Human lactate dehydrogenase A (LDHA) is an NADH-dependent oxidoreductase that catalyzes the conversion of pyruvate to lactate, playing a crucial role in the aerobic glycolysis of tumor cells. Additionally, LDHA is responsible for catalyzing the conversion of glyoxylate to oxalate in the liver, excessive accumulation of which leads to hyperoxaluria. Representative LDHA inhibitors reported to date include GNE-140, NCATS-SM1441, and CHK-336. In this study, NCATS-SM1441 was used as the lead compound. Based on the analysis of its cocrystal binding mode with LDH, the key carboxythiazole and aromatic pharmacophores were retained, while the original substituted pyrazole linker was replaced with urea linker moieties to simplify the structure. As a result, nine urea derivatives were designed and synthesized. Subsequently, on the basis of structure-activity relationship and molecular docking studies, nine target triazole compounds were further designed. Ultimately, triazole compound 25 was found to exhibit the most potent LDHA inhibitory activity (IC50 = 1.59 μmol/L) in vitro. Molecular dynamics simulations were employed to analyze the interactions between compound 25 and key amino acid residues. Finally, the prediction of physicochemical properties and the evaluation of cell viability were performed for compound 25. The study provides an experimental basis for future development of novel LDHA inhibitors with improved drugability.

Objective To investigate the temporal changes in pathological damage and macrophage polarization in liver and spleen tissues of mice infected with Angiostrongylus cantonensis, and to preliminarily unravel the peripheral immune responses during the early stage of A. cantonensis infection. Methods Forty female BALB/c mice at ages of 6 to 8 weeks were randomly divided into four groups, including the control group and 7-, 14-, and 21-day infection groups, with 10 mice in each group. Each mouse in the infection groups was inoculated with 30 third-stage (L3) larvae of A. cantonensis by oral gavage, and five mice were randomly selected from each infection group on days 7, 14, and 21 post-infection, while mice in the control group were given the same volume of physiological saline and five mice were randomly selected from the control group on the day of oral gavage. Mouse liver and spleen tissues were sampled. The histopathological changes of mouse liver and spleen tissues were observed using hematoxylin and eosin (HE) staining, and the percentage of positive staining area and the co-localization positive rates of the macrophage surface antigens F4/80, CD86, and CD206 were quantified in mouse liver and spleen tissues using immunohistochemical and immunofluorescence staining. In addition, five mice were collected from each infection group on days 7, 14, and 21 post-infection, and five mice were collected from the control group on the day of oral gavage. Mouse liver and spleen tissues were sampled for detection of macrophage markers CD86 and CD206 and macrophage phenotyping using flow cytometry, and the expression of M1 macrophage markers, including inducible nitric oxide synthase (Nos2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and M2 markers, including arginase 1 (Arg1), mannose receptor C-type 1 (Mrc1) and chitinase-like protein 3 (Chil3) was quantified in mouse liver and spleen tissues using real-time quantitative PCR (RT-qPCR) assay. Results Proliferative lesions of the hepatocyte were observed in mouse liver tissues and the follicular structures of the mouse spleen white pulp were disrupted 21 days post-infection with A. cantonensis. Immunohistochemical staining showed that there were significant differences in the percentages of F4/80, CD86 and CD206 positive staining areas in the liver and spleen tissues among the four groups of mice (F = 242.40, 197.14, 183.19, 157.65, 242.35 and 146.24; all P values < 0.001), and the percentages of positive staining in the liver and spleen tissues of mice in the 14-day infection group [(4.45 ± 0.51)%, (3.74 ± 0.67)%, (8.32 ± 0.72)%, (16.56 ± 1.14)%, (11.62 ± 0.52)%, and (8.29 ± 0.72)%, respectively] and the 21-day infection group [(3.70 ± 0.11)%, (3.22 ± 0.43)%, (11.53 ± 1.03)%, (12.59 ± 1.05)%, (9.02 ± 0.83)%, and (11.67 ± 1.10)%, respectively] were higher than in the control group [(0.35 ± 0.16)%, (0.40 ± 0.02)%, (0.93 ± 0.05)%, (2.78 ± 0.26)%, (2.33 ± 0.20)%, and (1.85 ± 0.20)%, respectively] (all P values < 0.05). Immunofluorescence staining showed significant differences in the positive rates of F4/80 co-localization with CD86 and CD206 in mouse liver and spleen tissues among the four groups (F = 24.42, 25.28, 54.51 and 130.55; all P values < 0.001). Flow cytometry detected significant differences in the proportions of CD86⁺ and CD206⁺ macrophages in mouse liver and spleen tissues among the four groups (F = 67.98, 18.41, 29.77, 172.80; all P values < 0.001), and the proportions of CD206⁺ macrophages in the liver and spleen of the 21-day infection group were significantly higher than those in the control group [(9.25 ± 2.55)% vs (3.83 ± 0.72)%, and (4.22 ± 0.56)% vs (0.47 ± 0.18)%, respectively] (both P values < 0.05). In addition, RT-qPCR assay quantified significant differences in the relative mRNA expression of M1 macrophage markers (IL-1β, TNF-α and Nos2) and M2 macrophage markers (Arg1, Chil3 and Mrc1) in mouse liver and spleen tissues among the four groups (F = 41.30, 31.82, 199.33, 19.96, 62.01, 119.76, 23.67, 95.90, 72.27, 82.59, 123.41 and 29.75; all P values < 0.05). Conclusions A. cantonensis infection may cause progressive pathological damage in mouse liver and spleen tissues, accompanied by dynamic temporal changes in macrophage polarization. M1 macrophage polarization predominates at the early stage of A. cantonensis infection and shifts towards M2 polarization at the later stages, suggesting that M2 polarization may participate in immune regulation at late stages of A. cantonensis infection by suppressing excessive inflammatory responses and promoting tissue repair.

Objective To investigate the changes in eosinophil counts and the activation of microglial cells in the brain tissues of mice at different stages of Angiostrongylus cantonensis infection, and to examine the role of microglia in regulating the progression of angiostrongyliasis and unravel the possible molecular mechanisms. Methods Fifty BALB/c mice were randomly divided into the control group and the 7-d, 14-d, 21-day and 25-d infection groups, of 10 mice in each group. All mice in infection groups were infected with 30 stage III A. cantonensis larvae by gavage, and animals in the control group was given an equal amount of physiological saline. Five mice were collected from each of infection groups on days 7, 14, 21 d and 25 d post-infection, and 5 mice were collected from the control group on the day of oral gavage. The general and focal functional impairment was scored using the Clark scoring method to assess the degree of mouse neurological impairment. Five mice from each of infection groups were sacrificed on days 7, 14, 21 d and 25 d post-infection, and 5 mice from the control group were sacrificed on the day of oral gavage. Mouse brain tissues were sampled, and the pathological changes of brain tissues were dynamically observed using hematoxylin and eosin (HE) staining. Immunofluorescence staining with eosinophilic cationic protein (ECP) and ionized calcium binding adaptor molecule 1 (Iba1) was used to assess the degree of eosinophil infiltration and the counts of microglial cells in mouse brain tissues in each group, and the morphological parameters of microglial cells (skeleton analysis and fractal analysis) were quantified by using Image J software to determine the morphological changes of microglial cells. In addition, the expression of M1 microglia markers Fcγ receptor III (Fcgr3), Fcγ receptor IIb (Fcgr2b) and CD86 antigen (Cd86), M2 microglia markers Arginase 1 (Arg1), macrophage mannose receptor C-type 1 (Mrc1), chitinase-like 3 (Chil3), and phagocytosis genes myeloid cell triggering receptor expressed on myeloid cells 2 (Trem2), CD68 antigen (Cd68), and apolipoprotein E (Apoe) was quantified using real-time quantitative reverse transcription PCR (RT-qPCR) assay in the mouse cerebral cortex of mice post-infection. Results A large number of A. cantonensis larvae were seen on the mouse meninges surface post-infection, and many neuronal nuclei were crumpled and deeply stained, with a large number of bleeding points in the meninges. The median Clark scores of mouse general functional impairment were 0 (interquartile range, 0), 0 (interquartile range, 0.5), 6 (interquartile range, 1.0), 14 (interquartile range, 8.5) points and 20 (interquartile range, 9.0) points in the control group and the 7-d, 14-d, 21-d and 25-d groups, respectively (H = 22.45, P < 0.01), and the median Clark scores of mouse focal functional impairment were 0 (interquartile range, 0), 2 (interquartile range, 2.5), 7 (interquartile range, 3.0), 18 (interquartile range, 5.0) points and 25 (interquartile range, 6.5) points in the control group and the 7-d, 14-d, 21-d and 25-d groups, respectively (H = 22.72, P < 0.01). The mean scores of mice general and focal functional impairment were all higher in the infection groups than in the control group (all P values < 0.05). Immunofluorescence staining showed a significant difference in the eosinophil counts in mouse brain tissues among the five groups (F = 40.05, P < 0.000 1), and the eosinophil counts were significantly higher in mouse brain tissues in the 14-d (3.08 ± 0.78) and 21-d infection groups (5.97 ± 1.37) than in the control group (1.00 ± 0.28) (both P values < 0.05). Semi-quantitative analysis of microglia immunofluorescence showed a significant difference in the counts of microglial cells among the five groups (F = 17.66, P < 0.000 1), and higher Iba1 levels were detected in mouse brain tissues in 14-d (5.75 ± 1.28), 21-d (6.23 ± 1.89) and 25-d infection groups (3.70 ± 1.30) than in the control group (1.00 ± 0.30) (all P values < 0.05). Skeleton and fractal analyses showed that the branch length [(162.04 ± 34.10) μm vs. (395.37 ± 64.11) μm; t = 5.566, P < 0.05] and fractal dimension of microglial cells (1.30 ± 0.01 vs. 1.41 ± 0.03; t = 5.266, P < 0.05) were reduced in mouse brain tissues in the 21-d infection group relative to the control group. In addition, there were significant differences among the 5 groups in terms of M1 and M2 microglia markers Fcgr3 (F = 48.34, P < 0.05), Fcgr2b (F = 55.46, P < 0.05), Cd86 (F = 24.44, P < 0.05), Arg1 (F = 31.18, P < 0.05), Mrc1 (F = 15.42, P < 0.05) and Chil3 (F = 24.41, P < 0.05), as well as phagocytosis markers Trem2 (F = 21.19, P < 0.05), Cd68 (F = 43.95, P < 0.05) and Apoe (F = 7.12, P < 0.05) in mice brain tissues. Conclusions A. cantonensis infections may induce severe pathological injuries in mouse brain tissues that are characterized by massive eosinophil infiltration and persistent activation of microglia cells, thereby resulting in progressive deterioration of neurological functions.

Objective:To analyze the correlation between metabolic syndrome indexes and thyroid nodules in individuals receiving health examinations.Methods:It′s a retrospective cohort study. A total of 2 678 individuals who received health examinations in the Health Management Center of the First Hospital of Shanxi Medical University for four consecutive years and met the admission criteria were selected as the research objects. According to the metabolic syndrome index data of health examination, according to the different duration of metabolic syndrome during the observation period, the group-based trajectory model, Bayesian information criterion and average posterior grouping probability were used to determine the best trajectory groups, and the objects were divided into three different metabolic syndrome index trajectory groups: normal, abnormal and recovery group. During the physical examination in 2022 and 2023, the detection of thyroid nodules in each group was followed up, and the difference of detection rate of thyroid nodules in different metabolic syndrome trajectory groups was compared by Log-rank test, and the correlation between different metabolic syndrome index change trajectories and thyroid nodules was analyzed by logistic regression model.Results:The cumulative detection rate of thyroid nodules in normal group, abnormal group and recovery group was 18.8% (77/410), 27.5% (327/1 190) and 24.7% (266/1 078), respectively ( χ2=19.482, P<0.001). In model 4, after adjusting for age, gender, smoking, drinking, staying up late, insomnia, physical activity, family history and other confounding factors, the risk of thyroid nodules in abnormal group and recovery group was still 2.011 times (95% CI: 1.457-2.776) and 2.006 times (95% CI: 1.389-2.897) of that in normal group. Conclusion:There is a positive correlation between metabolic syndrome index and thyroid nodules in individuals receiving health examinations, and metabolic syndrome index can be used as a predictive index of thyroid nodules.

Objective:To describe the trend of changes in the disease burden of age-related hearing loss in China and globally from 1990 to 2021,to forecast the prevalence and years lived with disability(YLD)rates of age-related hearing loss from 2022 to 2036,and to provide a reference for the prevention and control of the disease burden associated with age-related hearing loss.Methods:Using the Global Burden of Disease 2021(GBD2021)data,this study selected age-standardized prevalence rate(ASPR)and YLD as indicators.The disease burden and long-term trends of age-related hearing loss in China and globally from 1990 to 2021 were described by different socio-demographic index(SDI)and gender.Joinpoint regression was used to calculate the average annual percent change(AAPC)to assess the trend changes in the disease burden.Decomposition analysis was applied to explore the relative im-pacts of aging,population growth,and epidemiological changes on the variation in disease burden.An autoregressive integrated moving average(ARIMA)model was used to forecast the age-standardized pre-valence rate and YLD rates from 2022 to 2036.Results:The prevalence of age-related hearing loss in China in 2021 was 82 162.49(73 288.08-89 187.21)per 100 000,higher than the global SDI level of 66 238.16(59 982.54-72 669.82)per 100 000,the high SDI region's level of 57 650.42(52 059.12-63 889.02)per 100 000,the upper-middle SDI region's level of 69 115.59(62 494.18-75 340.64)per 100 000,the middle SDI region's level of 72 365.56(65 181.43-78 912.01)per 100 000,the lower-middle SDI region's level of 64 439.66(58 368.22-71 468.27)per 100 000,and the low SDI region's level of 61 725.25(55 749.18-68 477.67)per 100 000.The age-related hearing loss YLD rate in China was 2 762.98[95％uncertainty interval(UI):1 855.28-3 880.68]per100000,higher than the global SDI level of 2 236.75(95％UI:1 511.56-3 155.88)per 100 000,the high SDI region's level of 1 805.79(95％UI:1 212.69-2 577.17)per 100 000,the upper-middle SDI re-gion's level of 2 316.58(95％UI:1 557.53-3 274.87)per 100 000,the middle SDI region's level of 2 480.99(95％UI:1 678.17-3 489.24)per 100 000,the lower-middle SDI region's level of 2 313.28(95％UI:1 578.35-3 271.50)per 100 000,and the low SDI region's level of 2 383.55(95％UI:1 623.66-3 365.68)per 100 000.From 1990 to 2021,both the prevalence and YLD rate of age-related hearing loss in China showed an increasing trend,rising by an average of 0.18％(95％CI:0.16％-0.19％)and 0.29％(95％CI:0.27％-0.30％)per year,respectively.The rates of in-crease in prevalence were the same for both men and women,with men showing a 0.18％increase(95％CI:0.17％-0.19％,P＜0.001)and women showing a 0.18％increase(95％CI:0.16％-0.19％,P＜0.001).However,the YLD rate increase was faster in men than in women,with men experiencing a 0.32％increase(95％CI:0.27％-0.37％,P＜0.001)and women experiencing a 0.27％increase(95％CI:0.26％-0.28％,P＜0.001).Decomposition analysis showed that population growth was the main factor driving the increase in prevalence and YLD rate globally and across different SDI regions.However,aging was the primary factor contributing to the increase in prevalence and YLD rate in China.ARIMA model predictions suggested that the prevalence and YLD rate of age-related hearing loss would continue to rise from 2022 to 2036,with the predicted prevalence and YLD rate in 2036 reaching 89 723.99 per 100 000 and 2 872.47 per 100 000,respectively.Conclusion:The prevalence and disease burden of age-related hearing loss in individuals aged 60 and above in China rank first globally.From 1990 to 2021,both the prevalence and YLD rate of age-related hearing loss have shown a continuous upward trend,consistently surpassing the levels observed in various SDI regions worldwide.The prevalence and disease burden of age-related hearing loss are particularly significant among elderly men.Moreover,projections indicate that the disease burden of age-related hearing loss will continue to rise over the next 15 years.Therefore,it is urgent to pay close attention to age-related hearing loss in this specific population,and early intervention measures are crucial to reduce the disease burden associated with age-related hearing loss.

Ischemic obstruction is a dangerous condition with a high mortality rate.Professor Jin Shi proposed that vascular intesti-nal obstruction disease is based on the intestinal tract while the structure of mesenteric vascular structure in modern medicine is highly similar to the morphological description of"intestinal collateral"in traditional Chinese medicine.The"hypercoagulable state"of blood is highly consistent with the core of the pathogenesis of"intestinal stasis"in traditional Chinese medicine.Blood stasis is a key patho-logical product and pathogenic factor of vascular intestinal obstruction and it is necessary to pay attention to the combination of disease identification,clarification of urgency,and phased treatment.This study provides a theoretical basis and practical example for the treatment of vascular intestinal obstruction in traditional Chinese medicine.

Ischemic obstruction is a dangerous condition with a high mortality rate.Professor Jin Shi proposed that vascular intesti-nal obstruction disease is based on the intestinal tract while the structure of mesenteric vascular structure in modern medicine is highly similar to the morphological description of"intestinal collateral"in traditional Chinese medicine.The"hypercoagulable state"of blood is highly consistent with the core of the pathogenesis of"intestinal stasis"in traditional Chinese medicine.Blood stasis is a key patho-logical product and pathogenic factor of vascular intestinal obstruction and it is necessary to pay attention to the combination of disease identification,clarification of urgency,and phased treatment.This study provides a theoretical basis and practical example for the treatment of vascular intestinal obstruction in traditional Chinese medicine.

Objective:To describe the trend of changes in the disease burden of age-related hearing loss in China and globally from 1990 to 2021,to forecast the prevalence and years lived with disability(YLD)rates of age-related hearing loss from 2022 to 2036,and to provide a reference for the prevention and control of the disease burden associated with age-related hearing loss.Methods:Using the Global Burden of Disease 2021(GBD2021)data,this study selected age-standardized prevalence rate(ASPR)and YLD as indicators.The disease burden and long-term trends of age-related hearing loss in China and globally from 1990 to 2021 were described by different socio-demographic index(SDI)and gender.Joinpoint regression was used to calculate the average annual percent change(AAPC)to assess the trend changes in the disease burden.Decomposition analysis was applied to explore the relative im-pacts of aging,population growth,and epidemiological changes on the variation in disease burden.An autoregressive integrated moving average(ARIMA)model was used to forecast the age-standardized pre-valence rate and YLD rates from 2022 to 2036.Results:The prevalence of age-related hearing loss in China in 2021 was 82 162.49(73 288.08-89 187.21)per 100 000,higher than the global SDI level of 66 238.16(59 982.54-72 669.82)per 100 000,the high SDI region's level of 57 650.42(52 059.12-63 889.02)per 100 000,the upper-middle SDI region's level of 69 115.59(62 494.18-75 340.64)per 100 000,the middle SDI region's level of 72 365.56(65 181.43-78 912.01)per 100 000,the lower-middle SDI region's level of 64 439.66(58 368.22-71 468.27)per 100 000,and the low SDI region's level of 61 725.25(55 749.18-68 477.67)per 100 000.The age-related hearing loss YLD rate in China was 2 762.98[95％uncertainty interval(UI):1 855.28-3 880.68]per100000,higher than the global SDI level of 2 236.75(95％UI:1 511.56-3 155.88)per 100 000,the high SDI region's level of 1 805.79(95％UI:1 212.69-2 577.17)per 100 000,the upper-middle SDI re-gion's level of 2 316.58(95％UI:1 557.53-3 274.87)per 100 000,the middle SDI region's level of 2 480.99(95％UI:1 678.17-3 489.24)per 100 000,the lower-middle SDI region's level of 2 313.28(95％UI:1 578.35-3 271.50)per 100 000,and the low SDI region's level of 2 383.55(95％UI:1 623.66-3 365.68)per 100 000.From 1990 to 2021,both the prevalence and YLD rate of age-related hearing loss in China showed an increasing trend,rising by an average of 0.18％(95％CI:0.16％-0.19％)and 0.29％(95％CI:0.27％-0.30％)per year,respectively.The rates of in-crease in prevalence were the same for both men and women,with men showing a 0.18％increase(95％CI:0.17％-0.19％,P＜0.001)and women showing a 0.18％increase(95％CI:0.16％-0.19％,P＜0.001).However,the YLD rate increase was faster in men than in women,with men experiencing a 0.32％increase(95％CI:0.27％-0.37％,P＜0.001)and women experiencing a 0.27％increase(95％CI:0.26％-0.28％,P＜0.001).Decomposition analysis showed that population growth was the main factor driving the increase in prevalence and YLD rate globally and across different SDI regions.However,aging was the primary factor contributing to the increase in prevalence and YLD rate in China.ARIMA model predictions suggested that the prevalence and YLD rate of age-related hearing loss would continue to rise from 2022 to 2036,with the predicted prevalence and YLD rate in 2036 reaching 89 723.99 per 100 000 and 2 872.47 per 100 000,respectively.Conclusion:The prevalence and disease burden of age-related hearing loss in individuals aged 60 and above in China rank first globally.From 1990 to 2021,both the prevalence and YLD rate of age-related hearing loss have shown a continuous upward trend,consistently surpassing the levels observed in various SDI regions worldwide.The prevalence and disease burden of age-related hearing loss are particularly significant among elderly men.Moreover,projections indicate that the disease burden of age-related hearing loss will continue to rise over the next 15 years.Therefore,it is urgent to pay close attention to age-related hearing loss in this specific population,and early intervention measures are crucial to reduce the disease burden associated with age-related hearing loss.

Objective:To analyze the correlation between metabolic syndrome indexes and thyroid nodules in individuals receiving health examinations.Methods:It′s a retrospective cohort study. A total of 2 678 individuals who received health examinations in the Health Management Center of the First Hospital of Shanxi Medical University for four consecutive years and met the admission criteria were selected as the research objects. According to the metabolic syndrome index data of health examination, according to the different duration of metabolic syndrome during the observation period, the group-based trajectory model, Bayesian information criterion and average posterior grouping probability were used to determine the best trajectory groups, and the objects were divided into three different metabolic syndrome index trajectory groups: normal, abnormal and recovery group. During the physical examination in 2022 and 2023, the detection of thyroid nodules in each group was followed up, and the difference of detection rate of thyroid nodules in different metabolic syndrome trajectory groups was compared by Log-rank test, and the correlation between different metabolic syndrome index change trajectories and thyroid nodules was analyzed by logistic regression model.Results:The cumulative detection rate of thyroid nodules in normal group, abnormal group and recovery group was 18.8% (77/410), 27.5% (327/1 190) and 24.7% (266/1 078), respectively ( χ2=19.482, P<0.001). In model 4, after adjusting for age, gender, smoking, drinking, staying up late, insomnia, physical activity, family history and other confounding factors, the risk of thyroid nodules in abnormal group and recovery group was still 2.011 times (95% CI: 1.457-2.776) and 2.006 times (95% CI: 1.389-2.897) of that in normal group. Conclusion:There is a positive correlation between metabolic syndrome index and thyroid nodules in individuals receiving health examinations, and metabolic syndrome index can be used as a predictive index of thyroid nodules.

Objective To construct clinical imaging model,radiomics model,and a combined model based on the above two for predicting lymph node metastasis(LNM)of colon cancer(CC),and to compare the diagnostic performance of each model.Methods The data from 328 CC patients confirmed by surgical pathology were analyzed retrospectively,including 156 with LNM.All patients were randomly divided into training group(229 cases)and validation group(99 cases)at a ratio of 7∶3.The difference of clinical imaging indicators were compared between groups and a clinical imaging model for diagnosing LNM was constructed.The tumor three-dimensional volume of interest(VOI)was used for radiomics feature extraction,and after dimensionality reduction and selection,8 features were obtained to construct the Radiomics score(Radscore).A combined model of clinical imaging indicators and Radscore was built.The diagnostic performance of each model for LNM was compared,and the calibration and clinical benefit of the optimal model were evaluated.Results There were statistical differences in clinical imaging indicators between the two groups:carcinoembryonic antigen(CEA),CA199,tumor long diameter,and lymph node short diameter(P＜0.05).The area under the curve(AUC)of the clinical imaging model,radiomics model,and combined model were 0.721,0.814,0.854(training group),and 0.744,0.732,0.808(validation group),respectively.The AUC of the combined model was the highest,and both the training and validation groups were higher than that of the clinical imaging model(P＜0.05).The combined model demonstrated higher calibration,with a clinical benefit from decision curve analysis(DCA)threshold range of 0.09 to 0.91.Conclusion The nomogram constructed based on clinical imaging indicators and CT radiomics holds high value in diagnosing LNM of CC.