Selpercatinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß1 signaling pathway.

IPF is a chronic, progressive, interstitial lung disease with high mortality. Current drugs have limited efficacy in curbing disease progression and improving quality of life. Selpercatinib, a highly selective inhibitor of receptor tyrosine kinase RET (rearranged during transfection), was approved in 2020 for the treatment of a variety of solid tumors with RET mutations. In this study, the action and mechanism of Selpercatinib in pulmonary fibrosis were evaluated in vivo and in vitro. In vivo experiments demonstrated that Selpercatinib significantly ameliorated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro, Selpercatinib inhibited the proliferation, migration, activation and extracellular matrix deposition of fibroblasts by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathway, and suppressed epithelial-mesenchymal transition (EMT) like process of lung epithelial cells via inhibiting TGF-ß1/Smad pathway. The results of in vivo pharmacological tests corroborated the results obtained from the in vitro experiments. Further studies revealed that Selpercatinib inhibited abnormal phenotypes of lung fibroblasts and epithelial cells in part by regulating its target RET. In short, Selpercatinib inhibited the activation of fibroblasts and EMT-like process of lung epithelial cells by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathways, thus alleviating BLM-induced pulmonary fibrosis in mice.

A Multiplanar Radiomics Model Based on Cranial Ultrasound to Predict the White Matter Injury in Premature Infants and an Analysis of its Correlation With Neurodevelopment.

OBJECTIVES: To develop and evaluate a multiplanar radiomics model based on cranial ultrasound (CUS) to predict white matter injury (WMI) in premature infants and explore its correlation with neurodevelopment. METHODS: We retrospectively reviewed 267 premature infants. The radiomics features were extracted from five standard sections of CUS. The Spearman's correlation coefficient combined with the least absolute shrinkage and selection operator (LASSO) was applied to select features and build radiomics signature, and a multiplanar radiomics model was constructed based on the radiomics signature of five planes. The performance of the model was evaluated using the area under the receiver operating characteristic curve (AUC). Infants with WMI were re-examined by ultrasound at 2 and 4 weeks after birth, and the recovery degree of WMI was evaluated using multiplanar radiomics. The relationship between WMI and the recovery degree and neurodevelopment was analyzed. RESULTS: The AUC of the multiplanar radiomics in the training and validation sets were 0.94 and 0.91, respectively. The neurodevelopmental function scores in infants with WMI were significantly lower than those in healthy preterm infants and full-term newborns (P < .001). There were statistically significant differences in the neurodevelopmental function scores of infants between the 2- and 4-week lesion disappearance and 4-week lesion persistence (P < .001). CONCLUSIONS: The multiplanar radiomics model showed a good performance in predicting the WMI of premature infants. It can not only provide objective and accurate results but also dynamically monitor the degree of recovery of WMI to predict the prognosis of premature infants.

Zanubrutinib Ameliorates Cardiac Fibrosis and Inflammation Induced by Chronic Sympathetic Activation.

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which have now become a severe public health problem worldwide. ß-Adrenergic receptor (ß-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous research has demonstrated that Bruton's tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-ß related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by ß-AR overactivation; (2) Methods: In vivo: Male C57BL/6J mice were treated with or without the ß-AR agonist isoproterenol (ISO) to establish a cardiac fibrosis animal model; (3) Results: In vivo: Results showed that the BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by ß-AR. In vitro: Results showed that ZB alleviated ß-AR-induced cardiac fibroblast activation and macrophage pro-inflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited ß-AR-induced cardiac fibrosis and inflammation by the BTK, STAT3, NF-κB, and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates ß-AR-induced cardiac fibrosis and inflammation.

The Cropping Obstacle of Garlic Was Associated With Changes in Soil Physicochemical Properties, Enzymatic Activities and Bacterial and Fungal Communities.

Aims: In garlic cultivation, long-time monoculture has resulted in continuous-cropping obstacles. However, the cause has not been studied to date. Methods: We analyzed soils from garlic fields in Pengzhou, China, to determine continuous-cropping obstacle related changes in soil physicochemical properties and enzyme activities, and in the diversity and composition of bacterial and fungal communities. Furthermore, we examined the relationships between soil properties and the bacterial and fungal communities. Results: The soil pH and the soil catalase, urease, invertase, and polyphenol oxidase activities were lower in the cropping obstacle soil than in the healthy control soil. The richness and diversity of the bacteria were lower in the cropping obstacle soil than in the control. The bacterial and fungal communities in the cropping obstacle soil were clearly different from those in the control soil. The differences in bacterial communities between the cropping obstacle soil and the control soil were associated with differences in pH and available potassium content. The taxa with higher relative abundances in the cropping obstacle soils included potential plant pathogens and the taxa with lower relative abundances included potential plant growth promoters. Conclusion: The enrichment of plant pathogens and the depletion of plant growth promoting fungi may have contributed to the poor growth of garlic in the cropping obstacle soil. The enzyme activity and microbial community differences were associated with acidification that was likely an important factor in the deterioration of the soil ecological environment and the garlic cropping obstacle. The results provide information to guide agricultural practices in cultivating garlic.

Lycopene, polyphenols and antioxidant activities of three characteristic tomato cultivars subjected to two drying methods.

The aim of this study was to evaluate the effects of freeze drying and oven drying on appearance, chemical components and antioxidant activities of three cultivars of tomatoes. This study showed cultivar 18,131 would provide the highest phenolic contents and ABTS radical scavenging activity, and cultivar 1862 provide the highest lycopene content after oven drying. On the basis of appearance and contents of polyphenols, freeze drying showed better results. However, oven drying was found superior in decreasing degradation of lycopene. The effects of drying on the polyphenol contents varied depending on the cultivars. In addition, there is no significant difference of antioxidant activities between freeze dried and oven dried tomatoes. These results also demonstrated that freeze drying is superior in maintaining physical structure and phenolic contents of tomato slices. However, oven drying is a viable option for drying tomatoes considering both costing and contents of lycopene.

Potential Drug Targets Against Hepatitis B Virus Based on Both Virus and Host Factors.

BACKGROUND: Hepatitis B is a very harmful and epidemic disease caused by hepatitis B virus (HBV). Although an effective anti-HBV vaccine is available, chronic infection poses still a huge health burden in the whole world. The present anti-HBV drugs including nucleoside analogues and interferonalpha have their limitations without exception. There is no effective drug and therapeutic method that can really and truly cure hepatitis B so far. The variability of HBV genome results in that a significant number of patients develop drug resistance during the long-term use of anti-HBV drugs. Hence, it is urgently needed to discover novel targets and develop new drugs against hepatitis B. OBJECTIVE: The review aims to provide the theory support for designing of the anti-HBV innovative drugs by offering a summary of the current situation of antiviral potential targets. RESULTS AND CONCLUSION: Since HBV is obligate intracellular parasite, and as such it depends on host cellular components and functions to replicate itself. The targeting both virus and host might be a novel therapeutic option for hepatitis B. Accordingly, we analyse the advances in the study of the potential drug targets for anti-HBV infection, focusing on targeting virus genome, on targeting host cellular functions and on targeting virus-host proteins interactions, respectively. Meanwhile, the immune targets against chronic hepatitis B are also emphasized. In short, the review provides a summary of antiviral therapeutic strategies to target virus factors, host factors and immune factors for future designing of the innovative drug against HBV infection.

Comparison of Pathogenicity between PR8F and Different Mutants on the NS1 Locus in Mice.

The aim of this study was to explore the influence of mutation of different non-structural (NS) 1 amino-acid residues on the pathogenicity of influenza viruses and the function of NS1 virulence-related sites on the pathogenesis of influenza viruses. We analyzed segments of the NS1 protein gene and key sites related to virulence of influenza viruses based on a literature review. Fragments of the NS1 gene were cloned from the HIN1 subtype PR8F (non-mutated) and preserved by our research team with encoding sequence site-specific mutagenesis at aa42, aa8l, and aa149. Via a reverse genetics system, we rescued the mutant strains PR8F-42, PR8F-81, and PR8F-149, which were inoculated into chick embryos and could replicate stably after five passages. Efficiency of viral replication was measured by testing hemagglutination titers. BALB/c mice were inoculated With mutated or non-mutated PR8F (10(6) TCIDO(50)/100 µl for each mouse), respectively. The typical clinical manifestations (weight change and survival) were recorded. Autopsies, as well as observations of the pathologic features and pulmonary-tissue slices of mice that died after inoculation, were done. RNA of mouse lungs was extracted, and the residual quantity of virus in lungs was detected by quantitative polymerase chain reaction (qPCR). Results showed that mutation of NS1 at aa42 from Ser to Pro did not change the pathogenicity of PR8F in mice, but a low pathogenicity of PR8F occurred after mutation of NS1 at aa8l and aa149. The present study lays the foundation for further investigations of the function of NS1 pathogenicity-related sites in the pathogenesis of influenza viruses.

High expression of prostate tumor overexpressed 1 (PTOV1) is a potential prognostic biomarker for cervical cancer.

BACKGROUND: To investigate the role of prostate tumor overexpressed 1 (PTOV1) in the development and progression of human cervical cancer. METHODS: Real-time quantitative PCR, Western blot, and immunohistochemistry were used to explore PTOV1 expression in cervical cancer tissues and cell lines. Cell proliferation capability was examined by MTT assay. Statistical analyzes were applied to evaluate the correlation of PTOV1 expression with clinical parameters and prognosis. RESULTS: The expression level of PTOV1 was markedly higher in cervical cancer tissues and cell lines than that in adjacent noncancerous tissues and the normal cervical epithelial cells. PTOV1 overexpression was correlated with higher tumor stage (P = 0.001), larger tumor size (P = 0.004), and lymph node involvement (P = 0.036). Moreover, patients with high PTOV1 expression showed shorter overall and recurrence-free survival time (P = 0.013 and P = 0.010, respectively). PTOV1 knockdown by short hairpin RNAi inhibited cancer cell growth in vitro. CONCLUSION: PTOV1 may be an important factor associated with proliferation of cervical cancer.

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling.

AIM: Accumulating evidence shows that lipopolysaccharides (LPS) derived from gut gram-negative bacteria can be absorbed, leading to endotoxemia that triggers systemic inflammation and insulin resistance. In this study we examined whether metformin attenuated endotoxemia, thus improving insulin signaling in high-fat diet fed mice. METHODS: Mice were fed a high-fat diet for 18 weeks to induce insulin resistance. One group of the mice was treated with oral metformin (100 mg·kg(-1)·d(-1)) for 4 weeks. Another group was treated with LPS (50 µg·kg(-1)·d(-1), sc) for 5 days followed by the oral metformin for 10 d. Other two groups received a combination of antibiotics for 7 d or a combination of antibiotics for 7 d followed by the oral metformin for 4 weeks, respectively. Glucose metabolism and insulin signaling in liver and muscle were evaluated, the abundance of gut bacteria, gut permeability and serum LPS levels were measured. RESULTS: In high-fat fed mice, metformin restored the tight junction protein occludin-1 levels in gut, reversed the elevated gut permeability and serum LPS levels, and increased the abundance of beneficial bacteria Lactobacillus and Akkermansia muciniphila. Metformin also increased PKB Ser473 and AMPK T172 phosphorylation, decreased MDA contents and redox-sensitive PTEN protein levels, activated the anti-oxidative Nrf2 system, and increased IκBα in liver and muscle of the mice. Treatment with exogenous LPS abolished the beneficial effects of metformin on glucose metabolism, insulin signaling and oxidative stress in liver and muscle of the mice. Treatment with antibiotics alone produced similar effects as metformin did. Furthermore, the beneficial effects of antibiotics were addictive to those of metformin. CONCLUSION: Metformin administration attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which contributes to its anti-diabetic effects.

[Relationship between polymorphism of hypoxia inducible factor-1alpha and cervical cancer in Han population in Sichuan Province of China].

OBJECTIVE: To investigate the relationship between single nucleotide polymorphism (SNP) of hypoxia inducible factor-1alpha (HIF-1alpha) C1772T and genetic susceptibility to and clinical-pathological features of cervical cancers in Han population in Sichuan province of China. METHODS: A case control study was undertaken in Sichuan province of China, with 97 patients with uterine cervical cancer as case group and 117 negative for intraepithelial lesion or malignancy (NILM) patients as control group. Their gene types in HIF-1alpha C1772T were identified with a combination of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The distribution of the frequencies of T/T, T/C and C/C genotypes in the two groups differed significantly (P < 0.01); T allele frequency in the patients with cervical cancer was much higher than that in the controls (P < 0.01). There were no significant differences in the distributions of T/T, T/C and C/C genotypes among cervical cancer patients at different FIGO stages, pathological grading, stromal invasive depth, lymph node metastasis and vascular invasions (P > 0.05). CONCLUSION: T/C and T/T genotypes of HIF-1alpha C1772T are genetic susceptibility factors for cervical cancer in Han population in Sichuan province of China. HIF-1alpha C1772T SNP probably has no relationship with clinical-pathological features of cervical cancer.

[Influences of human beta-defensin 1 on the replication and expression of HPV18 in Hela cell].

OBJECTIVE: Investigate the influences of human beta-defensinl (hbetaD1) on the replication and expression of HPV18 in Hela cell. METHODS: Gene transfection: mediated by Fugen HD, hbetaD1/psectag plasmid was transfected to Hela cell [hbetaD1/psectag : liposome complexes (hbetaD1/psectag : lip)group], and control groups [psectag : liposome complexes(psectag : lip) group and blank group) were also established. After transfection, the expression of the target gene in Hela cell was investigated by the method of immunocytochemistry. 48 h and 72 h after the transfection, the change of the copy number of HPV18 DNA in Hela cell was investigated respectively by the quantitative fluorescent PCR method, and the change of the HPV18 E6 mRNA in Hela cell was evaluated by the semiquantitative RT-PCR. RESULTS: 48 h and 72 h after the transfection of hbetaD1/psectag plasmid to Hela cell, hbetaD1 was expressed in both of the two groups, and the latter showed a tendency of stronger expression. Compared with the control groups, the copy number of HPV18 DNA in Hela cell in the hbetaD1/psectag : lip group increased at 48 h and decreased at 72 h after the transfection, but the change was not statistically significant. 48 h after the transfection, compared with the control groups, the expression of HPV18 E6 mRNA in Hela cell in the hbetaD1/psectag : lip group changed a little; and 72 h after the transfection, the expression level of HPV18 E6 mRNA decreased significantly (P < 0.05). CONCLUSION: hbetaD1 displayed an inhibitory effect to the expression of HPV18 mRNA in Hela cell in a concentration-dependent pattern, but no significant effect on the duplication of HPV18 DNA.

[An exploration of the expression of MK and MVD in cervical cancer tissues before and after NACT].

OBJECTIVE: To investigate the clinical effect of neoadjuvant chemotherapy (NACT) and its influence on the expressions of MK and MVD in cervical cancer cells. METHODS: The expressions of MK, CD34 were determined by immunohistochemistry in 35 cases of cervical cancer before and after NACT. RESULTS: Among the 35 cases treated with NACT, 4 (11.43%) were complete remission (CR), 25 (71.43%) partial remission (PR). The total effective rate of NACT (CR+PR) was 82.86%. The expressions of MK and MVD decreased dramatically after NACT. In cases who reacted positively to NACT, the expression of MK and the level of MVD decreased significantly after the treatment (P<0.05). While in cases who reacted poorly to NACT no such changes were observed in the expression of MK (P>0.05); but the level of MVD also decreased in those cases. CONCLUSION: NACT is an effective treatment for cervical cancer. The expressions of MK and MVD decreased after NACT treatment. It implied that one of the mechanisms of NACT may be the suppression of angiogenesis, and the expression of MK may serve as an indicator for predicting the therapeutic effect of NACT.