Rescue of cardiac dysfunction during chemotherapy in acute myeloid leukaemia by blocking IL-1α.

BACKGROUND AND AIMS: Patients with acute myeloid leukaemia (AML) suffer from severe myocardial injury during daunorubicin (DNR)-based chemotherapy and are at high risk of cardiac mortality. The crosstalk between tumour cells and cardiomyocytes might play an important role in chemotherapy-related cardiotoxicity, but this has yet to be demonstrated. This study aimed to identify its underlying mechanism and explore potential therapeutic targets. METHODS: Cardiac tissues were harvested from an AML patient after DNR-based chemotherapy and were subjected to single-nucleus RNA sequencing. Cardiac metabolism and function were evaluated in AML mice after DNR treatment by using positron emission tomography, magnetic resonance imaging, and stable-isotope tracing metabolomics. Plasma cytokines were screened in AML mice after DNR treatment. Genetically modified mice and cell lines were used to validate the central role of the identified cytokine and explore its downstream effectors. RESULTS: In the AML patient, disruption of cardiac metabolic homeostasis was associated with heart dysfunction after DNR-based chemotherapy. In AML mice, cardiac fatty acid utilization was attenuated, resulting in cardiac dysfunction after DNR treatment, but these phenotypes were not observed in similarly treated tumour-free mice. Furthermore, tumour cell-derived interleukin (IL)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1α neutralizing antibody could improve cardiac functions in AML mice after DNR treatment. CONCLUSIONS: This study revealed that crosstalk between tumour cells and cardiomyocytes during chemotherapy could disturb cardiac energy metabolism and impair heart function. IL-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients.

Effects of trimetazidine on cardiac function in adult cyanotic congenital heart disease patients: Protocol for a 3-month multicenter, randomized, double-blind controlled trial.

BACKGROUND: Nearly 20% Patients with cyanotic congenital heart disease (CCHD) are not able to receive surgery. These patients experience a decline in cardiac function as they age, which has been demonstrated to be associated with changes in energy metabolism in cardiomyocytes. Trimetazidine (TMZ), a metabolic regulator, is supposed to alleviate such maladaptation and reserve cardiac function in CCHD patients. METHODS: This is a randomized, double-blind, placebo-controlled clinical trial. Eighty adult CCHD patients will be recruited and randomized to the TMZ (20 mg TMZ 3 times a day for 3 months) or placebo group (placebo 3 times a day for 3 months). The primary outcome is the difference in cardiac ejection fractions (EF) measured by cardiac magnetic resonance (MRI) between baseline and after 3 months of TMZ treatment. The secondary outcomes include TMZ serum concentration, rate of cardiac events, NYHA grading, fingertip SpO2, NT-proBNP levels, 6-minute walking test (6MWT), KCCQ-CSS questionnaire score, echocardiography, ECG, routine blood examination, liver and kidney function test, blood pressure and heart rate. DISCUSSION: This trial is designed to explore whether the application of TMZ in adult CCHD patients can improve cardiac function, reduce cardiac events, and improve exercise performance and quality of life. The results will provide targeted drug therapy for CCHD patients with hypoxia and support the application of TMZ in children with CCHD.

Molecular phylogeny of Hesperiidae (Lepidoptera) with an emphasis on Asian and African genera.

Despite considerable research efforts in recent years, the deeper phylogenetic relationships among skipper butterflies (Hesperiidae) remain unresolved. This is primarily because of limited sampling, especially within Asian and African lineages. In this study, we consolidated previous data and extensively sampled Asian and African taxa to elucidate the phylogenetic relationships within Hesperiidae. The molecular dataset comprised sequences from two mitochondrial and two nuclear gene regions from 563 species that represented 353 genera. Our analyses revealed seven subfamilies within Hesperiidae: Coeliadinae, Euschemoninae, Eudaminae, Pyrginae, Heteropterinae, Trapezitinae, and Hesperiinae. The systematics of most tribes and genera aligned with those of prior studies. However, notable differences were observed in several tribes and genera. Overall, the position of taxa assigned to incertae sedis in Hesperiinae is largely clarified in this study. Our results strongly support the monophyly of the tribe Tagiadini (Pyrginae), and the systematics of some genera are clarified with comprehensive discussion. We recognize 15 tribes within the subfamily Hesperiinae. Of these, nine tribes are discussed in detail: Aeromachini, Astictopterini, Erionotini, Unkanini (new status), Ancistroidini, Ismini (confirmed status), Plastingini (new status), Gretnini (confirmed status), and Eetionini (confirmed status). We propose four subtribes within Astictopterini: Hypoleucina subtrib.n., Aclerosina, Cupithina, and Astictopterina. Furthermore, we describe a new genus (Hyarotoidesgen.n.) and reinstate two genera (Zeareinst.stat. and Separeinst.stat.) as valid. Additionally, we propose several new combinations: Zea mythecacomb.n.,Sepa bononiacomb.n. & reinst.stat., and Sepa umbrosacomb.n. This study, with extensive sampling of Asian and African taxa, greatly enhances the understanding of the knowledge of the skipper tree of life.

Ginsenoside Rg3 exhibits anti-catabolic and anti-apoptotic effects in IL-1ß treated human disc nucleus pulposus cells and in a rat model of disc degeneration by inactivating the MAPK pathway.

Intervertebral disc degeneration (IDD) is the major cause of degeneration of joint diseases. IDD is characterized by a large number of apoptosis of nucleus pulposus cells (NPCs) and extracellular matrix (ECM) degradation. Ginsenoside Rg3 is the active component extracted from ginseng and has a vital function in modulating diseases. This study aimed to investigate the regulatory functions of ginsenoside Rg3 in IDD. We established the IDD cell model via inducing NPCs with IL-1ß. The rat model of IDD was established by fibrous ring puncture method. Cell apoptotic capability was assessed through TUNEL assay. The levels of catabolic proteases MMPs and ADAMTSs were tested by western blot and RT-qPCR. IL-1ß induction notably promoted the apoptosis of NPCs, while ginsenoside Rg3 treatment reversed the promoting function of IL-1ß. Furthermore, we found that MMP2, MMP3, Adamts4, and Adamts5 levels were increased in IL-1ß-induced NPCs, while ginsenoside Rg3 treatment markedly reduced their levels. Additionally, ginsenoside Rg3 was found to suppress the IL-1ß-stimulated p38 MAPK pathway in NPCs. In the IDD rat model, we found that ginsenoside Rg3 treatment can alleviate NPC degeneration, recover the arrangement of annulus fibrous, and preserve more proteoglycan matrix. Moreover, ginsenoside Rg3 reduced apoptosis and catabolism and inactivated the p38 MAPK pathway in IDD rats. Ginsenoside Rg3 exhibits anti-catabolic and anti-apoptotic effects in IL-1ß-stimulated NPCs and IDD rats by inactivating MAPK pathway.

Using Arterial Pulse and Laser Doppler Analyses to Discriminate between the Cardiovascular Effects of Different Running Levels.

BACKGROUND AND AIMS: Running can induce advantageous cardiovascular effects such as improved arterial stiffness and blood-supply perfusion. However, the differences between the vascular and blood-flow perfusion conditions under different levels of endurance-running performance remains unclear. The present study aimed to assess the vascular and blood-flow perfusion conditions among 3 groups (44 male volunteers) according to the time taken to run 3 km: Level 1, Level 2, and Level 3. METHODS: The radial blood pressure waveform (BPW), finger photoplethygraphy (PPG), and skin-surface laser-Doppler flowmetry (LDF) signals of the subjects were measured. Frequency-domain analysis was applied to BPW and PPG signals; time- and frequency-domain analyses were applied to LDF signals. RESULTS: Pulse waveform and LDF indices differed significantly among the three groups. These could be used to evaluate the advantageous cardiovascular effects provided by long-term endurance-running training, such as vessel relaxation (pulse waveform indices), improvement in blood supply perfusion (LDF indices), and changes in cardiovascular regulation activities (pulse and LDF variability indices). Using the relative changes in pulse-effect indices, we achieved almost perfect discrimination between Level 3 and Level 2 (AUC = 0.878). Furthermore, the present pulse waveform analysis could also be used to discriminate between the Level-1 and Level-2 groups. CONCLUSIONS: The present findings contribute to the development of a noninvasive, easy-to-use, and objective evaluation technique for the cardiovascular benefits of prolonged endurance-running training.

Sodium butyrate inhibits aerobic glycolysis of hepatocellular carcinoma cells via the c-myc/hexokinase 2 pathway.

Aerobic glycolysis is a well-known hallmark of hepatocellular carcinoma (HCC). Hence, targeting the key enzymes of this pathway is considered a novel approach to HCC treatment. The effects of sodium butyrate (NaBu), a sodium salt of the short-chain fatty acid butyrate, on aerobic glycolysis in HCC cells and the underlying mechanism are unknown. In the present study, data obtained from cell lines with mouse xenograft model revealed that NaBu inhibited aerobic glycolysis in the HCC cells in vivo and in vitro. NaBu induced apoptosis while inhibiting the proliferation of the HCC cells in vivo and in vitro. Furthermore, the compound inhibited the release of lactate and glucose consumption in the HCC cells in vitro and inhibited the production of lactate in vivo. The modulatory effects of NaBu on glycolysis, proliferation and apoptosis were related to its modulation of hexokinase 2 (HK2). NaBu downregulated HK2 expression via c-myc signalling. The upregulation of glycolysis in the HCC cells induced by sorafenib was impeded by NaBu, thereby enhancing the anti-HCC effect of sorafenib in vitro and in vivo. Thus, NaBu inhibits the expression of HK2 to downregulate aerobic glycolysis and the proliferation of HCC cells and induces their apoptosis via the c-myc pathway.

Out of Asia: Intercontinental dispersals after the Eocene-Oligocene transition shaped the zoogeography of Limenitidinae butterflies (Lepidoptera: Nymphalidae).

Most members of the nymphalid subfamily Limenitidinae are distributed in tropical regions of Africa, Asia, and the Americas. Previous studies have inferred their higher-level phylogeny and found that Southeast Asia seems to be the center of origin, with numerous dispersal events to other continents. However, the complete biogeographic history of Limenitidinae butterflies is still largely unknown. We sampled 181 taxa from 164 species and used a metagenomic method to obtain 40 genes (mitogenomes and three nuclear ribosomal loci) for inferring the historical biogeography of the group. We find that Limenitidinae originated in eastern Asia during the early Eocene (ca. 52 Ma) and started to diversify and disperse into Africa before the end of Eocene. Intercontinental exchanges between Africa and eastern Asia continued in the early Miocene: Asian Adoliadini and Asian endemic taxa Bhagadatta had African origins in the Oligocene, whereas African Neptini dispersed in the opposite direction from Asia in the early Miocene. In addition, ancestors of the tribes Limenitidini and Adoliadini dispersed into the Neotropics and Australasia multiple times during the early-to-middle Miocene. Eastern Asia is the center of origin of the tribe Limenitidini, with several taxa disjunctly distributed in eastern Asia and the Americas. Our work provides a robust phylogenetic hypothesis of relationships in the tribe Limenitidini and suggests that the alala-species group of Adelpha should be placed in the genus Limenitis. Renamed taxa comb. nov. based on our findings are listed in the text.

Cordycepin Protects against Hepatic Ischemia/Reperfusion Injury via Inhibiting MAPK/NF-κB Pathway.

Hepatic ischemia/reperfusion injury (HIRI) is a common complication of liver surgery requiring hepatic disconnection, such as hepatectomy and liver transplantation. The aim of this study was to investigate the effects of cordycepin on HIRI and to elucidate the underlying mechanisms. Balb/c mice were randomly divided into six groups: a normal control group, sham group, H-cordycepin group, HIRI group, L-cordycepin (25 mg/kg) + HIRI group, and H-cordycepin (50 mg/kg) + HIRI group. Mice were subjected to I/R, and cordycepin was intragastrically administered for seven consecutive days before surgery. Orbital blood and liver specimens were collected at 6 and 24 h after HIRI. Serum levels of ALT and AST were decreased in the cordycepin pretreatment groups. Notably, cordycepin attenuated the inflammatory response and the production of proapoptosis proteins, while increasing expression of antiapoptosis proteins and decreasing expression of autophagy-linked proteins. Furthermore, cordycepin inhibited activation of the MAPK/NF-κB signaling pathway. Collectively, these results indicate that cordycepin pretreatment ameliorated hepatocyte injury caused by HIRI. As compared with the HIRI group, cordycepin pretreatment mitigated the inflammatory response and inhibited apoptosis and autophagy via regulation of the MAPK/NF-κB signaling pathway.

Machine-Learning Classification of Pulse Waveform Quality.

Pulse measurements made using wearable devices can aid the monitoring of human physiological condition. Accurate estimation of waveforms is often difficult for nonexperts; motion artifacts may occur during tonometry measurements when the skin-sensor contact pressure is insufficient. An alternative approach is to extract only high-quality pulses for use in index calculations. The present study aimed to determine the effectiveness of using machine-learning analysis in discriminating between high-quality and low-quality pulse waveforms induced by applying different contact pressures. Radial blood pressure waveform (BPW) signals were measured noninvasively in healthy young subjects using a strain-gauge transducer. One-minute-long trains of pulse data were measured when applying the appropriate contact pressure (67.80 ± 1.55 mmHg) and a higher contact pressure (151.80 ± 3.19 mmHg). Eight machine-learning algorithms were employed to evaluate the following 40 harmonic pulse indices: amplitude proportions and their coefficients of variation and phase angles and their standard deviations. Significant differences were noted in BPW indices between applying appropriate and higher skin-surface contact pressures. The present appropriate contact pressure could not only provide a suitable holding force for the wearable device but also helped to maintain the physiological stability of the underlying tissues. Machine-learning analysis provides an effective method for distinguishing between the high-quality and low-quality pulses with excellent discrimination performance (leave-one-subject-out test: random-forest AUC = 0.96). This approach will aid the development of an automatic screening method for waveform quality and thereby improve the noninvasive acquisition reliability. Other possible interfering factors in practical applications can also be systematically studied using a similar procedure.

Relationship between ideal cardiovascular health metrics and hearing loss: A 10-year retrospective cohort study.

OBJECTIVE: The role of ideal cardiovascular health (CVH) metrics in developing hearing loss remains uncertain. Thus, our objective was to analyse the connection between hearing loss and ideal CVH metrics in a 10-year retrospective cohort. STUDY DESIGN: Retrospective cohort study. SETTING: A health management centre in Taiwan. PARTICIPANTS: Participants who underwent the first annual health check-up between 2000 and 2006 and with a follow-up check-up more than ten years later. MAIN OUTCOME MEASURES: Hearing thresholds were measured at 500 Hz, 1000 Hz, 2000 Hz and 4000 Hz. Individuals with a best ear pure-tone audiometry four-frequency average of >25 dB HL were defined as having hearing loss. The ideal CVH metrics were classified into 7 categories based on the American Heart Association's definition. The associations of hearing loss with the sum of the ideal CVH metrics and each ideal CVH metric were examined by multiple logistic regression analysis. RESULTS: The present study consisted of 6974 participants. The 10-year follow-up showed that the odds ratio (OR) of hearing loss was .74 for participants with 5-7 ideal CVH metrics (95% CI, .59-.93, p = .01) compared with those with 0-2 ideal CVH metrics. Among the CVH metrics, participants with an ideal smoking status might have reduced odds of developing hearing loss; the OR was .72 (95% CI, .58-.89, p = .003). CONCLUSIONS: Participants with an increased number of ideal CVH metrics and better performance on the smoking metric had a significantly protective effect regarding hearing loss development.

A novel autophagy-related lncRNA survival model for lung adenocarcinoma.

Long non-coding RNA (lncRNA) is an important regulatory factor in the development of lung adenocarcinoma, which is related to the control of autophagy. LncRNA can also be used as a biomarker of prognosis in patients with lung adenocarcinoma. Therefore, it is important to determine the prognostic value of autophagy-related lncRNA in lung adenocarcinoma. In this study, autophagy-related mRNAs-lncRNAs were screened from lung adenocarcinoma and a co-expression network of autophagy-related mRNAs-lncRNAs was constructed by using The Cancer Genome Atlas (TCGA). The univariate and multivariate Cox proportional hazard analyses were used to evaluate the prognostic value of the autophagy-related lncRNAs and finally obtained a survival model composed of 11 autophagy-related lncRNAs. Through Kaplan-Meier analysis, univariate and multivariate Cox regression analysis and time-dependent receiver operating characteristic (ROC) curve analysis, it was further verified that the survival model was a new independent prognostic factor for patients with lung adenocarcinoma. In addition, based on the survival model, gene set enrichment analysis (GSEA) was used to illustrate the function of genes in low-risk and high-risk groups. These 11 lncRNAs were GAS6-AS1, AC106047.1, AC010980.2, AL034397.3, NKILA, AL606489.1, HLA-DQB1-AS1, LINC01116, LINC01806, FAM83A-AS1 and AC090559.1. The hazard ratio (HR) of the risk score was 1.256 (1.196-1.320) (P < .001) in univariate Cox regression analysis and 1.215 (1.149-1.286) (P < .001) in multivariate Cox regression analysis. And the AUC value of the risk score was 0.809. The 11 autophagy-related lncRNA survival models had important predictive value for the prognosis of lung adenocarcinoma and may become clinical autophagy-related therapeutic targets.

IRF1 as a potential biomarker in Mycobacterium tuberculosis infection.

Pulmonary tuberculosis (PTB) is a major global public health problem. The purpose of this study was to find biomarkers that can be used to diagnose tuberculosis. We used four NCBI GEO data sets to conduct analysis. Among the four data sets, GSE139825 is lung tissue microarray, and GSE83456, GSE19491 and GSE50834 are blood microarray. The differential genes of GSE139825 and GSE83456 were 68 and 226, and intersection genes were 11. Gene ontology (GO) analyses of 11 intersection genes revealed that the changes were mostly enriched in regulation of leucocyte cell-cell adhesion and regulation of T-cell activation. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEGs revealed that the host response in TB strongly involves cytokine-cytokine receptor interactions and folate biosynthesis. In order to further narrow the range of biomarkers, we used protein-protein interaction to establish a hub gene network of two data sets and a network of 11 candidate genes. Eventually, IRF1 was selected as a biomarker. As validation, IRF1 levels were shown to be up-regulated in patients with TB relative to healthy controls in data sets GSE19491 and GSE50834. Additionally, IRF1 levels were measured in the new patient samples using ELISA. IRF1 was seen to be significantly up-regulated in patients with TB compared with healthy controls with an AUC of 0.801. These results collectively indicate that IRF1 could serve as a new biomarker for the diagnosis of pulmonary tuberculosis.

Identification and phylogenetic analysis of five Crataegus species (Rosaceae) based on complete chloroplast genomes.

MAIN CONCLUSION: The chloroplast genomes of the five Crataegus species were shown to have a conserved genome structure. Complete chloroplast genome sequences were more suitable than highly variable regions for the identification and phylogenetic analysis of Crataegus species. Hawthorn, which is commonly used as a traditional Chinese medicine, is one of the most popular sour fruits and has high economic value. Crataegus pinnatifida var. pinnatifida and C. pinnatifida var. major are frequently adulterated with other Crataegus species on the herbal medicine market. However, most Crataegus plants are difficult to identify using traditional morphological methods. Here, we compared five Crataegus chloroplast (CP) genomes comprising two newly sequenced (i.e., C. pinnatifida var. pinnatifida and C. pinnatifida var. major) and three previously published CP genomes. The CP genomes of the five Crataegus species had a conserved genome structure, gene content and codon usage. The total length of the CP genomes was 159,654-159,865 bp. A total of 129-130 genes, including 84-85 protein-coding genes, 37 tRNA genes and 8 rRNA genes, were annotated. Bioinformatics analysis revealed 96-103 simple sequence repeats (SSRs) and 48-70 long repeats in the five CP genomes. Combining the results of mVISTA and nucleotide diversity, five highly variable regions were screened for species identification and relationship studies. Maximum likelihood trees were constructed on the basis of complete CP genome sequences and highly variable regions. The results showed that the former had higher discriminatory power for Crataegus species, indicating that the complete CP genome could be used as a super-barcode to accurately authenticate the five Crataegus species.

Associations between different measurements of sarcopenic obesity and health outcomes among non-frail community-dwelling older adults in Taiwan.

The most important issue for the clinical application of sarcopenic obesity (SO) is the lack of a consensus definition. The aim of the present study was to determine the best measurement for SO by estimating the association between various definitions and the risk of falls and metabolic syndrome (MS). We studied a community of 765 adults aged 65 years and older in 2015-2017. Sarcopenia obesity was measured by sarcopenia (defined by low muscle mass with either low handgrip strength or low gait speed or both) plus obesity (defined by waist circumference, body fat percentage and BMI). The MS was defined according to the National Cholesterol Education Program ATP III. Logistic regression models were constructed to examine the relationships between sarcopenia obesity and risk of fall and MS. In the analysis of the fall risk with SO defined by waist circumference, the participants with non-sarcopenia/non-obesity were treated as the reference group. The OR to fall in participants with SO was 10·16 (95 % CI 2·71, 38·13) after adjusting for confounding covariates. In the analysis of the risk of the MS between participants with individual components of sarcopenia coupled with obesity defined by waist circumference, the risk was statistically significant for low gait speed (OR: 7·19; 95 % CI 3·61, 14·30) and low grip strength (OR: 9·19; 95 % CI 5·00, 16·91). A combination of low grip strength and abdominal obesity for identifying SO may be a more precise and practical method for predicting target populations with unfavourable health risks, such as falls risk and MS.

Fucoidan and Fucoxanthin Attenuate Hepatic Steatosis and Inflammation of NAFLD through Modulation of Leptin/Adiponectin Axis.

Non-alcoholic fatty liver disease (NAFLD) is the emerging cause of chronic liver disease globally and lack of approved therapies. Here, we investigated the feasibility of combinatorial effects of low molecular weight fucoidan and high stability fucoxanthin (LMF-HSFx) as a therapeutic approach against NAFLD. We evaluated the inhibitory effects of LMF-HSFx or placebo in 42 NAFLD patients for 24 weeks and related mechanism in high fat diet (HFD) mice model and HepaRGTM cell line. We found that LMF-HSFx reduces the relative values of alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride, fasting blood glucose and hemoglobin A1c in NAFLD patients. For lipid metabolism, LMF-HSFx reduces the scores of controlled attenuation parameter (CAP) and increases adiponectin and leptin expression. Interestingly, it reduces liver fibrosis in NAFLD patients, either. The proinflammatory cytokines interleukin (IL)-6 and interferon-γ are reduced in LMF-HSFx group. In HFD mice, LMF-HSFx attenuates hepatic lipotoxicity and modulates adipogenesis. Additionally, LMF-HSFx modulates SIRI-PGC-1 pathway in HepaRG cells under palmitic acid-induced lipotoxicity environment. Here, we describe that LMF-HSFx ameliorated hepatic steatosis, inflammation, fibrosis and insulin resistance in NAFLD patients. LMF-HSFx may modulate leptin-adiponectin axis in adipocytes and hepatocytes, then regulate lipid and glycogen metabolism, decrease insulin resistance and is against NAFLD.

Hypermethylation of SHISA3 DNA as a blood-based biomarker for colorectal cancer.

In Taiwan, colorectal cancer (CRC) is the second most common cancer and the cancer with the third highest mortality rate. This may be because of the difficulty of detecting the disease in the early stages, as well as the fact that colonoscopy, a typical method used in screening for CRC, causes discomfort to the recipient and is prone to technical interference. For the earlier detection of CRC, finding an easier screening method with a simpler collection procedure is essential. Thus, in the present study, plasma samples from patients with CRC were analyzed to determine the extent of methylation in SHISA3 DNA. Studies have suggested that SHISA3, a newly identified tumor suppressor, can regulate tumor growth, and that the inactivation of its DNA can be traced to epigenomic alterations in CRC. Another study reported the presence of hypermethylated SHISA3 DNA in CRC biopsy specimens. In the present study, the plasma of 30 patients with CRC and nine healthy controls was collected and analyzed for the concentration of cell-free DNA through bisulfite sequencing. The methylation rates were determined. Our results have shown that an increasing amount of cell-free DNA in the group of CRC patient's plasma compared to the healthy group. Moreover, patients with later stages of CRC had higher concentrations of cell-free DNA. Notably, the methylation rate of SHISA3 was higher in the plasma of the CRC group than in that of the healthy group. The results indicated that the presence of tumor cells does not reduce the degree of SHISA3 DNA in the peripheral blood of patients with CRC. In other words, the hypermethylation of SHISA3, which inactivates the gene, is a potential cause of tumorigenesis. Furthermore, the methylation rate of SHISA3 DNA was higher in the plasma of patients with stage II CRC than in that of those with stage I CRC. In conclusion, the combination of conventional testing and screening for SHISA3 hypermethylation in plasma could improve the rate at which CRC is detected.

Therapeutic potential of PPARγ natural agonists in liver diseases.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a vital subtype of the PPAR family. The biological functions are complex and diverse. PPARγ plays a significant role in protecting the liver from inflammation, oxidation, fibrosis, fatty liver and tumours. Natural products are a promising pool for drug discovery, and enormous research effort has been invested in exploring the PPARγ-activating potential of natural products. In this manuscript, we will review the research progress of PPARγ agonists from natural products in recent years and probe into the application potential and prospects of PPARγ natural agonists in the therapy of various liver diseases, including inflammation, hepatic fibrosis, non-alcoholic fatty liver and liver cancer.

TGF-ß/Smad and JAK/STAT pathways are involved in the anti-fibrotic effects of propylene glycol alginate sodium sulphate on hepatic fibrosis.

Liver fibrosis, a consequence of unhealthy modern lifestyles, has a growing impact on human health, particularly in developed countries. Here, we have explored the anti-fibrotic effects of propylene glycol alginate sodium sulphate (PSS), a natural extract from brown algae, in fibrotic mice and cell models. Thus, we established bile duct ligature and carbon tetrachloride mouse models and LX-2 cell models with or without PSS treatment. Liver pathological sections and the relevant indicators in serum and liver tissues were examined. PSS prevented hepatic injury and fibrosis to a significant extent, and induced up-regulation of matrix metalloproteinase-2 and down-regulation of tissue inhibitor of metalloproteinase-1 through suppressing the transforming growth factor ß1 (TGF-ß1)/Smad pathway. PSS additionally exerted an anti-autophagy effect through suppressing the Janus kinase (JAK) 2/transducer and activator of transcription 3 (STAT3) pathway. In conclusion, PSS prevents hepatic fibrosis by suppressing inflammation, promoting extracellular matrix (ECM) decomposition and inactivating hepatic stellate cells through mechanisms involving the TGF-ß1/Smad2/3 and JAK2/STAT3 pathways in vivo and in vitro.

Platelet-derived growth factor-AA is a substantial factor in the ability of adipose-derived stem cells and endothelial progenitor cells to enhance wound healing.

Nonhealing wounds with various forms of complications have been a major challenge for patients with different diseases, and few data are available regarding the clinical significance of platelet-derived growth factor-AA (PDGF-AA) in the enhanced wound healing with stem cells, and the precise molecular mechanism remains unclear. The study aims to investigate the role of PDGF-AA in adipose-derived stem cells (ASCs) and endothelial progenitor cells (EPCs) enhancing wound healing. In this study, ASCs and EPCs were applied to treat wounds in an animal wound model with a wound-healing assay. We knocked down PDGF-AA expression in ASCs using the PDGF-AA short hairpin RNA technique and investigated the related molecular mechanism. The wound model and wound-healing assay of the study showed that transplantation of ASCs could enhance wound healing. The results showed that the PDGF-AA knockdown ASC group had much less improvement of wound healing than other groups treated with wild-type ASCs in wound tissues. The regulation of PDGF-AA in ASCs may contribute to improve wound healing through the PI3K/Akt/eNOS signaling pathway. The data indicated that PDGF-AA might play a vital role in ASCs and EPCs enhancing wound healing, possibly by its effects on angiogenesis. It would be a potential approach using PDGF-AA for clinical treatment of chronic wounds.-Wu, L.-W., Chen, W.-L., Huang, S.-M., Chan, J. Y.-H. Platelet-derived growth factor AA is a substantial factor in the ability of adipose-derived stem cells and endothelial progenitor cells to enhance wound healing.

Procyanidin B2 inhibits the activation of hepatic stellate cells and angiogenesis via the Hedgehog pathway during liver fibrosis.

BACKGROUND: Liver fibrosis is a wound-healing process of liver featured by the over-deposition of extracellular matrix (ECM) and angiogenesis. However, the effective treatment is lacking. Procyanidin B2 (PB2) is a flavonoid extract abundant in grape seeds with anti-oxidant, anti-inflammatory and anti-cancer properties. The present study aimed to determine effects of PB2 on liver fibrosis. METHOD: The CCl4-induced mouse liver fibrosis model and a human hepatic stellate cell (HSC) line (LX2 cells) were used to study the activation, ECM production and angiogenesis of HSCs through Western blotting analysis, immunohistochemistry, immunofluorescence staining, flow cytometry and tubulogenesis assay. A Hedgehog (Hh) pathway inhibitor (cyclopamine) and Smoothened agonist (SAG) were used to investigate the role of PB2 on Hh pathway. RESULTS: The results showed that PB2 could inhibit the proliferation and induce apoptosis of HSCs. PB2 could also down-regulate the expressions of VEGF-A, HIF-1α, α-SMA, Col-1 and TGF-ß1 of HSCs in vivo and in vitro. The application of SAG and cyclopamine proved that PB2 targets on Hh pathway. CONCLUSIONS: PB2 inhibited the Hh pathway to suppress the activation, ECM production and angiogenesis of HSCs, therefore reverses the progression of liver fibrosis in vivo and in vitro.