A Combination of Astragaloside IV and Hydroxysafflor Yellow A Attenuates Cerebral Ischemia-Reperfusion Injury via NF-κB/NLRP3/Caspase-1/GSDMD Pathway.

Cerebral ischemia-reperfusion injury (IRI), occurring after blood supply restoration, contributes significantly to stroke-related deaths. This study explored the combined impact and mechanisms of astragaloside IV (AS-IV), hydroxysafflor yellow A (HSYA), and their combination in mitigating IRI. Male Sprague-Dawley (SD) rats were randomized to the Sham, MCAO, MCAO+AS-IV, MCAO+HSYA, and MCAO+AS-IV+HSYA groups. Neurological deficits and cerebral infarction were examined after restoring the blood supply to the brain. Pathomorphological changes in the cerebral cortex were observed via HE staining. IL-1ß and IL-18 were quantified using ELISA. The expression of NF-κB and GSDMD in the ischemic cerebrum was analyzed using immunohistochemistry. The expression levels of NLRP3, ASC, IL-1ß, Caspase-1, and GSDMD in the ischemic cerebrum were evaluated using Western blot. The MCAO+AS-IV, MCAO+HSYA, and MCAO+AS-IV+HSYA groups exhibited notably better neurological function and cerebral infarction compared with the MCAO group. The combined treatment demonstrated superior brain tissue injury alleviation. Reductions in NF-κB, GSDMD positive cells, and NLRP3/ASC/IL-1ß/Caspase-1/GSDMD protein expression in the ischemic brain were significantly more pronounced with the combined therapy, indicating a synergistic effect in countering cerebral IRI via the NF-κB/NLRP3/Caspase-1/GSDMD pathway inhibition of cell pyroptosis-induced injury.

Versatile Bioactive Glass/Zeolitic Imidazolate Framework-8-Based Skin Scaffolds toward High-Performance Wound Healing.

Designing a novel biomaterial for wound healing is based on biocompatibility and excellent mechanical strength. In this study, bioactive glass (BG) and zeolitic imidazolate framework-8 (ZIF-8) have been incorporated into poly(ε-caprolactone)/poly(vinyl alcohol) (PCL/PVA) composite skin scaffolds via microfluidic electrospinning. Interestingly, the addition of ZIF-8 further strengthens the BG stability and demonstrates better antibacterial effects. Utilizing the slow release of Zn, Ca, and Si ions, it also significantly promotes growth factor expression and skin regeneration. In addition, it is further demonstrated by in vitro and in vivo studies that the prepared composite skin scaffolds possess excellent biocompatibility, antibacterial capabilities, and mechanical properties. The prepared BG/ZIF-8-loaded scaffold possesses high tensile strength (26 MPa) and excellent antibacterial properties (achieves 89.64 and 78.8% inhibition of E. coli and S. aureus, respectively), and cell viability increased by 51.2%. More importantly, the wound shrinkage of the BG/ZIF-8-loaded scaffold is better than that of an unloaded scaffold, and the shrinkage rates of PCL/PVA@BG/ZIF-8(1 wt %) group is 95% with 2.2 mm granulation growth thickness within 12 days. Thus, the composite skin scaffold loaded with BG/ZIF-8 prepared by microfluidic electrospinning provides a new perspective for accelerating wound healing and is a potential novel therapeutic strategy for efficient wound healing.

The information-motivation-behavioral skills (IMB) model of antiretroviral therapy (ART) adherence among people living with HIV in Shanghai.

The Information-Motivation-Behavioral skills (IMB) model of antiretroviral therapy (ART) adherence was applied in people living with HIV/AIDS in Shanghai, China to understand how adherence-related information, motivation and behavioral skills would affect ART adherence. The LifeWindows Information-Motivation-Behavioral Skills ART Adherence Questionnaire (LW-IMB-AAQ) was translated into Chinese and used. The IMB model was then implemented by testing standardized path estimates with standard model fitness indices in the participants. 426 participants from 11 community centres in Putuo district of Shanghai were recruited, of which 95.3% reported a high level of adherence (>95% adherence). The fitness indices of the final adjusted model were χ2 = 6.110, df = 7, p = 0.527(>0.05), CFI = 1.000(>0.9) and RMSEA = 0.000 (<0.08). In the model, information, which was separated into two sections (the perceived effect of ART on health and knowledge about ART medication), had an indirect effect on the ART adherence through behavioral skills, while motivation did not have such an effect. Neither information nor motivation had a direct effect on ART adherence. In addition, motivation was related to the two sections of information. The feasibility of the IMB model of ART adherence is verified by its application to predictive of adherence-related behaviors among HIV+ patients in this study.

Danhong injection enhances the therapeutic effect of mannitol on hemispheric ischemic stroke by ameliorating blood-brain barrier disruption.

Mannitol, a representative of hyperosmolar therapy, is indispensable for the treatment of malignant cerebral infarction, but its therapeutic effect is limited by its exacerbation of blood-brain barrier (BBB) disruption. This study was to explore whether Danhong injection (DHI), a standardized product extracted from Salvia miltiorrhiza Bunge and Carthamus tinctorius L., inhibits the destructive effect of mannitol on BBB and thus enhancing the treatment of hemispheric ischemic stroke. SD rats were subjected to pMCAO followed by intravenous bolus injections of mannitol with/without DHI intervention. Neurological deficit score, brain edema, infarct volume at 24 h after MCAO and histopathology, microvascular ultrastructure, immunohistochemistry and immunofluorescence staining of endothelial cell junctions, energy metabolism in the ischemic penumbra were assessed. Intravenous mannitol after MCAO resulted in a decrease in 24 h mortality and cerebral edema, whereas no significant benefit on neurological deficits, infarct volume and microvascular ultrastructure. Moreover, mannitol led to the loss of endothelial integrity, manifested by the decreased expression of occludin, junctional adhesion molecule-1 (JAM-1) and zonula occluden-1 (ZO-1) and the discontinuity of occludin staining around the periphery of endothelial cells. Meanwhile, after mannitol treatment, energy-dependent vimentin and F-actin, ATP content, and ATP5D expression were down-regulated, while MMP2 and MMP9 expression increased in the ischemic penumbra. All the insults after mannitol treatment were attenuated by addition of intravenous DHI. The results suggest DHI as a potential remedy to attenuate mannitol-related BBB disruption, and the potential of DHI to upregulate energy metabolism and inhibit the activity of MMPs is likely attributable to its effects observed.

Thioredoxin reductase is a major regulator of metabolism in leukemia cells.

Despite the fact that AML is the most common acute leukemia in adults, patient outcomes are poor necessitating the development of novel therapies. We identified that inhibition of Thioredoxin Reductase (TrxR) is a promising strategy for AML and report a highly potent and specific inhibitor of TrxR, S-250. Both pharmacologic and genetic inhibition of TrxR impairs the growth of human AML in mouse models. We found that TrxR inhibition leads to a rapid and marked impairment of metabolism in leukemic cells subsequently leading to cell death. TrxR was found to be a major and direct regulator of metabolism in AML cells through impacts on both glycolysis and the TCA cycle. Studies revealed that TrxR directly regulates GAPDH leading to a disruption of glycolysis and an increase in flux through the pentose phosphate pathway (PPP). The combined inhibition of TrxR and the PPP led to enhanced leukemia growth inhibition. Overall, TrxR abrogation, particularly with S-250, was identified as a promising strategy to disrupt AML metabolism.

Concise Review; The Recent Methods that Enhance the Osteogenic Differentiation of Human Induced Pluripotent Stem Cells.

Bone regeneration is a critical problem in modern clinical practice. Osteocytes are the most abundant cell population of mature adult bone that play a major role in the regulation of bone formation. In humans, segmental bone defects cannot be repaired by endogenous regenerative mechanisms. Bone tissue engineering (BTE) is a promising option for the treatment of difficult segmental and skeletal defects. BTE requires suitable cell sources with rapid expansion and adequate function, inducible factors, and scaffolds to successfully regenerate or repair the bone injury. To overcome the disadvantages of using allogeneic and autologous tissue grafts, stem cell-based therapy has progressed in regenerative medicine. In the past few decades, numerous attempts have been made to generate osteocytes by using pluripotent stem cells (PSCs) to repair and regenerate bone defects. Human induced pluripotent stem cells (hiPSCs) are PSCs that can self-renew and differentiate into a variety of cell types. Reprogramming of human somatic cells into hiPSCs provides a new opportunity for regenerative medicine, cell-based drug discovery, disease modeling, and toxicity assessment. The ability to differentiate hiPSCs from mesenchymal stem cells (iPSC-MSCs) is essential for treating bone-related damages and injuries. Several in vitro studies revealed that the cell origin of iPSCs, a combination of transcription factors, the type of promoter in the vector, transduction methods, scaffolds, differentiating techniques, and culture medium, may affect the osteogenic differentiation potential of hiPSCs. This review will focus on several factors that influence the osteogenic differentiation of human iPSCs.

Reliability and Validity of the LifeWindows Information-Motivation-Behavioral Skills Antiretroviral Therapy Adherence Questionnaire Among HIV+ Patients in Shanghai.

OBJECTIVE: The purpose of this article was to examine the validity and reliability of the LifeWindows Information-Motivation-Behavioral Skills Antiretroviral Therapy (ART) Adherence Questionnaire (LW-IMB-AAQ) among HIV+ patients in Shanghai. METHODS: We surveyed 426 HIV+ patients in Shanghai's Putuo District to examine the validity and reliability of the questionnaire. The questionnaire includes self-reported demographic characteristics, the modified version of the Community Programs for Clinical Research on AIDS Antiretroviral Medication Self-Report (CPCRA) and LW-IMB-AAQ. CPCRA was used to calculate ART adherence. LW-IMB-AAQ, including the information section, the motivation section and the behavioral skills section, was used to analyze patients' ART adherence. We analyzed data by means, standard deviation, critical ratio, and item-total correlation. Reliability was assessed by internal consistency, split-half reliability, and test-retest reliability. Validity was assessed by exploratory factor analysis (EFA), confirmatory factor analysis (CFA), convergent validity and discriminant validity. RESULTS: Item analysis showed that except for motivation item 1, all items were acceptable. For reliability, Cronbach's alpha coefficients for the three sections and the total scale were all higher than 0.7, with interclass correlation coefficients (ICC) all higher than 0.6 (p<0.001). The Spearman-Brown coefficient for the total scale was 0.825. For validity, results showed that the information section could be divided into two subscales, motivation section and behavioral skills section could be divided into three and two subscales, respectively. The final model demonstrated good validity (p=0.471, χ 2/df=0.960, CFI=1.000, GFI=0.994 and RMSEA<0.001) without motivation item 4. CONCLUSION: Excluding motivation items 1 and 4, the LifeWindows Information-Motivation-Behavioral Skills ART Adherence Questionnaire (LW-IMB-AAQ) demonstrated good validity and reliability among HIV+ patients in Shanghai.

Repression of GSK3 restores NK cell cytotoxicity in AML patients.

Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity. The exact reasons for this dysfunction are not fully understood. Here we show that the glycogen synthase kinase beta (GSK3ß) expression is elevated in AML-NK cells. Interestingly, GSK3 overexpression in normal NK cells impairs their ability to kill AML cells, while genetic or pharmacological GSK3 inactivation enhances their cytotoxic activity. Mechanistic studies reveal that the increased cytotoxic activity correlates with an increase in AML-NK cell conjugates. GSK3 inhibition promotes the conjugate formation by upregulating LFA expression on NK cells and by inducing ICAM-1 expression on AML cells. The latter is mediated by increased NF-κB activation in response to TNF-α production by NK cells. Finally, GSK3-inhibited NK cells show significant efficacy in human AML mouse models. Overall, our work provides mechanistic insights into the AML-NK dysfunction and a potential NK cell therapy strategy.

Factors causing delay of access to tuberculosis diagnosis among new, active tuberculosis patients: a prospective cohort study.

Few studies have examined, in a prospective cohort study, factors causing delay of access to tuberculosis (TB) diagnosis among new, active TB patients. A prospective cohort study (2009-2011) was carried out among 408 889 Chinese. Data on known/potential influencing factors were obtained from baseline questionnaires. We used stepwise logistic regression models to analyze the association between several known/potential influencing factors and diagnosis delay, assessed the current situation, and explored determinants of diagnosis delay. During follow-up and final visits, 202 new, active TB patients were found. Median patient delay was 5.4 (quartile 2.7-26) weeks, health system delay was 0 (quartile 0-1.6) weeks, and diagnosis delay was 9.9 (quartile 3.1-28.1) weeks. The influencing factors on patient delay were age and duration of symptoms. Smoking and sputum smear status were influencing factors for health system delay, and duration of symptoms was one of the factors for diagnosis delay. These findings provide information on the current situation of diagnosis delay and evidence for specific strategy development for TB control in China.

Application of a hybrid model for predicting the incidence of tuberculosis in Hubei, China.

BACKGROUND: A prediction model for tuberculosis incidence is needed in China which may be used as a decision-supportive tool for planning health interventions and allocating health resources. METHODS: The autoregressive integrated moving average (ARIMA) model was first constructed with the data of tuberculosis report rate in Hubei Province from Jan 2004 to Dec 2011.The data from Jan 2012 to Jun 2012 were used to validate the model. Then the generalized regression neural network (GRNN)-ARIMA combination model was established based on the constructed ARIMA model. Finally, the fitting and prediction accuracy of the two models was evaluated. RESULTS: A total of 465,960 cases were reported between Jan 2004 and Dec 2011 in Hubei Province. The report rate of tuberculosis was highest in 2005 (119.932 per 100,000 population) and lowest in 2010 (84.724 per 100,000 population). The time series of tuberculosis report rate show a gradual secular decline and a striking seasonal variation. The ARIMA (2, 1, 0) × (0, 1, 1)12 model was selected from several plausible ARIMA models. The residual mean square error of the GRNN-ARIMA model and ARIMA model were 0.4467 and 0.6521 in training part, and 0.0958 and 0.1133 in validation part, respectively. The mean absolute error and mean absolute percentage error of the hybrid model were also less than the ARIMA model. DISCUSSION AND CONCLUSIONS: The gradual decline in tuberculosis report rate may be attributed to the effect of intensive measures on tuberculosis. The striking seasonal variation may have resulted from several factors. We suppose that a delay in the surveillance system may also have contributed to the variation. According to the fitting and prediction accuracy, the hybrid model outperforms the traditional ARIMA model, which may facilitate the allocation of health resources in China.

[Study on the risk factors of tuberculosis in four cities and provinces in China].

OBJECTIVE: To investigate the influencing factors on tuberculosis (TB) in four provinces in the eastern and central parts of China. METHODS: From Nov. 2009 to Feb. 2011, three population-based field surveys were conducted among the resident population in several townships/streets in Guangdong, Hunan and Jiangsu provinces and Shanghai municipality to collect TB-related information. 474 sputum smear positive TB patients and 1896 controls were randomly selected from the population under study and each case was matched by province, age and sex using a frequency matching method. Single-variable and multiple non-conditional logistic regression modeling were applied for data analysis, and odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated. RESULTS: Data from Single-variable analysis showed that TB history, history of exposure to TB, DM history, immigrant population and per-capita living space were risk factors for TB, and high level of education was protective factors. RESULTS: from multiple logistic regression showed that the risk factors of TB would include the following items: history of having had TB (OR = 52.356, 95%CI: 18.956 - 144.607), living space over 50 m(2)per-capita (OR = 8.742, 95%CI: 1.107 - 69.064), history of exposure to TB (OR = 6.083, 95%CI: 2.336 - 15.839) and being immigrants (OR = 3.306, 95%CI: 1.907 - 5.734), while having had high degree of education as the protective factor of TB (OR = 0.284, 95%CI: 0.110 - 0.733). CONCLUSION: Control programs targeting those ever having TB patients and contacts to TB patients as well as immigrants should be strengthened.

Pulmonary tuberculosis incidence and risk factors in rural areas of China: a cohort study.

The incidence of tuberculosis (TB) and its risk factors in China remains unclear. This study examined TB incidence and relative risk factors in rural areas of China. Participants (n = 177,529) were recruited in Xiangtan County (in the central area of China) and in Danyang County (in the eastern area of China) in 2009 and a followed-up study was conducted for one year. The incidence density of pulmonary TB and smear-positive TB were 91.6 (95% CI: 78.7, 106.0) per 100,000 person-year and 36.7 (95% CI: 33.1, 52.4) per 100,000 person-year respectively in Xiangtan, and 47.3 (95% CI: 38.2, 57.5) per 100,000 person-year and 22.7 (95% CI: 16.5, 30.8) per 100,000 person-year in Danyang. The medical history of TB was associated with TB, with the relative risk (RR) of 7.00 (95% CI: 2.76, 17.18) in Xiangtan and that of 31.08 (95% CI: 13.22, 73.10) in Danyang. The association between TB and per capita living space over median was found in Xiangtan, with the RR of 1.86 (95% CI: 1.15, 3.01). No association was found between TB and the insurance status, the contact history with TB, the history of diabetes, smoking, or per capita annual income. The host genetic susceptibility, and social factors such as education and income could be considered in future studies.

[Effects of heishunpian total alkaloids on Cassia acutifolia induced mice diarrhea and contraction of isolated intestinal smooth muscle in rats].

OBJECTIVE: To observe the effects of Heishunpian total alkaloids on Cassia acutifolia induced mice diarrhea and contraction of isolated intestinal smooth muscle in rats. METHODS: The experiment was carried out with Cassia acutifolia induced mice diarrhea model, small intestinal propulsive rate in mice was used to valuate the effect of Heishunpian total alkaloids on diarrhea mice; The effects of Heishunpian total alkaloids on contraction of isolated intestinal smooth muscle in rats and its mechanism were investigated by monitoring amplitude and tension of isolated intestinal smooth muscle in rats; The chemical constituents of Heishunpian total alkaloids were analyzed by HPLC. RESULTS: Heishunpian total alkaloids could significantly slow down intestine propulsive motility in diarrhea mice (P < 0. 05), and reduce amplitude and tension of isolated small intestinal smooth muscle contraction in normal rats in dose-dependent manner. Heishunpian total alkaloids had a certain inhibitory effect on acetylcholine chloride and neostigmine methylsulfate strengthening small intestine smooth muscle movement, however, had no significantly effect on Atropine sulfate inhibiting small intestine smooth muscle movement. By HPLC analysis, benzoylaconitine, benzoylmesaconitine, benzoylhypaconitine were the main chemical constituents of Heishunpian total alkaloids. CONCLUSION: Heishunpian total alkaloids have a certain role of antidiarrheal and its mechanism may be related to antagonizing muscarinic receptors.

[Construction of surveillance and early-warning-index-system on tuberculosis in China].

OBJECTIVE: To establish the surveillance and warning index system corresponding with the epidemic characteristics of tuberculosis, in China. METHODS: Literature review and expert meeting were conducted to formulate the preliminary index system frame. Delphi method was used for screening the index and determining the weight of each index. RESULTS: Two-round Delphi consultations were performed. The activity coefficients were 87.0%, 90.0% respectively, with means of authority coefficient as 0.850±0.055 and 0.917±0.017, respectively. Mean scores of the index were 7.063±1.435, 8.156±0.611 respectively, with the means of coefficient of variation as 0.352±0.161 and 0.170±0.057 respectively. The harmony coefficients were 0.322 (χ2=499.472, P<0.05) and 0.393 (χ2=241.126, P<0.05) respectively. After the two-round consultation, the tuberculosis monitoring and warning index system was developed, including 4 first-class indicators, 9 second-class indicators and 48 third-class indicators. CONCLUSION: An index system was established for tuberculosis monitoring and early warning that could provide evidence for tuberculosis prevention and control as well as for the forecasting and warning model of the disease.