OBJECTIVE: To explore the role of the natural compound hesperidin in glycolysis, the key ratelimiting enzyme, in colorectal cancer (CRC) cell lines. METHODS: In vitro, HCT116 and SW620 were treated with different doses of hesperidin (0-500 µmol/L), cell counting kit-8 and colone formation assays were utilized to detected inhibition effect of hesperidin on CRC cell lines. Transwell and wound healing assays were performed to detect the ability of hesperidin (0, 25, 50 and 75 µmol/L) to migrate CRC cells. To confirm the apoptotic-inducing effect of hesperidin, apoptosis and cycle assays were employed. Western blot, glucose uptake, and lactate production determination measurements were applied to determine inhibitory effects of hesperidin (0, 25 and 50 µmol/L) on glycolysis. In vivo, according to the random number table method, nude mice with successful tumor loading were randomly divided into vehicle, low-dose hesperidin (20 mg/kg) and high-dose hesperidin (60 mg/kg) groups, with 6 mice in each group. The body weights and tumor volumes of mice were recorded during 4-week treatment. The expression of key glycolysis rate-limiting enzymes was determined using Western blot, and glucose uptake and lactate production were assessed. Finally, protein interactions were probed with DirectDIA Quantitative Proteomics, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. RESULTS: Hesperidin could inhibit CRC cell line growth (P<0.05 or P<0.01). Moreover, hesperidin presented an inhibitory effect on the migrating abilities of CRC cells. Hesperidin also promoted apoptosis and cell cycle alterations (P<0.05). The immunoblotting results manifested that hesperidin decreased the levels of hexokinase 2, glucose transporter protein 1 (GLUT1), GLUT3, L-lactate dehydrogenase A, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), PFKFB3, and pyruvate kinase isozymes M2 (P<0.01). It remarkably suppressed tumor xenograft growth in nude mice. GO and KEGG analyses showed that hesperidin treatment altered metabolic function. CONCLUSION Hesperidin inhibits glycolysis and is a potential therapeutic choice for CRC treatment.
Hesperidin/therapeutic use* ; Colorectal Neoplasms/metabolism* ; Glycolysis/drug effects* ; Animals ; Humans ; Apoptosis/drug effects* ; Mice, Nude ; Cell Movement/drug effects* ; Cell Line, Tumor ; Cell Proliferation/drug effects* ; Glucose/metabolism* ; Cell Cycle/drug effects* ; Mice, Inbred BALB C ; Mice ; HCT116 Cells ; Lactic Acid

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

[This corrects the article DOI: 10.1016/j.apsb.2024.03.030.].

Enamel demineralization, the formation of white spot lesions, is a common issue in clinical orthodontic treatment. The appearance of white spot lesions not only affects the texture and health of dental hard tissues but also impacts the health and aesthetics of teeth after orthodontic treatment. The prevention, diagnosis, and treatment of white spot lesions that occur throughout the orthodontic treatment process involve multiple dental specialties. This expert consensus will focus on providing guiding opinions on the management and prevention of white spot lesions during orthodontic treatment, advocating for proactive prevention, early detection, timely treatment, scientific follow-up, and multidisciplinary management of white spot lesions throughout the orthodontic process, thereby maintaining the dental health of patients during orthodontic treatment.
Humans ; Consensus ; Dental Caries/etiology* ; Dental Enamel/pathology* ; Tooth Demineralization/etiology* ; Tooth Remineralization

Objective To evaluate the bioequivalence and safety of ezetimibe tablets in healthy Chinese subjects.Methods The study was designed as a single-center,randomized,open-label,two-period,two-way crossover,single-dose trail.Subjects who met the enrollment criteria were randomized into fasting administration group and postprandial administration group and received a single oral dose of 10 mg of the subject presparation of ezetimibe tablets or the reference presparation per cycle.The blood concentrations of ezetimibe and ezetimibe-glucuronide conjugate were measured by high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS),and the bioequivalence of the 2 preparations was evaluated using the WinNonlin 7.0 software.Pharmacokinetic parameters were calculated to evaluate the bioequivalence of the 2 preparations.The occurrence of all adverse events was also recorded to evaluate the safety.Results The main pharmacokinetic parameters of total ezetimibe in the plasma of the test and the reference after a single fasted administration:Cmax were(118.79±35.30)and(180.79±51.78)nmol·mL-1;tmax were 1.40 and 1.04 h;t1/2 were(15.33±5.57)and(17.38±7.24)h;AUC0-t were(1 523.90±371.21)and(1 690.99±553.40)nmol·mL-1·h;AUC0-∞ were(1 608.70±441.28),(1 807.15±630.00)nmol·mL-1·h.The main pharmacokinetic parameters of total ezetimibe in plasma of test and reference after a single meal:Cmax were(269.18±82.94)and(273.93±87.78)nmol·mL-1;Tmax were 1.15 and 1.08 h;t1/2 were(22.53±16.33)and(16.02±5.84)h;AUC0_twere(1 463.37±366.03),(1 263.96±271.01)nmol·mL-1·h;AUC0-∞ were(1 639.01±466.53),(1 349.97±281.39)nmol·mL-1·h.The main pharmacokinetic parameters Cmax,AUC0-tand AUC0-∞ of the two preparations were analyzed by variance analysis after logarithmic transformation.In the fasting administration group,the 90％CI of the log-transformed geometric mean ratios were within the bioequivalent range for the remaining parameters in the fasting dosing group,except for the Cmax of ezetimibe and total ezetimibe,which were below the lower bioequivalent range.The Cmax of ezetimibe,ezetimibe-glucuronide,and total ezetimibe in the postprandial dosing group was within the equivalence range,and the 90％CI of the remaining parameters were not within the equivalence range for bioequivalence.Conclusion This test can not determine whether the test preparation and the reference preparation of ezetimibe tablets have bioequivalence,and further clinical trials are needed to verify it.

Objective:To establish biological exposure index (BEI) of occupational exposure to arsenic and its inorganic compounds through occupational epidemiology and the regression analysis of internal and external exposure of workers.Methods:In November 2021, 125 workers with occupational exposure to arsenic and its inorganic compounds and 49 office administrators in a non-ferrous metal smelter in Yunnan Province were selected as the exposure group and control group, respectively. Air samples from the workplace of the study subjects on weekdays were collected and arsenic concentrations were determined. Urine samples were collected in end-of-work weekend and high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) was used to detect the levels of trivalent inorganic arsenic (iAs 3+) , pentavalent inorganic arsenic (iAs 5+) , monomethyl arsenic (MMA) and dimethyl arsenic (DMA) in urine. The correlations between arsenic concentration in the workplace air and arsenic species in urine of workers were analyzed. Arsenic exposure concentration and the level of urinary arsenic (∑iAs+MMA+DMA) of workers was analyzed by linear regression and the BEI of arsenic and its inorganic compounds in the workplace was proposed based on the results of micronucleus test. Results:The median of time-weighted average concentration ( CTWA) of arsenic in the workplace air of the exposure group was 0.0116 mg/m 3, and the over-standard rate was 71.2% (89/125) . The concentrations of iAs 3+, iAs 5+, inorganic arsenic (iAs=∑iAs 3++iAs 5+) 、MMA、DMA and urinary arsenic in the exposure group were higher than those in the control group at the end of shift, and the differences were statistically significant ( P<0.05) . The concentration of arsenic in the workplace air had the strongest correlation with the concentration of urinary arsenic at the end of the shift ( rs=0.909, P<0.001) . The regression equation was lg ( y) =7.662+2.968lg ( x) ( r=0.821, P<0.05) . According to the occupational exposure limit (OEL) of arsenic in China, the concentration of urinary arsenic in the end-of-work weekend was calculated to be 53.2 μg/L. Combined with the results of micronucleus test, the BEI of occupational exposure to arsenic and its inorganic compounds in the workplace was proposed to be 50 μg/L. Conclusion:The urinary arsenic in the end-of-work weekend can be used as a biomarker of occupational exposure to arsenic, and its BEI is recommended to be 50 μg/L.

Objective:To explore the correlation between urinary arsenic and health effects through the determination and analysis of urinary arsenic levels in occupational arsenic exposed workers.Methods:In November 2021, 95 workers exposed to arsenic and its inorganic compounds and 31 administrative personnel from a non-ferrous metal smelter in Yunnan Province were selected as the contact group and control group, respectively. Urine forms of arsenic, blood tumor markers, liver function were detected, and micronucleus test was used to analyze the chromosome damage. The correlation between urine forms of arsenic and health effects were analyzed.Results:Compared with the control group, the concentrations of urinary trivalent inorganic arsenic (iAs 3+) , pentavalent inorganic arsenic (iAs 5+) , inorganic arsenic (iAs=∑iAs 3++iAs 5+) , monomethyl arsenic (MMA) , dimethyl arsenic (DMA) and urinary arsenic (∑iAs+MMA+DMA) at the end of class in contact group were higher ( P<0.05) . There was no statistically significant difference in blood tumor markers and liver function indicators between the two groups ( P>0.05) . Compared with the control group, the peripheral blood micronucleus rate and cell micronucleus rate in the contact group were significantly increased ( P<0.05) . The urinary arsenic, iAs 5+, inorganic arsenic and DMA were positively correlated with peripheral blood micronucleus rate in contact group ( rs=0.48, 0.34, 0.37, 0.23, P<0.05) , and the urinary arsenic, iAs 5+, DMA were positively correlated with peripheral blood micronucleus rate ( rs=0.48, 0.34, 0.26, P<0.05) . Conclusion:There is a significant correlation between different valence states of arsenic in the urine and abnormal health effects of occupational arsenic exposed workers. It is necessary to strengthen the detection of arsenic species in the urine of occupational arsenic exposed workers to better protect their health.

Objective:To establish biological exposure index (BEI) of occupational exposure to arsenic and its inorganic compounds through occupational epidemiology and the regression analysis of internal and external exposure of workers.Methods:In November 2021, 125 workers with occupational exposure to arsenic and its inorganic compounds and 49 office administrators in a non-ferrous metal smelter in Yunnan Province were selected as the exposure group and control group, respectively. Air samples from the workplace of the study subjects on weekdays were collected and arsenic concentrations were determined. Urine samples were collected in end-of-work weekend and high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) was used to detect the levels of trivalent inorganic arsenic (iAs 3+) , pentavalent inorganic arsenic (iAs 5+) , monomethyl arsenic (MMA) and dimethyl arsenic (DMA) in urine. The correlations between arsenic concentration in the workplace air and arsenic species in urine of workers were analyzed. Arsenic exposure concentration and the level of urinary arsenic (∑iAs+MMA+DMA) of workers was analyzed by linear regression and the BEI of arsenic and its inorganic compounds in the workplace was proposed based on the results of micronucleus test. Results:The median of time-weighted average concentration ( CTWA) of arsenic in the workplace air of the exposure group was 0.0116 mg/m 3, and the over-standard rate was 71.2% (89/125) . The concentrations of iAs 3+, iAs 5+, inorganic arsenic (iAs=∑iAs 3++iAs 5+) 、MMA、DMA and urinary arsenic in the exposure group were higher than those in the control group at the end of shift, and the differences were statistically significant ( P<0.05) . The concentration of arsenic in the workplace air had the strongest correlation with the concentration of urinary arsenic at the end of the shift ( rs=0.909, P<0.001) . The regression equation was lg ( y) =7.662+2.968lg ( x) ( r=0.821, P<0.05) . According to the occupational exposure limit (OEL) of arsenic in China, the concentration of urinary arsenic in the end-of-work weekend was calculated to be 53.2 μg/L. Combined with the results of micronucleus test, the BEI of occupational exposure to arsenic and its inorganic compounds in the workplace was proposed to be 50 μg/L. Conclusion:The urinary arsenic in the end-of-work weekend can be used as a biomarker of occupational exposure to arsenic, and its BEI is recommended to be 50 μg/L.

Objective:To explore the correlation between urinary arsenic and health effects through the determination and analysis of urinary arsenic levels in occupational arsenic exposed workers.Methods:In November 2021, 95 workers exposed to arsenic and its inorganic compounds and 31 administrative personnel from a non-ferrous metal smelter in Yunnan Province were selected as the contact group and control group, respectively. Urine forms of arsenic, blood tumor markers, liver function were detected, and micronucleus test was used to analyze the chromosome damage. The correlation between urine forms of arsenic and health effects were analyzed.Results:Compared with the control group, the concentrations of urinary trivalent inorganic arsenic (iAs 3+) , pentavalent inorganic arsenic (iAs 5+) , inorganic arsenic (iAs=∑iAs 3++iAs 5+) , monomethyl arsenic (MMA) , dimethyl arsenic (DMA) and urinary arsenic (∑iAs+MMA+DMA) at the end of class in contact group were higher ( P<0.05) . There was no statistically significant difference in blood tumor markers and liver function indicators between the two groups ( P>0.05) . Compared with the control group, the peripheral blood micronucleus rate and cell micronucleus rate in the contact group were significantly increased ( P<0.05) . The urinary arsenic, iAs 5+, inorganic arsenic and DMA were positively correlated with peripheral blood micronucleus rate in contact group ( rs=0.48, 0.34, 0.37, 0.23, P<0.05) , and the urinary arsenic, iAs 5+, DMA were positively correlated with peripheral blood micronucleus rate ( rs=0.48, 0.34, 0.26, P<0.05) . Conclusion:There is a significant correlation between different valence states of arsenic in the urine and abnormal health effects of occupational arsenic exposed workers. It is necessary to strengthen the detection of arsenic species in the urine of occupational arsenic exposed workers to better protect their health.