and the expression of RIPK3 and p-MLKL were down-regulated, while Nrf2 levels were further increased, and the differences were statistically significant (P<0.05). Compared with B group, treatment with Nrf2 inhibitor had antagonized the protective effect of berberine on fatty liver. Serum ALT, AST, LDH, TG, TC and TNF-α, IL-1β levels, fatty liver index, and SAF scores were significantly increased and the expressions of RIPK3 and p-MLKL were relatively increased, and the differences were statistically significant (P < 0.05). Conclusion: Berberine can significantly improve the metabolic-associated fatty liver disease injury in mice, and its mechanism is related to activation of Nrf2 and inhibition of programmed necrosis of hepatocytes.
Animals ; Berberine/therapeutic use* ; Fatty Liver ; Male ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/metabolism* ; Necrosis

Objective: To understand the characteristics and associated factors of viral nucleic acid conversion in children infected with Omicron variant strain of SARS-CoV-2 in Shanghai. Methods: The clinical symptoms, laboratory results and other data of 177 children infected with SARS-CoV-2 who were hospitalized in Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University (designated hospital for SARS-CoV-2 infection in Shanghai) from April 25 to June 8, 2022 were retrospectively analyzed. According to the chest imaging findings, the children were divided into mild and common type groups. According to their age, the unvaccinated children were divided into<3 years old group and 3-<18 years old group. According to the vaccination status, the children aged 3-<18 year were divided into non-vaccination group, 1-dose vaccination group and 2-dose vaccination group. Comparison between groups was performed by independent sample t-test and analysis of variance, and multivariate linear regression analysis was used for multivariate analysis. Results: Among the 177 children infected with Omicron variant of SARS-CoV-2, 96 were males and 81 were females, aged 3 (1, 6) years. The time of viral nucleic acid negative conversion was (10.3±3.1) days. The 177 children were 138 cases of mild type and 39 cases of common type. Among the children aged 3-<18 years old, 55 cases were not vaccinated, 5 cases received 1-dose and 36 cases received 2-dose vaccination. Among the 36 children who received 2 doses of vaccination, the time of viral nucleic acid negative conversion was shorter in those vaccinated within 6 months than those over 6 months ((7.1±1.9) vs. (10.8±3.0) d, t=-3.23, P=0.004). Univariate analysis showed that the time of nucleic acid negative conversion of SARS-CoV-2 was associated with age, underlying diseases, gastrointestinal symptoms, white blood cell count, proportion of neutrophils, proportion of lymphocytes, and the number of doses of SARS-CoV-2 vaccine (t=3.87, 2.55, 2.04, 4.24, 3.51, 2.92, F=16.27, all P<0.05). Multiple linear regression analysis showed that older age (β=-0.33, 95% CI -0.485--0.182, P<0.001) and more doses of vaccination (β=-0.79, 95% CI -1.463--0.120, P=0.021) were associated with shortened nucleic acid negative conversion time in children, while lower lymphocyte proportion (β=-0.02, 95% CI -0.044--0.002, P=0.031) and underlying diseases (β=1.52, 95% CI 0.363-2.672, P=0.010) were associated with prolonged nucleic acid negative conversion time in children. Conclusion: The children infected with Omicron variant of SARS-CoV-2 with reduced lymphocyte proportion and underlying diseases may have longer time of viral nucleic acid negative conversion,while children with older age and more doses of vaccination may have shorter time of viral nucleic acid negative conversion.
Child ; Female ; Male ; Humans ; Child, Preschool ; Adolescent ; SARS-CoV-2 ; COVID-19 Vaccines ; Nucleic Acids ; COVID-19 ; Retrospective Studies ; China/epidemiology* ; Translocation, Genetic ; Hospitals, Pediatric

Objective:To master the iodine nutritional level of children aged 8-10 and pregnant women in non-iodine excess areas in Hebei Province, and provide scientific basis and targeted prevention and treatment strategies for prevention and treatment of iodine deficiency disorders.Methods:Iodine nutrition analysis was conducted in 162 counties (cities and districts, hereinafter referred to as counties) of Hebei Province in 2018. Each monitoring county was divided into 5 sampling areas according to east, west, south, north and middle locations. One township/street was randomly selected in each area, 1 primary school was selected in each township/street, and 40 non-boarding students aged 8-10 were selected from each primary school. In each monitoring county, 20 pregnant women were selected from each of the 5 townships/streets. Both children and pregnant women were collected samples for salt and urinary iodine (with a random urine sample) detection. The iodine content of salt was tested using the "General Test Method for Salt Industry-Determination of Iodine" (GB/T 13025.7-2012), and Sichuan salt and other fortified edible salt used the arbitration method. The urinary iodine content was tested using the "Arsenic-Cerium Catalytic Spectrophotometric Determination of Iodine in Urine" (WS/T 107-2006).Results:A total of 31 883 samples of edible salt were collected from children's homes in 162 counties, among which 28 539 were iodized salt, 26 456 were qualified iodized salt, the iodized salt coverage rate was 88.36% (after population standardization), and the qualified iodized salt consumption rate was 81.03% (after population standardization). A total of 31 883 urine samples were collected from children, with the median urinary iodine of 193.13 μg/L. There was one county with a median urinary iodine < 100 μg/L, and the median urinary iodine in 150 counties was 100-299 μg/L. A total of 15 572 salt samples of pregnant women were collected, among which the iodized salt samples were 14 260, the qualified iodized salt samples were 13 363, the iodized salt coverage rate was 90.10% (after population standardization), and the qualified iodized salt consumption rate was 83.54% (after population standardization). A total of 15 569 pregnant women were collected urine samples, the median urinary iodine was 164.86 μg/L, and the number of counties with a median urinary iodine < 150 μg/L was 67.Conclusions:Iodine nutrition of children and pregnant women is appropriate at the provincial level, but children and pregnant women in some counties are at risk of iodine deficiency. In the future, the prevention and treatment of iodine deficiency disorders should focus on the iodine nutrition monitoring of the special needs.

Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy. The precise control of the targeting and release of agents is critical in this methodology. This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy. To obtain a proof-of-concept, a co-delivery system was prepared