The Role of the Dysregulated JNK Signaling Pathway in the Pathogenesis of Human Diseases and Its Potential Therapeutic Strategies: A Comprehensive Review.

JNK is named after c-Jun N-terminal kinase, as it is responsible for phosphorylating c-Jun. As a member of the mitogen-activated protein kinase (MAPK) family, JNK is also known as stress-activated kinase (SAPK) because it can be activated by extracellular stresses including growth factor, UV irradiation, and virus infection. Functionally, JNK regulates various cell behaviors such as cell differentiation, proliferation, survival, and metabolic reprogramming. Dysregulated JNK signaling contributes to several types of human diseases. Although the role of the JNK pathway in a single disease has been summarized in several previous publications, a comprehensive review of its role in multiple kinds of human diseases is missing. In this review, we begin by introducing the landmark discoveries, structures, tissue expression, and activation mechanisms of the JNK pathway. Next, we come to the focus of this work: a comprehensive summary of the role of the deregulated JNK pathway in multiple kinds of diseases. Beyond that, we also discuss the current strategies for targeting the JNK pathway for therapeutic intervention and summarize the application of JNK inhibitors as well as several challenges now faced. We expect that this review can provide a more comprehensive insight into the critical role of the JNK pathway in the pathogenesis of human diseases and hope that it also provides important clues for ameliorating disease conditions.

Image characteristics and main types of abnormal branching of fetal pulmonary artery in prenatal echocardiography - a retrospective study.

OBJECTIVES: To explore the image characteristics and main types of abnormal branching of fetal pulmonary artery in prenatal echocardiography. MATERIAL AND METHODS: A retrospective analysis of 41 cases diagnosed with abnormal branching of fetal pulmonary artery by prenatal echocardiography was made. The image characteristics of the abnormalities, their combination with intra- or extra-cardiac malformations and chromosomal anomalies were analyzed. RESULTS: The results of prenatal echocardiography showed that, among the 41 cases, 1) 4 cases were with anomalous origin of single pulmonary artery, 8 cases with pulmonary artery agenesis, 9 cases with pulmonary artery sling; 20 cases with crossed pulmonary arteries. 2) 11 cases were complicated with intracardiac malformations and 10 with extracardiac malformations. 3) Only 7 case underwent chromosomal examination and 1 tested abnormal. 4) Pregnancy outcomes: 25 fetuses were born and their abnormalities confirmed by echocardiography (MRI or surgery) to be consistent with prenatal ultrasound diagnosis; 16 cases had their pregnancy terminated due to their combination with other severe malformations, which were confirmed by pathological anatomy after induced abortion. CONCLUSIONS: Prenatal echocardiography can provide detailed images for the diagnosis of abnormal branching of fetal pulmonary artery, which can be complicated by intra- and extracardiac malformations and chromosomal anomalies and should be alerted.

Effects of Tuina on newborns with jaundice: A meta-analysis.

BACKGROUND: The impact of Tuina on neonatal jaundice is not yet comprehensively understood, and its clinical application is rather limited. This study systematically assessed the relevant literature and conducted a meta-analysis to study the influence of Tuina on neonatal jaundice and provide convincing clinical evidence for promoting its clinical application. METHODS: We searched Pubmed, Embase, Cochrane Library, CNKI, Wanfang, CQVIP, and CBM from the establishment of the database up to July 2021. Studies that are randomized controlled trials were included. However, duplicate publications; manuscripts with no full text, incomplete information, or inability to extract data; animal experiments; and reviews and systematic reviews were excluded. STATA 15.1 was used to analyze the data. RESULTS: The pooled results showed that compared with the treatment of neonatal jaundice solely with blue light, Tuina combined with blue light significantly improved the total effective rate and frequency of defecation on days 1, 2, 3, 4, and 5 and significantly decreased the traditional Chinese medicine syndrome score; the third serum total bilirubin on days 3, 4, and 7; and duration of jaundice. Moreover, the incidence of adverse events in neonatal jaundice treated with Tuina combined with blue light was significantly lower than that with blue light alone. CONCLUSION: Tuina combined with blue light for treating neonatal jaundice can increase the effect of clinical treatment and reduce the adverse events caused by blue light therapy. Thus, the clinical application of traditional Chinese medicine Tuina in neonatal jaundice should be further promoted.

Characteristics of the gut microbiota in pregnant women with fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR) in utero leads to failure of fetus to reach the genetically normal growth potential. Currently available means of treating FGR are limited. And it remains unknown how pregnant women who give birth to FGR fetus differ in gut microbiota composition from normal pregnant women. METHODS: In this case-control study, fecal samples were obtained from maternal rectum in the operation room by an obstetrician under strict aseptic conditions. We compared gut microbiota of 14 pregnant women with FGR and 18 normal controls by performing 16S rDNA amplicon sequencing. RESULTS: We identified significant differences in ß-diversity between the FGR and control groups (P < 0.05). At genus level, Bacteroides, Faecalibacterium and Lachnospira were highly abundant in the FGR subjects, which are significantly enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to glycometabolism. CONCLUSION: These findings demonstrated that the distinct composition of the gut microbiota between FGR and normal pregnant women could contribute to an improved understanding of the prevention and treatment of FGR.

Combination of DESI2 and endostatin gene therapy significantly improves antitumor efficacy by accumulating DNA lesions, inducing apoptosis and inhibiting angiogenesis.

DESI2 is a novel pro-apoptotic gene. We previously reported that DESI2 overexpression induces S phase arrest and apoptosis by activating checkpoint kinases. This work was to test whether the combination of endostatin, an endogenous antiangiogenic inhibitor, with DESI2 could improve the therapy efficacy in vitro and in vivo. The recombinant plasmid co-expressing DESI2 and endostatin was encapsulated with DOTAP/Cholesterol cationic liposome. Mice bearing CT26 colon carcinoma and LL2 lung cancer were treated with the DNA-liposome complex. We found that, in vitro, the combination of DESI2 and endostatin more efficiently inhibited proliferation of CT26, LL2, HCT116 and A549 cancer cells via apoptosis, as assessed by MTT assay, colony-formation assays, flow cytometric analysis, hoechst staining and activation of caspase-3, respectively. In addition, DESI2 overexpression caused up-regulation of RPS7, a substrate of DESI2 deubiquitination. Furthermore, siRNA targeting RPS7 partially abrogated, whereas RPS7 overexpression enhanced DESI2-induced inhibition of cell proliferation. Importantly, the combination also caused DNA lesions accumulation, which further promotes apoptosis. Mechanistic rationale suggested that endostatin first inhibits DNA-PKcs kinase, and partly abrogated DESI2-induced phosphorylation of DNA-PKcs, leading to increase of DNA damage, then contributes to DESI2-induced apoptosis. In vivo, the combined gene therapy more significantly inhibited tumor growth and efficiently prolonged the survival of tumor bearing mice than mono therapy. The improved antitumor effect was associated with inhibition of cell proliferation via apoptosis, as analyzed by TUNEL assay and PCNA immunostaining. The combination also inhibited angiogenesis, as assessed by alginate-encapsulated tumor cell assay and CD31 staining. Our data suggest that the combined gene therapy of DESI2 and endostatin can significantly enhance the antitumor activity as a DNA lesions accumulator, apoptosis inducer and angiogenesis inhibitor. The present study may provide a novel method for the treatment of cancer.

ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin.

PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects. We found that KU-60019 preferentially sensitizes PTEN-deficient MDA-MB-468 breast cancer cells to cisplatin, though it also slightly enhances sensitivity of PTEN wild-type breast cancer cells. The increased cytotoxic sensitivity is associated with apoptosis, as evidenced by flow cytometry and PARP cleavage. Additionally, the increase of DNA damage accumulation due to the decreased capability of DNA repair, as indicated by γ-H2AX and Rad51 foci, also contributed to this selective cytotoxicity. Mechanistically, compared with PTEN wild-type MDA-MB-231 cells, PTEN-deficient MDA-MB-468 cells have lower level of Rad51, higher ATM kinase activity, and display the elevated level of DNA damage. Moreover, these differences could be further enlarged by cisplatin. Our findings suggest that ATM is a promising target for PTEN-defective breast cancer.

Combination of DESI2 and IP10 gene therapy significantly improves therapeutic efficacy against murine carcinoma.

DESI2 (also known as PNAS-4) is a novel pro-apoptotic gene activated during the early response to DNA damage. We previously reported that overexpression of DESI2 induces S phase arrest and apoptosis by activating checkpoint kinases. The present study was designed to test whether combination of DESI2 and IP10 could improve the therapy efficacy in vitro and in vivo. The recombinant plasmid co-expressing DESI2 and IP10 was encapsulated with DOTAP/Cholesterol nanoparticle. Immunocompetent mice bearing CT26 colon carcinoma and LL2 lung cancer were treated with the complex. We found that, in vitro, the combination of DESI2 and IP10 more efficiently inhibited proliferation of CT26, LL2, SKOV3 and A549 cancer cells via apoptosis. In vivo, the combined gene therapy more significantly inhibited tumor growth and efficiently prolonged the survival of tumor bearing mice. Mechanistically, the augmented antitumor activity in vivo was associated with induction of apoptosis and inhibition of angiogenesis. The anti-angiogenesis was further mimicked by inhibiting proliferation of immortalized HUVEC cells in vitro. Meanwhile, the infiltration of lymphocytes also contributed to the enhanced antitumor effects. Depletion of CD8+ T lymphocytes significantly abrogated the antitumor activity, whereas depletion of CD4+ T cells or NK cells showed partial abrogation. Our data suggest that the combined gene therapy of DESI2 and IP10 can significantly enhance the antitumor activity as apoptosis inducer, angiogenesis inhibitor and immune response initiator. The present study may provide a novel and effective method for treating cancer.

Alcohol exposure leads to unrecoverable cardiovascular defects along with edema and motor function changes in developing zebrafish larvae.

Maternal alcohol consumption during pregnancy can cause a series of developmental disorders in the fetus called FAS (fetal alcohol syndrome). In the present study we exposed zebrafish embryos to 1% and 2% alcohol and observed the morphology of heart and blood vessels during and after exposure to investigate motor function alterations, and damage and recovery to the cardiovascular system. The results showed that alcohol exposure could induce heart deformation, slower heart rate, and incomplete blood vessels and pericardium. After stopping exposure, larvae exposed to 1% alcohol could recover only in heart morphology, but larvae in 2% alcohol could not recover either morphology or function of cardiovascular system. The edema-like characteristics in the 2% alcohol group became more conspicuous afterwards, with destruction in the dorsal aorta, coarctation in segmental arteries and a decrease in motor function, implying more serious unrecoverable cardiovascular defects in the 2% group. The damaged blood vessels in the 2% alcohol group resulted in an alteration in permeability and a decrease of blood volume, which were the causes of edema in pathology. These findings contribute towards a better understanding of ethanol-induced cardiovascular abnormalities and co-syndrome in patients with FAS, and warns against excessive maternal alcohol consumption during pregnancy.