The discovery of a novel pyrrolo[2,3-b]pyridine as a selective CDK8 inhibitor offers a new approach against psoriasis.

Currently, the drugs used in clinical to treat psoriasis mainly broadly suppress cellular immunity. However, these drugs can only provide temporary and partial symptom relief, they do not cure the condition and may lead to recurrence or even serious toxic side effects. In this study, we describe the discovery of a novel potent CDK8 inhibitor as a treatment for psoriasis. Through structure-based design, compound 46 was identified as the most promising candidate, exhibiting a strong inhibitory effect on CDK8 (IC50 value of 57 nM) along with favourable inhibition against NF-κB. Additionally, it demonstrated a positive effect in an in vitro psoriasis model induced by TNF-α. Furthermore, this compound enhanced the thermal stability of CDK8 and exerted evident effects on the biological function of CDK8, and it had favourable selectivity across the CDK family and tyrosine kinase. This compound showed no obvious inhibitory effect on CYP450 enzyme. Further studies confirmed that compound 46 exhibited therapeutic effect on IMQ-induced psoriasis, alleviated the inflammatory response in mice, and enhanced the expression of Foxp3 and IL-10 in the dorsal skin in vivo. This discovery provides a new strategy for developing selective CDK8 inhibitors with anti-inflammatory activity for the treatment of psoriasis.

Discovery of novel and potent CDK8 inhibitors for the treatment of acute myeloid leukaemia.

It has been reported that CDK8 plays a key role in acute myeloid leukaemia. Here, a total of 40 compounds were rational designed and synthesised based on the previous SAR. Among them, compound 12 (3-(3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide) showed the most potent inhibiting activity against CDK8 with an IC50 value of 39.2 ± 6.3 nM and anti AML cell proliferation activity (molm-13 GC50 = 0.02 ± 0.01 µM, MV4-11 GC50 = 0.03 ± 0.01 µM). Mechanistic studies revealed that this compound 12 could inhibit the phosphorylation of STAT-1 and STAT-5. Importantly, compound 12 showed relative good bioavailability (F = 38.80%) and low toxicity in vivo. This study has great significance for the discovery of more efficient CDK8 inhibitors and the development of drugs for treating AML in the future.

A new perspective on the current and future development potential of ABCG1.

ABCG1 is an essential protein involved in the efflux of intracellular cholesterol to the extracellular space, thus playing a critical role in reducing cholesterol accumulation in neighboring tissues. Bibliometric analysis pertains to the interdisciplinary field of quantitative examination of diverse documents using mathematical and statistical techniques. It integrates the investigation of structural and temporal patterns in academic publications with an exploration of subject focus and forms of uncertainty. This research paper examines the historical evolution, current areas of interest, and future development trends of ABCG1 through bibliometric analysis. This study aims to offer readers insights into the research status and emerging trends of ABCG1, thereby assisting researchers in the exciting field to explore novel research avenues. Following rigorous selection, research on ABCG1 has remained highly active over the past two decades. ABCG1 has even started to emerge in previously unrelated fields, such as the field of cancer research. According to the analysis conducted by Citespace, a lot of keywords and influential citations were identified. ABCG1 has been found to establish a connection between cancer and cardiovascular disease, highlighting their interrelationship. This review aims to assist readers who have limited familiarity with ABCG1 research in gaining a rapid understanding of its developmental trajectory. Additionally, it aims to offer researchers potential areas of focus for future studies related to ABCG1.

Correlation of Coagulation Dysfunction with Infection and Hypercapnia in Acute Exacerbation of COPD Patients.

Background: This study aims to explore the factors influencing the coagulation function of patients with chronic obstructive pulmonary disease (COPD) and its effects on thrombosis. Methods: A total of 155 COPD patients, including 118 patients with acute exacerbation of COPD (AECOPD) and 37 patients with stable COPD (SCOPD), were enrolled in this study. Meanwhile, 50 patients with gastrointestinal polyps found during physical examination and treated with surgery in the same period were enrolled as the control group. The basic data, routine blood tests, C-reactive protein (CRP), procalcitonin (PCT), and coagulation indexes of the three groups were collected, as well as arterial blood gas indexes of AECOPD patients. Results: The differences in erythrocyte count and hemoglobin among groups were not statistically significant. Compared with the SCOPD group and control group, white blood cell (WBC), neutrophil percentage, PCT, CRP, prothrombin time (PT), and fibrinogen (FIB) in the AECOPD group increased significantly, while the international normalized ratio (INR) decreased (P < 0.05). The differences in activated partial thromboplastin time (APTT) and D-dimer among groups were not statistically significant (P > 0.05). Thrombin time (TT) in the AECOPD group was shorter than that of the control group, and PT was longer than that of the SCOPD group (P < 0.05). Five patients with AECOPD and one patient with SCOPD had venous thrombosis. Conclusion: The abnormal coagulation function in AECOPD patients is related to the degree of infection and hypercapnia, which may be a risk factor for thrombosis.

ZY-444 inhibits the growth and metastasis of prostate cancer by targeting TNFAIP3 through TNF signaling pathway.

Prostate cancer is one of the most lethal malignancies, and androgen deprivation therapy remains the mainstay of treatment for prostate cancer patients. Although androgen deprivation can initially come to remission, the disease often develops into castration-resistant prostate cancer (CRPC), which is still dependent on androgen receptor (AR) signaling and is related to a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance uninterrupted emerges, and new therapies are urgently needed. In this study, we identified a potent small molecule compound, ZY-444, that suppressed PCa cells proliferation and metastasis, and inhibited tumor growth both in subcutaneous. Transcriptome sequencing analysis showed that TNFAIP3 was significantly elevated in prostate cancer cells after ZY-444 treatment. Further studies through overexpression of TNFAIP3 confirmed that TNFAIP3, as a direct target gene of ZY-444, contributes to the functions of ZY-444. In addition, we demonstrated the effects of TNFAIP3 on prostate cancer cell apoptosis, migration and proliferation to elucidate the mechanism of ZY-444. We found that TNFAIP3 inhibited the TNF signaling pathway, which could inhibit cell migration and proliferation and contribute to apoptosis. Overall, these findings highlighted TNFAIP3 as a tumor suppressor gene in the regulation of the progression and metastatic potential of prostate cancer and that targeting TNFAIP3 by ZY-444 might be a promising strategy for prostate cancer treatment.

In situ orderly self-assembly strategy affording NIR-II-J-aggregates for in vivo imaging and surgical navigation.

J-aggregation, an effective strategy to extend wavelength, has been considered as a promising method for constructing NIR-II fluorophores. However, due to weak intermolecular interactions, conventional J-aggregates are easily decomposed into monomers in the biological environment. Although adding external carriers could help conventional J-aggregates stabilize, such methods still suffer from high-concentration dependence and are unsuitable for activatable probes design. Besides, these carriers-assisted nanoparticles are risky of disassembly in lipophilic environment. Herein, by fusing the precipitated dye (HPQ) which has orderly self-assembly structure, onto simple hemi-cyanine conjugated system, we construct a series of activatable, high-stability NIR-II-J-aggregates which overcome conventional J-aggregates carrier's dependence and could in situ self-assembly in vivo. Further, we employ the NIR-II-J-aggregates probe HPQ-Zzh-B to achieve the long-term in situ imaging of tumor and precise tumor resection by NIR-II imaging navigation for reducing lung metastasis. We believe this strategy will advance the development of controllable NIR-II-J-aggregates and precise bioimaging in vivo.

Discovery of a novel oral type â CDK8 inhibitor against acute myeloid leukemia.

CDK8 plays a key role in acute myeloid leukemia, colorectal cancer and other cancers. Here, a total of 54 compounds were designed and synthesized. Among them, the most potent one compound 43 (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide), a novel CDK8 Ⅰ inhibitor, showed strong inhibitory activity against CDK8 (IC50 = 51.9 nM), good kinase selectivity, good anti AML cell proliferation activity (molm-13 GC50 = 1.57 ± 0.59 µM) and low toxicity in vivo (acute toxicity: 2000 mg/kg). Further mechanistic studies revealed that this compound could target CDK8 and then phosphorylate STAT-1 and STAT-5 thereby inhibiting of AML cell proliferation. In addition, compound 43 showed relatively good bioavailability (F = 28.00%) and could inhibit the growth of AML tumors in a dose-dependent manner in vivo. This study facilitates the further development of more potent CDK8 inhibitors for the treatment of the AML.

Design and Synthesis of a 2-Amino-pyridine Derivative as a Potent CDK8 Inhibitor for Anti-colorectal Cancer Therapy.

CDK8 is a transcriptional cyclin-dependent kinase and considered as a potential target in colon cancer therapeutics. Here, a novel selective CDK8 inhibitor was identified against colon cancer in vivo. Specifically, based on the structural information of the sorafenib-bound CDK8 structure, a series of novel 2-amino-pyridine derivatives were designed, synthesized, and evaluated. Among them, compound 29 showed strong inhibitory activity against CDK8 with an IC50 value of 46 nM and favorable selectivity. And there is an apparent interaction between the endogenous or overexpressed CDK8 and biotinylated-29. This compound exhibited antiproliferation potency on colon cancer cell lines with a high CDK8 expression level, suppressed the activation of WNT/ß-catenin and transcriptional activity of the TCF family, and induced G1 phase arrested in HCT-116 cells. In addition, this compound showed potent activity against sorafenib-resistant HCT-116 cells. What's more, it exhibited low toxicity and suitable pharmacokinetic (PK) profiles and showed preferable antitumor effects in vivo.

Predictive factors and nomogram to evaluate the risk of below-ankle re-amputation in patients with diabetic foot.

BACKGROUND: Diabetes mellitus, as the most common metabolic disease, is common worldwide and represents a crucial global health concern. The purpose of this research was to investigate the related risk factors and to develop a re-amputation risk nomogram in diabetic patients who have undergone an amputation. METHODS: A observational analysis was performed on 459 patients who have underwent amputation for diabetic foot from January 2014 through December 2019 at the First Affiliated Hospital of Wenzhou Medical University. The least absolute shrinkage and selection operator regression and stepwise regression methods were implemented to determine risk selection for the re-amputation risk model, and the predictive nomogram was established with these features. Calibration curve, receiver operating characteristic curve, and decision curve analysis of this re-amputation nomogram were assessed. RESULTS: Predictors contained in this predictive model included smoking, glycated hemoglobin A1c (HbA1c), ankle-brachial index (ABI) and C-reactive protein (CRP). Good discrimination with a C-index of 0.725 (95% CI, 0.6624-0.7876) and good calibration were displayed with this predictive model. The decision curve analysis showed that this re-amputation nomogram predicting risk adds more benefit than none strategy if the threshold probability of a patient was >6% and <59%. CONCLUSIONS: This novel re-amputation nomogram incorporating smoking, glycated hemoglobin A1c (HbA1c), ankle-brachial index (ABI), C-reactive protein (CRP), and smoking could be easily used to predict individual re-amputation risk prediction in diabetic foot patients who have undergone an amputation. In the future, further analysis and external testing will be needed as much as possible to reconfirm that this new Nomogram can accurately predict the risk of toe re-amputation.

Discovery of the Novel 1H-Pyrrolo[2,3-b]pyridine Derivative as a Potent Type II CDK8 Inhibitor against Colorectal Cancer.

Few targeted drugs were approved for treatment of colorectal cancer (CRC). Cyclin-dependent kinase 8 played a vital role in regulating transcription and was a key colorectal oncogene associated to colorectal cancer. Here, through de novo drug design and in depth structure-activity relationship analysis, title compound 22, (3-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)propenamide), was discovered as a potent type II CDK8 inhibitor, which exhibited potent kinase activity with an IC50 value of 48.6 nM and could significantly inhibit tumor growth in xenografts of CRC in vivo. Further mechanism studies indicated that it could target CDK8 to indirectly inhibit ß-catenin activity, which caused downregulation of the WNT/ß-catenin signal and inducing cell cycle arrest in G2/M and S phases. More importantly, the title compound exhibited low toxicity with good bioavailability (F = 39.8%). These results could provide the reference for design of new type II CDK8 inhibitors against colorectal cancer.

Enhancing the Release Efficiency of a Molecular Chemotherapeutic Prodrug by Photodynamic Therapy.

Tumor-specific, hypoxia-activated prodrugs have been developed to alleviate the side effects of chemotherapy drugs. However, the release efficiency of hypoxia-activated prodrugs is restricted by the degree of tumor hypoxia, which further leads to poor cancer treatment effects. On the other hand, oxygen is consumed gradually in photodynamic therapy (PDT), which aggravates hypoxia at the tumor site. In this study, we combined hypoxia-activated prodrugs with PDT agents to promote the prodrugs release, thereby improving their bioavailability and therapeutic effects. As a proof of concept, a mitochondria-targeted molecular prodrug, CS-P, was designed and synthesized. It can be selectively activated by tumor hypoxia to release chemotherapeutic drugs and photosensitizers, and then further discharge drugs after light irradiation. The design strategy proposed in this paper provides a new idea for enhancing hypoxia-activated prodrug release and real-time monitoring prodrug release.

Discovery of Novel Pterostilbene-Based Derivatives as Potent and Orally Active NLRP3 Inflammasome Inhibitors with Inflammatory Activity for Colitis.

Studies have shown that the abnormal activation of the NLRP3 inflammasome is involved in a variety of inflammatory-based diseases. In this study, a high content screening model targeting the activation of inflammasome was first established and pterostilbene was discovered as the active scaffold. Based on this finding, total of 50 pterostilbene derivatives were then designed and synthesized. Among them, compound 47 was found to be the best one for inhibiting cell pyroptosis [inhibitory rate (IR) = 73.09% at 10 µM], showing low toxicity and high efficiency [against interleukin-1ß (IL-1ß): half-maximal inhibitory concentration (IC50) = 0.56 µM]. Further studies showed that compound 47 affected the assembly of the NLRP3 inflammasomes by targeting NLRP3. The in vivo biological activity showed that this compound significantly alleviated dextran sodium sulfate (DSS)-induced colitis in mice. In general, our study provided a novel lead compound directly targeting the NLRP3 protein, which is worthy of further research and structural optimization.

Circ_0057558 promotes nonalcoholic fatty liver disease by regulating ROCK1/AMPK signaling through targeting miR-206.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver disorders that is featured by the extensive deposition of fat in the hepatocytes. Current treatments are very limited due to its unclear pathogenesis. Here, we investigated the function of circ_0057558 and miR-206 in NAFLD. High-fat diet (HFD) feeding mouse was used as an in vivo NAFLD model and long-chain-free fatty acid (FFA)-treated liver cells were used as an in vitro NAFLD model. qRT-PCR was used to measure levels of miR-206, ROCK1 mRNA, and circ_0057558, while Western blotting was employed to determine protein levels of ROCK1, p-AMPK, AMPK, and lipogenesis-related proteins. Immunohistochemistry were performed to examine ROCK1 level. Oil-Red O staining was used to assess the lipid deposition in cells. ELISA was performed to examine secreted triglyceride (TG) level. Dual-luciferase assay was used to validate interactions of miR-206/ROCK1 and circ_0057558/miR-206. RNA immunoprecipitation was employed to confirm the binding of circ_0057558 with miR-206. Circ_0057558 was elevated while miR-206 was reduced in both in vivo and in vitro NAFLD models. miR-206 directly bound with ROCK1 3'-UTR and suppressed lipogenesis and TG secretion through targeting ROCK1/AMPK signaling. Circ_0057558 directly interacted with miR-206 to disinhibit ROCK1/AMPK signaling. Knockdown of circ_0057558 or overexpression of miR-206 inhibited lipogenesis, TG secretion and expression of lipogenesis-related proteins. ROCK1 knockdown reversed the effects of circ_0057558 overexpression. Injection of miR-206 mimics significantly ameliorated NAFLD progression in vivo. Circ_0057558 acts as a miR-206 sponge to de-repress the ROCK1/AMPK signaling and facilitates lipogenesis and TG secretion, which greatly contributes to NAFLD development and progression.

Effects of a Chinese Patent Medicine Gushen'antai Pills on Ongoing Pregnancy Rate of Hormone Therapy FET Cycles: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

In the past decade, the number of frozen-thawed embryo transfer (FET) has increased dramatically with the expansion of surgical indications and the improvement of freezing related technologies. How to improve the success rate and reduce the adverse effects of FET is our research priorities. This study aimed to investigate the safety and effectiveness of Gushen'antai pills (GSATP) by measuring the ongoing pregnancy rate (OPR) in patients from FET and hormone therapy (HT) cycle. From November 2019 to May 2020, 5 Chinese hospitals conducted a multi-center, randomized, double-blind, placebo-controlled study. In total, 271 HT FET cycles in patients were randomly divided (1:1 ratio) to receive GSATP (6 g, tid) or placebo (6g, tid) for 12 weeks of pregnancy. Patients, clinicians, and researchers were blinded to treatment allocation. The primary endpoint was the OPR at week 12 of pregnancy. The secondary endpoints were vaginal bleeding or brown discharge rate, implantation rate (IR), clinical pregnancy rate (CPR) and abortion rate (AR). Adverse events were recorded during the treatment period. The results showed that the OPR remained higher in the GSATP group when compared to placebo group (56.62% vs. 44.44%, p = 0.045). Vaginal bleeding or brown discharge rate was lower in the GSATP group than the placebo group (10% vs. 23.08%, p = 0.032), while the IR (35.16% vs. 27.64%, p = 0.070), CPR (58.82% vs. 48.15%, p = 0.078), incidence of total adverse events (8.09% vs. 3.22%, p = 0.051) and AR (3.75% vs. 7.69%, p = 0.504) were similar between GSATP and placebo groups. Subgroup analysis showed that there were significant differences in CPR (74.19% vs. 54.17%, p = 0.004) and OPR (72.04% vs. 51.04%, p = 0.003) between GSATP group and Placebo group when the patient was younger than 35 years old. This multi-center, randomized, double-blinded, placebo-controlled clinical study showed for the first evidence that GSATP may have potential to improve the OPR and decrease vaginal bleeding or brown discharge rate in HT FET cycle patients.

[Adenovirus pneumonia with hemophagocytic lymphohistiocytosis in children: a clinical analysis of 7 children].

OBJECTIVE: To study the clinical features of children with adenovirus pneumonia and hemophagocytic lymphohistiocytosis (HLH). METHODS: A retrospective analysis was performed on the mediacal data of 7 children with adenovirus pneumonia and HLH from March to September, 2019. RESULTS: The age of these children ranged from 11 months to 5 years, and among these children, 5 were aged <2 years and 5 were boys. None of these children had underlying diseases. All children were hospitalized due to persistent high fever and cough, and the peak temperature of fever was 39°C to 41°C. With disease progression, 7 children developed hepatomegaly and 6 developed splenomegaly. Routine blood test results showed reductions in two or three lineages of blood cells, with increases in serum ferritin (SF), C-reactive protein (CRP), procalcitonin (PCT), and lactate dehydrogenase (LDH). Phagocytosis of blood cells was observed in 6 children. Radiological examination of lungs showed pneumonia changes. All 7 children were diagnosed with human adenovirus type 7 infection based on pathogenic metagenome detection. No abnormality was found by HLH gene detection and the children were diagnosed with secondary HLH. All children received intravenous immunoglobulin. Among these children, 4 received dexamethasone and etoposide chemotherapy, 3 received dexamethasone alone, and 4 received plasma exchange. Of the 7 children, 2 died and 5 were recovered. Compared with those who survived, the children who died had significantly greater reductions in the three lineages of blood cells and significantly greater increases in serum levels of CRP, PCT, SF, and LDH. CONCLUSIONS: The children with adenovirus pneumonia and HLH have main clinical features of persistent high fever, progressive reductions in two or three lineages of peripheral blood cells, and involvement of other organ systems, including hepatosplenomegaly. Significant increases in serum levels of CRP, PCT, SF, and LDH may suggest a poor prognosis.

Long non-coding RNA small nucleolar RNA host gene 6 aggravates pancreatic cancer through upregulation of far upstream element binding protein 1 by sponging microRNA-26a-5p.

BACKGROUND: Pancreatic cancer (PC) is a highly deadly malignancy with few effective therapies. We aimed to unmask the role that long non-coding RNA small nucleolar RNA host gene 6 (SNHG6) plays in PC cells by targeting far upstream element binding protein 1 (FUBP1) via microRNA-26a-5p (miR-26a-5p). METHODS: SNHG6 expression was predicted by bioinformatics, followed by verification via reverse transcription quantitative polymerase chain reaction. Then, the interactions among SNHG6, miR-26a-5p, and FUBP1 were detected through online software analysis, dual luciferase reporter assay and RNA pull-down. After that, cells were treated with different small interfering RNAs and/or mimic to determine the interactions among SNHG6, miR-26a-5p, and FUBP1 and their roles in PC cells. Finally, the role of SNHG6 in tumor growth in vivo was evaluated by measuring the growth and weight of transplanted tumors in nude mice. A t-test, one-way and two-way analysis of variance were used for data analysis. RESULTS: Compared with that in normal tissues, SNHG6 was highly expressed in PC tissues (1.00 ±â€Š0.05 vs. 1.56 ±â€Š0.06, t = 16.03, P < 0.001). Compared with that in human pancreatic duct epithelial cells (HPDE6-C7), SNHG6 showed the highest expression in PANC-1 cells (1.00 ±â€Š0.06 vs. 3.87 ±â€Š0.13, t = 34.72, P < 0.001) and the lowest expression in human pancreatic cancer cells (MIAPaCa-2) (1.00 ±â€Š0.06 vs. 1.41 ±â€Š0.07, t = 7.70, P = 0.0015). Compared with the levels in the si-negative control group, SNHG6 (0.97 ±â€Š0.05 vs. 0.21 ±â€Š0.06, t = 16.85, P < 0.001), N-cadherin (0.74 ±â€Š0.05 vs. 0.41 ±â€Š0.04, t = 8.93, P < 0.001), Vimentin (0.55 ±â€Š0.04 vs. 0.25 ±â€Š0.03, t = 10.39, P < 0.001), and ß-catenin (0.62 ±â€Š0.05 vs. 0.32 ±â€Š0.03, t = 8.91, P < 0.001) were decreased, while E-cadherin (0.65 ±â€Š0.06 vs. 1.36 ±â€Š0.07, t = 13.34, P < 0.001) was increased after SNHG6 knockdown or miR-26a-5p overexpression, accompanied by inhibited cell proliferation, migration, and invasion. SNHG6 overexpression exerted the opposite effects. SNHG6 upregulated FUBP1 expression by sponging miR-26a-5p. Silencing SNHG6 blocked the growth of PC in vivo. CONCLUSION: Silencing SNHG6 might ameliorate PC through inhibition of FUBP1 by sponging miR-26a-5p, thus providing further supporting evidence for its use in PC treatment.

A general strategy for development of a single benzene fluorophore with full-color-tunable, environmentally insensitive, and two-photon solid-state emission.

We report here a single-benzene based fluorescent framework, amino-terephthalonitrile, denoted SB-Fluor. This scaffold displays versatile emission wavelength tunability via structure modification, covering the full visible light spectrum, both in the solution and solid state. Moreover, one molecule, SBF3, exhibits polymorphism-dependent reversible mechanochromic luminescence.

LncRNA NEAT1 promotes hepatic lipid accumulation via regulating miR-146a-5p/ROCK1 in nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease, which influences the health of people worldwide. However, the specific mechanism of the disease remains unknown, and effective treatments are still lacking. It was reported that Nuclear enriched abundant transcript 1 (NEAT1) obviously was up-regulated in NAFLD model. But the role and underlying mechanism of NEAT1 in NAFLD is unclear. METHODS: HepG2 cells were treated by free fatty acids (FFA) and C57BL/6J mice were treated by high-fat diet to establish NAFLD in vitro and in vivo models, respectively. Cell transfection was applied to regulate the expression of NEAT1, ROCK1, and miR-146a-5p. Western blotting and qRT-PCR were used for measuring expression of protein and mRNA level, respectively. Dual luciferase assay was used to detect the target relationship. Oil Red O staining was used to measure the lipid accumulation. HE staining was used for observing pathological feature of liver tissues. RESULTS: High levels of NEAT1 and ROCK1, and low level of miR-146a-5p were identified in NAFLD models. NEAT1 could target miR-146a-5p to promote ROCK1 expression. Knockdown of NEAT1, overexpression of miR-146a-5p and knockdown of ROCK1 inhibited lipid accumulation through activating AMPK pathway. CONCLUSION: NEAT1 may regulate NAFLD through miR-146a-5p targeting ROCK1, and further affect AMPK/SREBP pathway. This study may provide a new thought for the treatment of NAFLD.

[Clinical and genetic characteristics of a young child with combined pituitary hormone deficiency type I caused by POU1F1 gene variation].

This paper reports the clinical and genetic characteristics of a case of combined pituitary hormone deficiency type I (CPHD1) caused by POU domain, class 1, transcription factor 1 (POU1F1) gene variation. A 2 years and 3 months old girl mainly presented with short stature, special facial features of prominent forehead, enophthalmos, and short mandible, loose skin, central hypothyroidism, complete growth hormone deficiency, and anterior pituitary hypoplasia. Gene analysis identified a novel heterozygous mutation, c.889C>T (p.R297W), in POU1F1 gene, and this locus of her parents was wild-type. This mutation was analyzed as a possible pathogenic variant according to the guidelines of the American College of Medical Genetics and Genomics, which has not been previously reported in the literature and conforms to the autosomal dominant inheritance. This child was diagnosed with CPHD1. Her height increased by 19.8 cm and showed a catch-up growth trend after one year of combined treatment with growth hormone and euthyrox. This study enriches the mutation spectrum of POU1F1 gene and has important significance for the diagnosis and classification of combined pituitary hormone deficiency.

The effect of Jianpi Yangzheng Xiaozheng Decoction and its components on gastric cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Yangzheng Xiaozheng Decoction (JPYZXZ) is an empirical compound prescription based on the theory of traditional Chinese medicine. JPYZXZ, which is "Qi-invigorating, spleen-strengthening and stasis-removing," can improve the quality of life of gastric cancer patients and prolong their survival; however, the exact mechanism underlying the antitumor effects of this compound is still not clear. AIM OF THE STUDY: The aim of this study is to clearly define the effect of JPYZXZ and its components, Jianpi Yangzheng Decoction (JPYZ) and Xiao Zheng San Jie Decoction (XZSJ), on inhibiting the progression of gastric cancer. MATERIALS AND METHODS: The effect of JPYZXZ and its components on the motility of gastric cancer MGC-803 cells was measured by MTT, adhesion, transwell assays and wound-healing assays. JPYZXZ, JPYZ and XZSJ were administered to 615 mice with gastric cancer xenografts, and their effect on the inhibition of subcutaneous transplantation was analyzed. THP-1 monocyte cells were used to establish tumor-associated macrophage (TAM) models. The polarized state of the TAMs was detected by Flow Cytometry, ELISA and Immunohistochemistry. The mRNA and protein expression of tumor epithelial-mesenchymal transition (EMT) and TAM-related genes was determined by Real-time PCR and Western Blot, respectively. RESULTS: We determined that both JPYZXZ and its components inhibited the progress of gastric cancer in vitro, and JPYZXZ was clearly more effective than JPYZ or XZSJ. The in vivo results demonstrated that the JPYZXZ and XZSJ group exhibited a significant decrease in the tumor weight compared to the control group. Further analysis indicated that JPYZXZ was more active than JPYZ or XZSJ in inhibiting the gastric cancer EMT transformation both in vivo and in vitro. However, JPYZ was more effective compared with JPYZXZ for inducing the phenotypic change in macrophages from M2 to M1. CONCLUSIONS: Our results demonstrate that both JPYZXZ and its components prevent the progress of gastric cancer. JPYZXZ inhibits the gastric cancer EMT more effectively than JPYZ and XZSJ, but JPYZ primarily works to regulate the phenotypic change in macrophages from M2 to M1.