Downregulation of DIP2B as a prognostic marker inhibited cancer proliferation and migration and was associated with immune infiltration in lung adenocarcinoma via CCND1 and MMP2.

Background: DIP2B is related to cancer progression. This study investigated the roles and pathways of DIP2B in lung adenocarcinoma (LUAD). Methods: DIP2B expression and the relationship between survival time of cancer patients and DIP2B expression were analyzed. The relationship between DIP2B expression and survival time in LUAD patients was evaluated by a meta-analysis. Cox and survival analyses were used to evaluate the prognostic factors and construct a prognostic nomogram. The mechanisms and effects of DIP2B and the relationship between DIP2B expression and the immune microenvironment were investigated using bioinformatics, CCK-8, western blotting, and transwell experiments. Results: DIP2B was overexpressed in LUAD tissues. DIP2B overexpression was associated with shorter prognosis and was an unfavorable risk factor for prognosis in LUAD patients. DIP2B co-expressed genes were involved in cell division, DNA repair, cell cycle, and others. Inhibition of DIP2B expression could downregulate the proliferation, migration, and invasion of LUAD A549 and H1299 cells, which was related to the decrease in CCND1 and MMP2 protein expression. BRCA1 overexpression was associated with short prognosis, and the nomogram formed by DIP2B and BRCA1 was associated with a poor prognosis in LUAD patients. DIP2B expression correlated with immune cells (such as CD8 T cells, Tcm, and iDCs) and cell markers. Conclusion: DIP2B is a potential biomarker of poor prognosis and the immune microenvironment in LUAD. Inhibition of DIP2B expression downregulated cancer cell proliferation, migration, and invasion, which might be related to the decrease in CCND1 and MMP2 protein expression. DIP2B-related nomograms might be useful tools for predicting the prognosis of LUAD patients.

Overexpression of MTFR1 promotes cancer progression and drug-resistance on cisplatin and is related to the immune microenvironment in lung adenocarcinoma.

OBJECTIVE: The roles of MTFR1 in the drug resistance of lung adenocarcinoma (LAC) to cisplatin remain unexplored. In this study, the expression, clinical values and mechanisms of MTFR1 were explored, and the relationship between MTFR1 expression and immune microenvironment was investigated in LAC using bioinformatics analysis, cell experiments, and meta-analysis. METHODS: MTFR1 expression and clinical values, and the relationship between MTFR1 expression and immunity were explored, through bioinformatics analysis. The effects of MTFR1 on the growth, migration and cisplatin sensitivity of LAC cells were identified using cell counting kit-8, wound healing and Transwell experiments. Additionally, the mechanisms of drug resistance of LAC cells involving MTFR1 were investigated using western blotting. RESULTS: MTFR1 was elevated in LAC tissues. MTFR1 overexpression was associated with sex, age, primary therapy outcome, smoking, T stage, unfavourable prognosis and diagnostic value and considered an independent risk factor for an unfavourable prognosis in patients with LAC. MTFR1 co-expressed genes involved in the cell cycle, oocyte meiosis, DNA replication and others. Moreover, interfering with MTFR1 expression inhibited the proliferation, migration and invasion of A549 and A549/DDP cells and promoted cell sensitivity to cisplatin, which was related to the inhibition of p-AKT, p-P38 and p-ERK protein expression. MTFR1 overexpression was associated with stromal, immune and estimate scores along with natural killer cells, pDC, iDC and others in LAC. CONCLUSIONS: MTFR1 overexpression was related to the unfavourable prognosis, diagnostic value and immunity in LAC. MTFR1 also participated in cell growth and migration and promoted the drug resistance of LAC cells to cisplatin via the p-AKT and p-ERK/P38 signalling pathways.

Association between optic atrophy 1 polymorphisms and primary open angle glaucoma risk: Based on a meta-analysis.

BACKGROUND: Emerging evidence suggested a significant association between optic atrophy 1 (OPA1) polymorphisms and primary open angle glaucoma (POAG) risk. However, the current data are inconsistent or even contradictory. Given these, we conducted a meta-analysis to examine the precise association between OPA1 polymorphisms and POAG risk. MATERIALS AND METHODS: Online databases were retrieved, and the related studies were reviewed from inception to December 1, 2022. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to examine the statistical power of each genetic model. In addition, heterogeneity, sensitivity, cumulative analysis, and publication bias were analyzed to guarantee statistical power. RESULT: Overall, 14 studies within 11 publications (involving 2,413 POAG patients and 1,904 controls) were included and some significant association between OPA1 rs166850 C/T (T vs. C: OR = 1.24, 95%CI = 1.06-1.45, P = 0.01, I2 = 39.0%; CT vs. CC: OR = 1.37, 95%CI = 1.05-1.79, P = 0.02, I2 = 41.6%; CT + TT vs. CC: 1.37, 95%CI = 1.06-1.77, P = 0.02, I2 = 41.6%), rs10451941T/C (TC + CC vs. TT: OR = 1.79, 95%CI = 1.41-2.28, P < 0.01, I2 = 71.9%) polymorphisms and POAG susceptibility. In addition, further significant associations were also observed in the stratified analysis, especially in normal tension glaucoma groups and Caucasian descendants. CONCLUSION: The observed evidences suggest that OPA1 polymorphisms may be associate with POAG susceptibility significantly.

HLA-DPA1 overexpression inhibits cancer progression, reduces resistance to cisplatin, and correlates with increased immune infiltration in lung adenocarcinoma.

PURPOSE: Human Leukocyte Antigen-DP alpha 1 (HLA-DPA1) is a critical gene in antigen-presenting cells and plays a significant role in immune regulation. The objective of this study was to comprehensively analyze the roles of HLA-DPA1 and its association with lung adenocarcinoma (LUAD). METHODS: We utilized bioinformatics and conducted a meta-analysis to examine the roles of HLA-DPA1 expression on the progression and immunity of LUAD. We also performed CCK-8, wound healing, and Transwell assays to validate the functions of HLA-DPA1 in LUAD. RESULTS: HLA-DPA1 expression is downregulated in LUAD tissues and is associated with gender, race, age, smoking history, clinical stage, histological type, lymph node metastasis, and prognosis of patients with LUAD. HLA-DPA1 is involved in immune responses, leukocyte cell-cell adhesion, and antigen processing and presentation. Overexpression of HLA-DPA1 inhibits cancer cell proliferation, migration, and invasion while promoting cell sensitivity to cisplatin in A549 and A549/DDP cells. Additionally, overexpression of HLA-DPA1 correlates with tumor purity, stromal, immune, and ESTIMATE scores, the abundance of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, dendritic cells, and neutrophils), and immune cell markers (programmed cell death 1, cytotoxic T-lymphocyte-associated protein 4, and cluster of differentiation 8A). CONCLUSIONS: Decreased HLA-DPA1 expression is associated with poor prognosis and immune infiltration in LUAD while HLA-DPA1 overexpression inhibits cancer cell proliferation and progression. Therefore, HLA-DPA1 shows potential as a prognostic biomarker and a therapeutic target for LUAD.

Association between serum α-klotho level and the prevalence of heart failure in the general population.

BACKGROUND: Heart failure is a major cause of global morbidity and mortality. Studies in laboratory animals have shown the direct protective effects of α-klotho on the cardiovascular system although it has limited expression in the heart. The association between α-klotho and cardiovascular disease is still controversial in different clinical studies. We designed a cross-sectional study in order to investigate the association between serum α-klotho level and the prevalence of heart failure in the American general population. METHODS: The data were obtained from the National Health and Nutrition Examination Survey (NHANES), which included 11 271 participants aged 40-80 years. Serum α-klotho level was examined by enzyme-linked immunosorbent assay and divided into four quartiles for further analysis. Heart failure status was obtained from self-reported questionnaires. To estimate the association between α-klotho level and prevalence of heart failure, multivariate logistic regression analyses were conducted. Interaction and stratified analyses were performed to evaluate the potential modifiers. RESULTS: After adjusting for multiple covariates, a per-standard deviation increase in serum α-klotho level was associated with a decrease in prevalence of heart failure [odds ratio (OR): 0.76, 95% confidence interval (CI): 0.68-0.85). The ORs for participants in quartiles 2 to 4 were 0.77 (95% CI: 0.58-1.01), 0.70 (95% CI: 0.52-0.93) and 0.71 (95% CI: 0.53-0.95), respectively, compared with those in quartile 1. Stratified analysis revealed significant gender and racial differences. CONCLUSION: We revealed an independent association between serum α-klotho level and the prevalence of heart failure in the American general population. The association was not always consistent and varied according to gender and race.

Anal fistulotomy with one-stage shaped skin grafting for intersphincter anal fistulas: study protocol on a multicentre randomised controlled trial.

BACKGROUND: Anal fistulas are mainly treated via surgery. They can be difficult to treat without surgical intervention. Numerous procedures, such as fistulectomy and fistulotomy, are performed to treat anal fistulas and achieve good effects. However, the wounds created through fistulectomy and fistulotomy take a long time to heal. Therefore, a multicentre randomised controlled trial (RCT) is proposed to study the efficacy of one-stage shaped skin grafting at the surgical wound to heal low simple intersphincter anal fistulas. METHODS: This study is a multicentre, hospital-based RCT. It will be performed at three hospitals. A total of 104 patients with low simple intersphincter anal fistulas who meet the inclusion criteria will be included in this trial and will be allocated randomly to two groups (test and control groups). The patients in the test group will receive one-stage anal fistulotomy surgery combined with shaped skin grafting, and those in the control group will undergo anal fistulotomy only. All the operations will be performed by attending colorectal surgeons or surgeons of a higher level. Effectiveness and safety indicators will be observed, recorded and analysed. DISCUSSION: Anal fistulotomy can heal low simple intersphincter anal fistulas effectively and safely with a low recurrence rate. Skin grafts promote wound epithelisation significantly. We believe that skin grafting can treat low simple intersphincter fistulas with a short healing time. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2000039174. Registered on 28 October 2020.

The Clinical Effect and Mechanism of Prostant on Urinary Retention and Anal Pain.

Anal pain and urinary retention are the two most outstanding complications of the procedure for prolapse and hemorrhoids (PPH) surgery. This study intended to assess the clinical effect and mechanism of Prostant on urinary retention and anal pain after the PPH. Here, 30 patients received PPH surgery. The role and mechanism of Prostant in patients and mice with urinary retention and anal pain were evaluated. ANOVA tests were executed and differences between groups were regarded as statistically significant when p < 0.05. Prostant effectively improved the urination status, lower abdomen symptoms, time to urinate and score of VAS, and the reduction of TNF-α and IL-6. Similarly, Prostant can ameliorate the outcome of urodynamics in urinary retention mice. Mechanically, Prostant reversed the urinary retention-elevated the serum level of hs-CRP and TNF-α, reduction of IL-2, imbalance of Treg/Th17, and level of JAK2 and phosphorylated STAT3. Besides, Prostant ameliorated the pain as shown by the reduction of writhing response, and the elevation of threshold of pain and degree of swelling. Moreover, Prostant antagonized the pain-induced dysregulation of Treg/Th17. Therefore, Prostant can treat patients and mice with anal pain and urinary retention by modulating the balance of Th17/Treg to regulate the secretion and production of inflammatory factors. We hope our results can establish a scientific treatment approach for solving anal pain and urinary retention after PPH surgery of mixed hemorrhoids.

CircKIF4A promotes non-small cell lung cancer proliferation and metastasis through MiR-1238/CLDN14 axis.

As the leading cause of cancer-related death worldwide, non-small-cell lung cancer (NSCLC) is still in need of improved therapeutic strategies. CircKIF4A has been found to be involved in the progression of multiple cancers while its role in NSCLC remains unclear. To investigate the functions of circKIF4A, we assessed the expression of circKIF4A in NSCLC cells and tissues and performed experiments to determine the detailed functions of circKIF4A in NSCLC, including migration and proliferation. We found CircKIF4A expressed more heavily in the cells and tissues of NSCLC patients, and functional studies showed that inhibition of circKIF4A reduced NSCLC cells metastasis and proliferation. Furthermore, we seek to identify the underlying regulatory effect of circKIF4A in NSCLC. Studies revealed that circKIF4A sponged miR-1238 to promote NSCLC progression by up-regulating claudin14 (CLDN14) expression. In conclusion, circKIF4A is a potential diagnostic and therapeutic target in the circKIF4A/miR-1238/CLDN14 axis that plays an important role in NSCLC progression.

Laparoscopic versus open surgery for elderly patients with colorectal cancer: a systematic review and meta-analysis of matched studies.

BACKGROUND: To compare clinical and survival outcomes between laparoscopic versus open surgery in elderly colorectal cancer patients. METHODS: PubMed, Embase and Scopus databases were systematically searched. The review included studies that were either randomized controlled trials (RCTs) or observational in design. STATA was used for statistical analysis. RESULTS: The meta-analysis was conducted with 24 studies. Compared with elderly subjects with open surgery, those undergoing laparoscopic surgery had a lower risk of mortality (within 3 months postoperatively) (RR 0.70, 95% CI: 0.53, 0.94). The long-term overall survival (HR 0.96, 95% CI: 0.89, 1.04), disease-free survival (HR 1.02, 95% CI: 0.93, 1.13), risk of recurrence (RR 1.44, 95% CI: 0.90, 2.30) and readmission (RR 1.11, 95% CI: 0.88, 1.40) rates were statistically similar in both the groups. The operative time (in minutes) was higher (WMD 30.37, 95% CI: 17.75, 43.0) and the blood loss (in ml) was lower (WMD -78.85, 95% CI: -101.96, -55.75) in those undergoing laparoscopic surgery. The length of hospital stay (in days) (WMD -2.53, 95% CI: -3.11, -1.95) and the time of return of bowel movements (in days) (WMD -1.06, 95% CI: -1.20, -0.93) was lower in those with laparoscopic surgery. The pooled risk of complications was lower in those with laparoscopic surgery (RR 0.66, 95% CI: 0.60, 0.74), compared with open surgery. CONCLUSIONS: Findings suggest that in elderly subjects with colorectal cancer, laparoscopic surgery appears to be more beneficial than open surgery and should be prioritized, subject to the availability of required technical skills and facilities.

Asymptotically local synchronization in interdependent networks with unidirectional interlinks.

Synchronization in complex networks has been investigated for decades. Due to the particularity of the interlinks between networks, the synchronization in interdependent networks has received increasing interest. Since the interlinks are not always symmetric in interdependent networks, we focus on the synchronization in unidirectional interdependent networks to study the control scheme. The mathematical model is put forward and some factors are taken into consideration, such as different coupling functions and strengths. Firstly, the feasibility of the control scheme is proved theoretically by using Lyapunov stability theory and verified by simulations. Then, we find that the synchronization could be maintained in one sub-network by utilizing our control scheme while the nodes in the other sub-network are in chaos. The result indicates that the influence of interlinks can be decreased and the proposed scheme can guarantee the synchronization in one sub-network at least. Moreover, we also discuss the robust of our control scheme against the cascading failure. The scheme is verified by simulations to be effective while the disturbances occur.

[Microscope assisted anterior cervical discectomy and fusion for the treatment of single segment cervical spondylotic myelopathy].

OBJECTIVE: To compare the efficacy of microscope assisted anterior cervical discectomy and fusion with conventional surgical approach in the treatment of single-segment cervical spondylotic myelopathy. METHODS: The clinical data of 89 patients with single-segment cervical spondylotic myelopathy treated from March 2015 to March 2019 were retrospectively analyzed. There were 55 males and 34 females, with an average of (52.00±11.36) years old. Among the patients, 34 cases were treated with conventional anterior cervical discectomy with fusion (conventional group), including C3,4 in 3 cases, C4,5 in 10 cases, C5,6 in 15 cases, C6,7 in 6 cases; 55 cases were treated with microscopeassisted anterior cervical discectomy with fusion (microscope group), including C3,4 in 5 cases, C4,5 in 23 cases, C5,6 in 20 cases, C6,7 in 7 cases. Operative time, intraoperative blood loss, hospital stay and complications were compared between two groups. Clinical efficacy was assessed by visual analogue scale(VAS), Japanese Orthopaedics Association (JOA) scores, Oswestry Disability Index(ODI) during follow-up period (postoperative 1 week, 3 months and 12 months). RESULTS: Intraoperative blood loss and hospital stay in microscope group were less than those in conventional group (P<0.05), and operative time of conventional group was shorter than that of microscope group (P<0.05). Postoperative JOA, VAS and ODI were significantly improved in each groups (P<0.05). VAS scores of microscope group were better than that of conventional group at 1 week and 3 months after operation(P<0.05), but there was no statistically significant difference between two groups at 12 months after operation (P>0.05). JOA scores of microscope group at each postoperative follow-up were better than that of conventional group (P<0.05). ODI scores of microscope group at 3, 12 months after operation were better than that of conventional group (P<0.05). CONCLUSION: Both methods can achieve satisfactory effect in treating single-segment cervical spondylotic myelopathy. However, microscope-assisted anterior cervical discectomy and fusion has advantages of clear vision, less bleeding and fewer intraoperative complications.

Selective Transfer Hydrogenation of Furfural into Furfuryl Alcohol on Zr-Containing Catalysts Using Lower Alcohols as Hydrogen Donors.

A series of zirconium-based catalysts were prepared for the selective transfer hydrogenation of biomass-derived furfural (FFR) into furfuryl alcohol with lower alcohols as hydrogen sources. The sample structures were clearly characterized using various methods, such as X-ray powder diffraction, thermogravimetric analysis, scanning electron microscope, NH3-temperature-programmed desorption (TPD), CO2-TPD, and nitrogen physisorption. Excellent furfuryl alcohol yield of 98.9 mol % was achieved over Zr(OH)4 using 2-propanol as a hydrogen donor at 447 K. The poisoning experiments indicated that basic centers displayed pronounced effect for FFR transfer hydrogenation. Moderate monoclinic phase content in ZrO2-x enhanced the conversion rate and furfuryl alcohol selectivity, whereas acid-basic site density ratio had slight influence on FFR conversion. Besides, Zr(OH)4 revealed good performance and stability after being repeated four times. The possible mechanism for this transfer hydrogenation process over Zr(OH)4 catalyst with 2-propanol as the hydrogen source was proposed.

Effects of Rosa laevigata Michx. extract on reactive oxygen species production and mitochondrial membrane potential in lens epithelial cells cultured under high glucose.

This study was to investigate the effects of Rosa laevigata Michx. (RLM) extract on reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) in lens epithelial cells (LECs) cultured under high glucose. SRA01/04 cell models of diabetic cataract were established by high glucose culture, and these cells were administrated with RLM extract. Levels of ROS and MMP in SRA01/04 cells were detected with fluorescent probes. HO-1 expression level, Akt phosphorylation, and Nrf2 translocation were detected by Western blot. RLM treatment could exert protective effects on SRA01/04 cells under high glucose condition, decreasing the ROS production and elevating the MMP in these cells. Western blot analysis indicated that the expression level of HO-1 was significantly elevated in SRA01/04 cells after the RLM treatment. Moreover, when HO-1 was interfered with siRNA, the effects of RLM on the levels of ROS and MMP were diminished, indicating that HO-1 induction was necessary for the function of RLM. Furthermore, HO-1 inducing effects of RLM were mediated by the PI3K/Akt and Nrf2/ARE pathways. The effects would be abolished when either pathway was inhibited by pharmacological manipulation or siRNA silencing. RLM inhibits ROS production and elevates MMP, through the induction of HO-1 expression, in LECs under high glucose condition. The protective effects of RLM are mediated by the PI3K/Akt and Nrf2/ARE pathways. Our findings provide theoretic basis and experimental evidence for the application of RLM in the treatment of diabetic cataract.

Tongxinluo Protects against Hypertensive Kidney Injury in Spontaneously-Hypertensive Rats by Inhibiting Oxidative Stress and Activating Forkhead Box O1 Signaling.

Hypertension is an independent risk factor for the progression of chronic renal failure, and oxidative stress plays a critical role in hypertensive renal damage. Forkbox O1(FoxO1) signaling protects cells against oxidative stress and may be a useful target for treating oxidative stress-induced hypertension. Tongxinluo is a traditional Chinese medicine with cardioprotective and renoprotective functions. Therefore, this study aimed to determine the effects of Tongxinluo in hypertensive renal damage in spontaneously hypertensive rats(SHRs)and elucidate the possible involvement of oxidative stress and FoxO1 signaling in its molecular mechanisms. SHRs treated with Tongxinluo for 12 weeks showed a reduction in systolic blood pressure. In addition to increasing creatinine clearance, Tongxinluo decreased urinary albumin excretion, oxidative stress injury markers including malondialdehyde and protein carbonyls, and expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and its activity in SHR kidneys. While decreasing phosphorylation of FoxO1, Tongxinluo also inhibited the phosphorylation of extracellular signal-regulated kinase1/2 and p38 and enhanced manganese superoxide dismutase and catalase activities in SHR kidneys. Furthermore, histology revealed attenuation of glomerulosclerosis and renal podocyte injury, while Tongxinluo decreased the expression of α-smooth muscle actin, extracellular matrixprotein, transforming growth factor ß1 and small mothers against decapentaplegic homolog 3,and improved tubulointerstitial fibrosis in SHR kidneys. Finally, Tongxinluo inhibited inflammatory cell infiltration as well as expression of tumor necrosis factor-α and interleukin-6. In conclusion, Tongxinluo protected SHRs against hypertension-induced renal injury by exerting antioxidant, antifibrotic, and anti-inflammatory activities. Moreover, the underlying mechanisms of these effects may involve inhibition of oxidative stress and functional activation of FoxO1 signaling.

Quality evaluation of randomized controlled trials reports of laparoscopy compared with open colorectal resection for colorectal cancer.

OBJECTIVES: Previously, there were no data looking at the quality evaluation of randomized controlled trials (RCTs) on effect comparison of laparoscopic surgery and open surgery for colorectal cancer in China. Here, we evaluate the completeness and transparency of RCT reports in this field. METHODS: The following databases were searched: Medline, EMbase, SCI Expanded, China National Knowledge Infrastructure, the Chinese Biological Medicine Database, VIP database and Wan Fang databases) to search RCT reports on the effect comparison of laparoscopic surgery and open surgery for colorectal cancer in China. Our study evaluated the reporting quality of RCTs based on 22 standards of Consolidated Standards for Reporting Trials (CONSORT) 2010 Statement. Two reviewers responded with 'yes' or 'no' to each standard to judge whether the authors had reported or had recorded concrete details of the reports accomplished in accordance with the requirement of each standard. RESULTS: A total of 40 relevant RCTs were included in the final analysis. For the 'Title and abstract', only three articles (7.5%) could be identified directly from its title as the report of RCTs. For the 'Methods', only three articles (7.5%) applied the method of random allocation of sequences; only two articles (5%) mentioned the type of randomization or gave the description of the mechanism of allocation concealment; no article referred the concrete implementation of random method. Only one article (2.5%) applied the method of blinding or sample size calculation; no article had analysis about the metaphase of an experiment or an explanation of its interruption. For 'results', only one article (2.5%) described participant flow, primary and secondary outcomes with estimated effect size or ancillary analyses. Only 13 articles (32.5%) showed baseline demographic and clinical characteristics, 10 (25%) referred to intention-to-treat analysis, and 12 (30%) mentioned important harms or unintended effects. For the 'discussion', only eight articles (20%) gave the description of trials' limitations and 13 (32.5%) presented the generalizability (external validity, applicability) of the trial findings. CONCLUSION: The quality of the RCT reports on effect comparison of laparoscopic surgery and open surgery for colorectal cancer in China is poor. The reporting of RCTs in this field should be standardized, according to the specifications of the CONSORT 2010.

Effects of ethyl pyruvate on cardiac function recovery and apoptosis reduction after global cold ischemia and reperfusion.

The present study used an in vitro model of cold cardioplegia in isolated working rat hearts to evaluate the possible role of ethyl pyruvate (EP) in promoting cardiac function and preventing apoptosis. Two groups of rats were evaluated; the EP (2 mM EP; n=8) and control (n=8) groups. Isolated rat hearts were perfused with Krebs-Henseleit buffer (KHB) for 30 min, arrested with cardioplegic solution and stored for 4 h in B21 solution at 4°C. The hearts were reperfused with KHB for 45 min. EP was added to the cardioplegic and storage solutions and also to KHB for reperfusion. Cardiac parameters of the heart rate, including left ventricular systolic pressure, left ventricular end-diastolic pressure, left ventricular developed pressure and maximal rise rate of the left ventricular pressure, were monitored. In addition, coronary flow, adenosine triphosphate (ATP) levels and malondialdehyde (MDA) content were recorded and apoptotic cell determination was detected. The functional parameters in the EP group were significantly higher compared with those in the control group during the reperfusion period (P<0.05). In addition, ATP levels were higher in the EP group than in the control group and the content of MDA was lower in the EP group than in the control group. A concentration of 2 mM EP significantly reduced the number of apoptotic cells in the EP group compared with that of the control group (P<0.05). Therefore, EP significantly preserved cardiac function, enhanced tissue ATP levels, attenuated myocardial oxidative injury and markedly reduced apoptosis following myocardial ischemia in an in vitro model of 4 h of cold cardioplegia and reperfusion.

Andrographolide inhibits proliferation of human lung cancer cells and the related mechanisms.

This study is to determine effect of Andrographolide (AD) on the growth of the non-small cell lung cancer cell line H3255. Expression of vascular endothelial growth factor (VEGF), transforming growth factor ß1 (TGF-ß1), and the activity of protein kinase C (PKC) were also detected. The H3255 cells were treated with 1.0, 2.5, or 5.0 µM AD for 24 h. MTT assay was performed to examine cell viability. Levels of VEGF and TGF-ß1 were detected by ELISA. The ATPase activity and PKC activity were tested. AD treatments decreased cell viability via a concentration-dependent manner, leading to decreases in the Na(+)-K(+)-ATPase activities (P < 0.05). AD also increased levels of the DNA fragmentation and releasing of lactate dehydrogenase. AD also reduced VEGF and TGF-ß1 levels, and inhibited protein kinase C activities in H3255 cells (P < 0.05). AD inhibits proliferation of lung cancer cells via a concentration-dependent manner by a mechanism related to reducing levels of VEGF and TGF-ß1. Thus, AD might be a potent anti-lung cancer agent.

Andrographolide inhibits the activation of NF-κB and MMP-9 activity in H3255 lung cancer cells.

This study aimed to determine the effect of andrographolide (AD) on the growth of H3255 lung cancer cells and its possible impact on the expression and activity of the matrix metalloproteinase (MMP)-9 protein. H3255 cells were cultured in vitro, and treated with AD (1, 5 or 10 µM) for 24, 48 or 72 h. Cell proliferation was detected using an MTT assay and the expression of MMP-9 mRNA was measured using a reverse transcription-polymerase chain reaction (RT-PCR). The activity of MMP-9 was assessed by gelatin zymography, while the nuclear translocation of the nuclear factor-κB (NF-κB) p65 subunit and the phosphorylation of IκB were determined by western blotting. AD inhibited the proliferation of the H3255 cells in a concentration- and time-dependent manner, in addition to downregulating the expression of MMP-9 mRNA and the activity of MMP-9. Moreover, AD significantly inhibited the nuclear translocation of the NF-κB p65 subunit and suppressed IκB phosphorylation. The significant inhibition of H3255 cell proliferation by AD may have been correlated with the reduction in MMP-9 expression and activity through the inhibition of the phosphorylation of IκB and the translocation of NF-κB. The results suggest that AD is a promising drug candidate for the treatment of the migration and invasion of malignant tumors.

Discovering patterns in drug-protein interactions based on their fingerprints.

BACKGROUND: The discovering of interesting patterns in drug-protein interaction data at molecular level can reveal hidden relationship among drugs and proteins and can therefore be of paramount importance for such application as drug design. To discover such patterns, we propose here a computational approach to analyze the molecular data of drugs and proteins that are known to have interactions with each other. Specifically, we propose to use a data mining technique called Drug-Protein Interaction Analysis (D-PIA) to determine if there are any commonalities in the fingerprints of the substructures of interacting drug and protein molecules and if so, whether or not any patterns can be generalized from them. METHOD: Given a database of drug-protein interactions, D-PIA performs its tasks in several steps. First, for each drug in the database, the fingerprints of its molecular substructures are first obtained. Second, for each protein in the database, the fingerprints of its protein domains are obtained. Third, based on known interactions between drugs and proteins, an interdependency measure between the fingerprint of each drug substructure and protein domain is then computed. Fourth, based on the interdependency measure, drug substructures and protein domains that are significantly interdependent are identified. Fifth, the existence of interaction relationship between a previously unknown drug-protein pairs is then predicted based on their constituent substructures that are significantly interdependent. RESULTS: To evaluate the effectiveness of D-PIA, we have tested it with real drug-protein interaction data. D-PIA has been tested with real drug-protein interaction data including enzymes, ion channels, and protein-coupled receptors. Experimental results show that there are indeed patterns that one can discover in the interdependency relationship between drug substructures and protein domains of interacting drugs and proteins. Based on these relationships, a testing set of drug-protein data are used to see if D-PIA can correctly predict the existence of interaction between drug-protein pairs. The results show that the prediction accuracy can be very high. An AUC score of a ROC plot could reach as high as 75% which shows the effectiveness of this classifier. CONCLUSIONS: D-PIA has the advantage that it is able to perform its tasks effectively based on the fingerprints of drug and protein molecules without requiring any 3D information about their structures and D-PIA is therefore very fast to compute. D-PIA has been tested with real drug-protein interaction data and experimental results show that it can be very useful for predicting previously unknown drug-protein as well as protein-ligand interactions. It can also be used to tackle problems such as ligand specificity which is related directly and indirectly to drug design and discovery.

EvoMD: an algorithm for evolutionary molecular design.

Traditionally, Computer-Aided Molecular Design (CAMD) uses heuristic search and mathematical programming to tackle the molecular design problem. But these techniques do not handle large and nonlinear search space very well. To overcome these drawbacks, graph-based evolutionary algorithms (EAs) have been proposed to evolve molecular design by mimicking chemical reactions on the exchange of chemical bonds and components between molecules. For these EAs to perform their tasks, known molecular components, which can serve as building blocks for the molecules to be designed, and known chemical rules, which govern chemical combination between different components, have to be introduced before the evolutionary process can take place. To automate molecular design without these constraints, this paper proposes an EA called Evolutionary Algorithm for Molecular Design (EvoMD). EvoMD encodes molecular designs in graphs. It uses a novel crossover operator which does not require known chemistry rules known in advanced and it uses a set of novel mutation operators. EvoMD uses atomics-based and fragment-based approaches to handle different size of molecule, and the value of the fitness function it uses is made to depend on the property descriptors of the design encoded in a molecular graph. It has been tested with different data sets and has been shown to be very promising.