Enhancing Pseudomonas syringae pv. Actinidiae sensitivity in kiwifruit by repressing the NBS-LRR genes through miRNA-215-3p and miRNA-29-3p identification.

Kiwifruit bacterial canker, caused by Pseudomonas syringae pv. actinidiae (PSA), poses a grave threat to the global kiwifruit industry. In this study, we examined the role of microRNAs (miRNAs) in kiwifruit's response to PSA. Kiwifruit seedlings subjected to PSA treatment showed significant changes in both miRNA and gene expression compared to the control group. We identified 364 differentially expressed miRNAs (DEMs) and 7170 differentially expressed genes (DEGs). Further analysis revealed 180 miRNAs negatively regulating 641 mRNAs. Notably, two miRNAs from the miRNA482 family, miRNA-215-3p and miRNA-29-3p, were found to increase kiwifruit's sensitivity to PSA when overexpressed. These miRNAs were linked to the regulation of NBS-LRR target genes, shedding light on their role in kiwifruit's defence against PSA. This study offers insights into the miRNA482-NBS-LRR network as a crucial component in enhancing kiwifruit bioresistance to PSA infestation and provides promising candidate genes for further research.

A half sandwich Ru(II)-p-cymene nitrite complex selectively induces cell death in cisplatin-resistant malignant melanoma cells.

The Ru(II)-nitrite complex, Ru4, is explored to release nitric oxide (NO) under acidic conditions and selectively induce a cytotoxic effect towards SK-MEL-28 cisplatin-resistant malignant melanoma cells. These findings suggest that targeting the tumor-associated pHe level could be an effective strategy for the drug function of Ru(II)-nitrite compounds.

Prognostic impact of interstitial lung abnormalities in lung cancer: a systematic review and meta-analysis.

Background: Newly identified as a radiological concept, interstitial lung abnormalities (ILA) is emerging as a prognostic factor for lung cancer. Yet, debates persist regarding the prognostic significance of ILA in lung cancer. Our inaugural meta-analysis aimed to investigate the correlation between ILA and lung cancer outcomes, offering additional insights for clinicians in predicting patient prognosis. Methods: Articles meeting the criteria were found through PubMed, the Cochrane Library, EMBASE, and Web of Science by February 29, 2024. The outcomes evaluated were the survival rates such as overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS). Results: A total of 12 articles with 4416 patients were included in this meta-analysis. The pooled results showed that lung cancer patients with interstitial lung abnormalities had an inferior OS (n=11; HR=2.22; 95% CI=1.68-2.95; P<0.001; I2 = 72.0%; Ph<0.001), PFS (n=3; HR=1.59; 95% CI=1.08-2.32; P=0.017; I2 = 0%; Ph=0.772), and CSS (n=2; HR=4.00; 95% CI=1.94-8.25; P<0.001; I2 = 0%; Ph=0.594) than those without, however, the ILA was not significantly associated with the DFS (n=2; HR=2.07; 95% CI=0.94-7.02; P=0.066; I2 = 90.4%; Ph=0.001). Moreover, lung cancer patients with ILA were significantly correlated with male (OR=2.43; 95% CI=1.48-3.98; P<0.001), smoking history (OR=2.11; 95% CI=1.37-3.25; P<0.001), advanced age (OR=2.50; 95% CI=1.56-4.03; P<0.001), squamous carcinoma (OR=0.42; 95% CI=0.24-0.71; P=0.01), and EGFR mutation (OR=0.50; 95% CI=0.32-0.78; P=0.002). The correlation between ILA and race, stage, ALK, however, was not significant. Conclusion: ILA was a availability factors of prognosis in patients with lung cancers. These findings highlight the importance of early pulmonary fibrosis, namely ILA for prognosis in patients with lung cancer, and provide a partial rationale for future clinical work.

ß-Sitosterol attenuates anlotinib resistance in non-small cell lung cancer cells by inhibiting miR-181a-3p/SHQ1 signaling.

Anlotinib is used for the treatment of advanced non-small cell lung cancer; however, the emergence of drug resistance limits its clinical application. ß-sitosterol may also be used to treat lung cancer, but there have been no studies evaluating ß-sitosterol against anlotinib-resistant lung cancer. The purpose of this study was to determine the mechanism by which ß-sitosterol enhances the sensitivity of lung cancer cells to anlotinib. A549 cells were treated with different concentrations of anlotinib to generate anlotinib-resistant cells (A549/anlotinib cells). miR-181a-3p mimics were transfected into A549/anlotinib cells. A549 and A549/anlotinib cells were treated with ß-sitosterol at various concentrations. The Cell Counting Kit-8 (CCK-8) assay was used to measure cell proliferation. Apoptosis was assessed by flow cytometry. Real-time quantitative PCR was used to measure the expression of miR-181a-3p. The interaction of miR-181a-3p with the H/ACA ribonucleoprotein assembly factor (SHQ1) was predicted using the miRDB and TargetScan Human databases and verified with a luciferase reporter assay. The expression of SHQ1, activating transcription factor 6 (ATF6), and glucose-regulated protein 78 (GRP78) were measured by western blot analysis. ß-Sitosterol effectively suppressed A549/anlotinib cell proliferation and promoted apoptosis. SHQ1 is a downstream target of miR-181a-3p. The expression of miR-181a-3p was inhibited; however, SHQ1 expression was increased by ß-sitosterol treatment of A549/anlotinib cells. The inhibition of SHQ1, ATF6, and GRP78 protein expression by ß-sitosterol in A549/anlotinib cells was rescued by increased miR-181a-3p. ß-Sitosterol markedly promotes anlotinib-resistant A549 cell apoptosis and inhibits cell proliferation by activating SHQ1/UPR signaling through miR-181a-3p inhibition.

Chronic exposure to BDE-47 aggravates acute pancreatitis and chronic pancreatitis by promoting acinar cell apoptosis and inflammation.

The effect of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a persistent environmental pollutant commonly used as a flame retardant in various consumer products, on pancreatitis has not been clearly elucidated, although it has been reported to be toxic to the liver, nervous system, and reproductive system. Acute pancreatitis (AP) and chronic pancreatitis (CP) models were induced in this study by intraperitoneal injection of caerulein. The aim was to investigate the impact of BDE-47 on pancreatitis by exposing the animals to acute (1 week) or chronic (8 weeks) doses of BDE-47 (30 mg/kg in the low-concentration group and 100 mg/kg in the high-concentration group). Additionally, BDE-47 was utilized to stimulate mouse bone marrow-derived macrophages, pancreatic primary stellate cells, and acinar cells in order to investigate the impact of BDE-47 on pancreatitis. In vivo experiments conducted on mice revealed that chronic exposure to BDE-47, rather than acute exposure, exacerbated the histopathological damage of AP and CP, leading to elevated fibrosis in pancreatic tissue and increased infiltration of inflammatory cells in the pancreas. In vitro experiments showed that BDE-47 can promote the expression of the inflammatory cytokines Tnf-α and Il-6 in M1 macrophages, as well as promote acinar cell apoptosis through the activation of the PERK and JNK pathways via endoplasmic reticulum stress. The findings of this study imply chronic exposure to BDE-47 may exacerbate the progression of both AP and CP by inducing acinar cell apoptosis and dysregulating inflammatory responses.

Essential genes analysis reveals small ribosomal subunit protein eS28 may be a prognostic factor and potential vulnerability in osteosarcoma.

Background: Osteosarcoma, the most common primary malignant bone tumor, is currently treated with surgery combined with chemotherapy, but the limited availability of targeted drugs contributes to a poor prognosis. Identifying effective therapeutic targets is crucial for improving the prognosis of osteosarcoma patients. Methods: We screened the DepMap database to identify essential genes as potential therapeutic targets for osteosarcoma. Gene Set Enrichment Analysis (GSEA) was employed to elucidate the biological roles of these essential genes. Promising candidates were filtered through univariate and multivariate Cox analyses, as well as Kaplan-Meier survival analyses using the GSE21257-OSA and TARGET-OSA datasets. The functional role of the target gene was assessed through cell experiments. Additionally, an in situ nude mice model was established to observe the gene's function, and RNA sequencing was utilized to explore the underlying molecular mechanism. Results: A total of 934 essential genes were identified based on their effects (Chronos) using the DepMap database. These genes were primarily enriched in the ribosome pathway according to GSEA analysis. Among them, 195 genes were associated with the ribosome pathway. Rps28, Rps7, and Rps25 were validated as promising candidates following univariate and multivariate Cox analyses of the TARGET-OSA and GSE21257-OSA datasets. Kaplan-Meier survival analyses indicated Rps28 represented an especially promising target, with high expression correlating with poor prognosis. Knockdown of small ribosomal subunit protein eS28, the protein of Rps28, inhibited proliferation, migration, and invasion in both in vitro and in vivo experiments. Silencing RPS28 affected the MAPK signaling pathway in osteosarcoma. Conclusion: In summary, Rps28 has been identified as an essential gene for osteosarcoma cell survival and eS28 may serve as a potential vulnerability in osteosarcoma.

KDM3B Single-Nucleotide Polymorphisms Impact Radiation Therapy Toxicity Through Circular RNA-Mediated KDM3B Expression and Inflammatory Responses.

PURPOSE: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with radiation therapy (RT) toxicities in patients with prostate cancer. SNP rs17599026 in intron 21 of KDM3B is significantly associated with the development of late urinary toxicity, specifically in the increase in urinary frequency 2 years after RT compared with pretreatment conditions. The present study aimed to provide mechanistic insights for this association. METHODS AND MATERIALS: Using human tissues and cell lines, we examined the protein expression of KDM3B and molecular mechanisms underlying the SNP modulation by variants of KDM3B SNP alleles. In animals with normal and heterozygous expressions of Kdm3b, we examined the relationship between Kdm3b expression and radiation toxicity. RESULTS: KDM3B rs17599026 lies in a motif important for circular RNA expression that is responsible for sponging miRNAs to regulate KDM3B expression. Using a murine model with heterozygous deletion of the Kdm3b gene, we found that lower Kdm3b expression is associated with altered pattern of urination after bladder irradiation, which is related to differential degrees of tissue inflammation as measured by analyses of gene expression, lymphocyte infiltration, and noninvasive ultrasound imaging. CONCLUSIONS: KDM3B SNPs can impact its expression through regulating noncoding RNA expression. Differential KDM3B expression underlies radiation toxicity through tissue inflammation at the molecular and physiological level. Our study outcome offers a foundation for mechanism-based mitigation for radiation toxicity for prostate cancer survivors.

[Effect of miR-22 Targeting FMNL2 on Cell Migration and Apoptosis in Childhood Acute Myeloid Leukemia].

OBJECTIVE: To investigate the effect of miR-22 targeting formin-like protein 2 (FMNL2) on the migration and apoptosis of childhood acute myeloid leukemia (AML) cells. METHOD: Peripheral blood samples from 11 children with AML, 10 children with immune thrombocytopenia, human AML cell lines TF-1a, HL-60, THP-1 and human bone marrow stromal cells HS-5 were used as the research objects. UniCel DxH 800 automatic hematology analyzer detected platelet count, hemoglobin, and white blood cell count in peripheral blood samples, and RT-qPCR detected miR-22 expression in peripheral blood samples and AML cells. HL-60 cells were transfected with LipofectamineTM 2000 kit, the experiments were divided into seven groups: blank (no cells transfected), miR-NC, miR-22 mimics, si-NC, si-FMNL2 , miR-22 mimics+OE-NC and miR-22 mimics+OE-FMNL2 . RT-qPCR was used to detect the expression of miR-22 in each group. Transwell was used to detect cell migration. Flow cytometry was used to detect cell apoptosis. Dual-luciferase reporter gene detection experiments verified the targeting relationship between miR-22 and FMNL2 . Western blot was used to detect the expression of FMNL2 protein. RESULTS: Compared with the control group, the number of leukocytes in the peripheral blood of children with AML was significantly increased (P <0.001), while the concentration of hemoglobin and the number of platelets were significantly decreased P <0.001). The expression level of miR-22 in peripheral blood of children with AML was significantly lower than that in control group (P <0.001). Compared with HS-5 cells, the expression levels of miR-22 in TF-1a, HL-60, and THP-1 cells were significantly decreased (P <0.05), and in HL-60 cells was the lowest. Therefore, HL-60 cells were selected for subsequent experiments. Up-regulation of miR-22 or silencing of FMNL2 could reduce the number of migrating cells and increase apoptosis rate (P <0.05). MiR-22 targeted and negatively regulated the expression of FMNL2 . FMNL2 overexpression reversed the effects of up-regulated miR-22 on migration and apoptosis of HL-60 cells. CONCLUSION: MiR-22 can inhibit the migration and promote apoptosis of HL-60 cells by down regulating the expression of FMNL2 .

Mobile Prenatal Education and Its Impact on Reducing Adverse Pregnancy Outcomes: Retrospective Real-World Study.

BACKGROUND: Pregnancy is a pivotal phase in a woman's life, demanding special attention to ensure maternal and fetal health. Prenatal education plays a vital role in promoting healthy pregnancies and reducing adverse outcomes for pregnant women. Mobile prenatal education programs have gained traction due to their accessibility and timeliness, especially in light of finite health care resources and the constraints imposed by the COVID-19 pandemic. OBJECTIVE: This study aims to develop and evaluate the effectiveness of a mobile-based prenatal education program in improving pregnancy outcomes. METHODS: We developed a mobile-based prenatal education curriculum in collaboration with a multidisciplinary maternal care team from Peking Union Medical College Hospital (PUMCH) in Beijing, China. Data were retrospectively collected from 1941 pregnant women who had registered for the PUMCH mobile prenatal education program and subsequently delivered at PUMCH between May 2021 and August 2022. The study compared pregnancy outcomes between the completing group, which were pregnant women who had completed at least 1 course, and the noncompleting group. We also analyzed differences among course topics within the completing group and assessed course topic popularity among pregnant women. RESULTS: The PUMCH mobile prenatal education curriculum consists of 436 courses across 9 topics. Out of the participants, a total of 1521 did not complete any courses, while 420 completed at least 1 course. Compared with the noncompleting group, pregnant women who completed courses exhibited a significant reduction in the risk of gestational diabetes mellitus, induced abortion, postpartum infection, fetal intrauterine distress, and neonatal malformation. Among those in the completing group, a total of 86% (361/420) started course completion during the first and second trimesters. Furthermore, completing courses related to topics of pregnancy psychology and pregnancy nutrition was associated with reduced risks of premature rupture of membranes and small for gestational age infants, respectively. Pregnancy psychology and postpartum recovery were the preferred topics among pregnant women. CONCLUSIONS: The study demonstrates the potential of mobile-based prenatal education programs in improving pregnancy outcomes and supporting health care providers in delivering effective prenatal education. The rise of mobile prenatal education presents an opportunity to improve maternal and child health outcomes. Further research and broader implementation of such programs are warranted to continually improve maternal and child health.

Design, synthesis, and biological evaluation of diaminopyrimidine derivatives as novel focal adhesion kinase inhibitors.

Focal adhesion kinase (FAK) is a cytoplasmic non-receptor protein tyrosine kinase that belongs to the family of focal adhesion complexes and is responsible for the development of various tumors. Herein, 24 diaminopyrimidine derivatives were designed and synthesized based on TAE-226. Several compounds with good activity were further evaluated regarding their antiproliferative activities against two cancer cells with high FAK expression. Compound A12 showed potent anticancer activity against A549 and MDA-MB-231 cell lines with IC50 values of 130 nM and 94 nM, respectively. In vitro metabolic stability and cytochrome P450 (CYP) inhibition assays showed that A12 exhibited favorable stability and weak inhibitory activity on CYP isoforms. Preliminary evaluation of kinase selectivity showed that A12 was a multi-kinase inhibitor. The acute toxicity in vivo indicated that A12 possessed acceptable safety. Compound A12 was also selected for molecular docking studies and the prediction of molecular properties and drug-like properties. These results indicated that compound A12 could be used as a potential lead compound targeting FAK for further development.

Design, synthesis, and biological evaluation of novel pyrimidin-2-amine derivatives as potent PLK4 inhibitors.

Serine/threonine protein kinase PLK4 is a master regulator of centriole duplication, which is significant for maintaining genome integrity. Accordingly, due to the detection of PLK4 overexpression in a variety of cancers, PLK4 has been identified as a candidate anticancer target. Thus, it is a very meaningful to find effective and safe PLK4 inhibitors for the treatment of cancer. However, the reported PLK4 inhibitors are scarce and have potential safety issues. In this study, a series of novel and potent PLK4 inhibitors with an aminopyrimidine core was obtained utilizing the scaffold hopping strategy. The in vitro enzyme activity results showed that compound 8h (PLK4 IC50 = 0.0067 µM) displayed high PLK4 inhibitory activity. In addition, compound 8h exhibited a good plasma stability (t1/2 > 289.1 min), liver microsomal stability (t1/2 > 145 min), and low risk of DDIs. At the cellular level, it presented excellent antiproliferative activity against breast cancer cells. Taken together, these results suggest that compound 8h has potential value in the further research of PLK4-targeted anticancer drugs.

Ginsenoside Rg5 Improves Sleep by Regulating Energy Metabolism in Sleep-Deprived Rats.

Sleep deprivation (SD) has become a universal social problem. There is a causal relationship between SD and energy metabolism disorder. Phytochemicals have been demonstrated to have excellent sleep-promoting effects, and studies have shown that ginsenoside Rg5 (Rg5) exerts sedative and hypnotic effects. The present study aimed to investigate the role of Rg5 in regulating energy metabolism and explore the potential mechanism of improving sleep. Sleep-deprived rats were randomly divided into a control group (Ctrl), SD model group (SD), Rg5 group (GRg5), and melatonin group (MT). Sleep-deprived model rats were generated by housing rats in an SD box for 4 weeks. The Ctrl and SD groups were given equal volumes of saline. The Rg5 groups were given 25[Formula: see text]mg/kg Rg5 or 50[Formula: see text]mg/kg Rg5, and the MT group was given 0.27[Formula: see text]g/kg MT. A Western blot analysis and ELISA were used to detect the metabolic levels, mitochondrial functional proteins, AMPK pathway proteins, clock-related proteins, adenosine receptors, and neurotransmitter receptors. The results showed that Rg5 corrected abnormal glucose and lipid metabolism as well as improved ATP levels. In addition, Rg5 alleviated mitochondrial structural damage and improved the expression of proteins involved in mitochondrial biosynthesis, fission, and fusion. Moreover, Rg5 improved the expression of AMPK/PGC-1/Nrf-1 pathway proteins, regulated mitochondrial biological functions, and affected the rhythm characteristics of circadian clock-related proteins. Further, Rg5 improved the expression of A1R and A[Formula: see text]R as well as regulated the expression levels of GABAA1[Formula: see text] and mGluR5 to improve sleep in SD rats.

Circ-RAPGEF5 promotes intrahepatic cholangiocarcinoma progression by stabilizing SAE1 to facilitate SUMOylation.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with a poor prognosis. The underlying functions and mechanisms of circular RNA and SUMOylation in the development of ICC remain poorly understood. METHODS: Circular RNA hsa_circ_0001681 (termed Circ-RAPGEF5 hereafter) was identified by circular RNA sequencing from 19 pairs of ICC and adjacent tissue samples. The biological function of Circ-RAPGEF5 in tumor proliferation and metastasis was examined by a series of in vitro assays. A preclinical model was used to validate the therapeutic effect of targeting Circ-RAPGEF5. RNA pull-down and dual-luciferase reporter assays were used to access the RNA interactions. Western blot and Co-IP assays were used to detect SUMOylation levels. RESULTS: Circ-RAPGEF5, which is generated from exons 2 to 6 of the host gene RAPGEF5, was upregulated in ICC. In vitro and in vivo assays showed that Circ-RAPGEF5 promoted ICC tumor proliferation and metastasis, and inhibited apoptosis. Additionally, high Circ-RAPGEF5 expression was significantly correlated with a poor prognosis. Further investigation showed that SAE1, a potential target of Circ-RAPGEF5, was also associated with poor oncological outcomes. RNA pull-down and dual-luciferase reporter assays showed an interaction of miR-3185 with Circ-RAPGEF5 and SAE1. Co-IP and western blot assays showed that Circ-RAPGEF5 is capable of regulating SUMOylation. CONCLUSION: Circ-RAPGEF5 promotes ICC tumor progression and SUMOylation by acting as a sponge for miR-3185 to stabilize SAE1. Targeting Circ-RAPGEF5 or SAE1 might be a novel diagnostic and therapeutic strategy in ICC.

Panax quinquefolius polysaccharides ameliorate ulcerative colitis in mice induced by dextran sulfate sodium.

This study aimed to investigate the ameliorative effect of the polysaccharides of Panax quinquefolius (WQP) on ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in mice and to explore its mechanism. Male C57BL/6J mice were randomly divided into the control group (C), model group (DSS), positive control mesalazine (100 mg/kg, Y) group, and low (50 mg/kg, L), medium (100 mg/kg, M) and high dose (200 mg/kg, H) of WQP groups. The UC model was induced by free drinking water with 2.5% DSS for 7 days. During the experiment, the general condition of the mice was observed, and the disease activity index (DAI) was scored. The conventional HE staining was used to observe pathological changes in mice's colon, and the ELISA method was used to detect the levels of interleukin-6 (IL-6), IL-4, IL-8, IL-10, IL-1ß and tumor necrosis factor-α (TNF-α) in mice's colon. The changes in gut microbiota in mice were detected by high-throughput sequencing; the concentration of short-chain fatty acids (SCFAs) was determined by gas chromatography; the expression of related proteins was detected by Western blot. Compared with the DSS group, the WQP group showed a significantly lower DAI score of mice and an alleviated colon tissue injury. In the middle- and high-dose polysaccharides groups, the levels of pro-inflammatory cytokines IL-6, IL-8, IL-1ß and TNF-α in the colonic tissue were significantly decreased (P<0.05), while the levels of IL-4 and IL-10 were significantly increased (P<0.05). The 16S rRNA gene sequencing results showed that different doses of WQP could regulate the composition and diversity of gut microbiota and improve its structure. Specifically, at the phylum level, group H showed an increased relative abundance of Bacteroidetes and a decreased relative abundance of Firmicutes compared with the DSS group, which was closer to the case in group C. At the family level, the relative abundance of Rikenellaceae in L, M and H groups increased significantly, close to that in group C. At the genus level, the relative abundance of Bacteroides, Shigella and Oscillospira in the H group increased significantly, while that of Lactobacillus and Prevotella decreased significantly. The high-dose WQP group could significantly increase the contents of acetic acid, propionic acid, butyric acid, and total SCFAs. Different doses of WQP also increased the expression levels of tight junction proteins ZO-1, Occludin and Claudin-1. To sum up, WQP can regulate the gut microbiota structure of UC mice, accelerate the recovery of gut microbiota, and increase the content of Faecal SCFAs and the expression level of tight junction proteins in UC mice. This study can provide new ideas for the treatment and prevention of UC and theoretical references for the application of WQP.

Ellagic acid inhibits the formation of hypertrophic scars by suppressing TGF-ß/Smad signaling pathway activity.

Hypertrophic scar (HS) is a benign fibroproliferative skin disease, which lacks the ideal treatment and drugs. Ellagic acid (EA) is a natural polyphenol that prevents fibroblasts from proliferating and migrating. This study aimed to determine the role of EA in HS formation and its possible mechanism by in vitro experiments. HS fibroblasts (HSFs) and normal fibroblasts (NFs) were separated from HS tissue and normal skin tissue, respectively. HSFs were treated with 10 and 50 µM EA to assess their effect on HS formation. In particular, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and scratch assay were used to detect the viability and migration ability of HSFs. Quantitative reverse transcriptase real-time polymerase chain reaction was used to measure the mRNA expression level of basic fibroblast growth factor (bFGF), extracellular matrix (ECM)-related gene collagen-I (COL-I), and fibronectin 1 (FN1) in HSFs. Finally, Western blot was utilized to measure the expression level of TGF-ß/Smad signaling pathway-related proteins in HSFs. The viability of HSFs was significantly increased compared with NFs. 10 and 50 µM EA treatment markedly inhibition the cell viability and migration of HSFs. EA treatment upregulated the bFGF expression level and downregulated the COL-I and FN1 expression level in HSFs. In addition, p-Smad2, p-Smad3, and transforming growth factor (TGF)-ß1 expression levels as well as p-Smad2/Smad2 and p-Smad3/Smad3 ratios remarkably decreased in HSFs after EA treatment. EA inhibited the formation of HSs by suppressing the viability and migration of HSFs and ECM deposition as well as by preventing the activation of TGF-ß/Smad signaling.

Discovery of the First Potent, Selective, and In Vivo Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of TRIM37-Amplified Breast Cancer.

Polo-like kinase 4 (PLK4) is a master regulator of centriole replication and has been proposed as a therapeutic target for multiple cancers, especially TRIM37-amplified breast cancer. The development of novel and effective therapeutic strategies for TRIM37-amplified breast cancer therapy is challenging and extremely desirable. Herein, a structure-activity relationship (SAR) study with an emphasis on exploring different linker lengths and compositions was performed to report the discovery and characterization of SP27 as the first selective PLK4 proteolysis targeting chimera (PROTAC) degrader. SP27 exhibited effective PLK4 degradation, more potent inhibition of cell growth, and more efficient precision-therapeutic effect in the TRIM37-amplified MCF-7 cell line than conventional inhibitor CZS-035. Moreover, SP27 showed 149% bioavailability after intraperitoneal administration in PK studies and potent antitumor efficacy in vivo. The discovery of SP27 demonstrated the practicality and importance of PLK4 PROTAC and paved the way for studying PLK4-dependent biological functions and treat TRIM37-amplified breast cancer.

American ginseng with different processing methods ameliorate immunosuppression induced by cyclophosphamide in mice via the MAPK signaling pathways.

This study aimed to clarify the effects of two processed forms of American ginseng (Panax quinquefolius L.) on immunosuppression caused by cyclophosphamide (CTX) in mice. In the CTX-induced immunosuppressive model, mice were given either steamed American ginseng (American ginseng red, AGR) or raw American ginseng (American ginseng soft branch, AGS) by intragastric administration. Serum and spleen tissues were collected, and the pathological changes in mice spleens were observed by conventional HE staining. The expression levels of cytokines were detected by ELISA, and the apoptosis of splenic cells was determined by western blotting. The results showed that AGR and AGS could relieve CTX-induced immunosuppression through the enhanced immune organ index, improved cell-mediated immune response, increased serum levels of cytokines (TNF-α, IFN-γ, and IL-2) and immunoglobulins (IgG, IgA, and IgM), as well as macrophage activities including carbon clearance and phagocytic index. AGR and AGS downregulated the expression of BAX and elevated the expression of Bcl-2, p-P38, p-JNK, and p-ERK in the spleens of CTX-injected animals. Compared to AGS, AGR significantly improved the number of CD4+CD8-T lymphocytes, the spleen index, and serum levels of IgA, IgG, TNF-α, and IFN-γ. The expression of the ERK/MAPK pathway was markedly increased. These findings support the hypothesis that AGR and AGS are effective immunomodulatory agents capable of preventing immune system hypofunction. Future research may investigate the exact mechanism to rule out any unforeseen effects of AGR and AGS.

Design, synthesis and biological evaluation of novel indolin-2-one derivatives as potent second-generation TRKs inhibitors.

Tropomyosin receptor kinases (TRKs) are effective targets for anti-cancer drug discovery. The first-generation type I TRKs inhibitors, larotrectinib and entrectinib, exhibit durable disease control in the clinic. The emergence of acquired resistance mediated by secondary mutations in the TRKs domain significantly reduces the therapeutic efficacy of these two drugs, indicating an unmet clinical need. In this study, we designed a potent and orally bioavailable TRK inhibitor, compound 24b, using a molecular hybridization strategy. Compound 24b exhibited significant inhibitory potency against multiple TRK mutants in both biochemical and cellular assays. Furthermore, compound 24b induced apoptosis of Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells in a dose-dependent manner. Additionally, compound 24b exhibited moderate kinase selectivity. In vitro stability revealed that compound 24b showed excellent plasma stability (t1/2 > 289.1 min) and moderate liver microsomal stability (t1/2 = 44.3 min). Pharmacokinetic studies have revealed that compound 24b is an orally bioavailable TRK inhibitor with a good oral bioavailability of 116.07%. These results indicate that compound 24b be used as a lead molecule for further modifications to overcome drug-resistant mutants of TRK.

Discovery of CZS-241: A Potent, Selective, and Orally Available Polo-Like Kinase 4 Inhibitor for the Treatment of Chronic Myeloid Leukemia.

Recent studies demonstrate that PLK4 has emerged as a therapeutic target for the treatment of multiple cancers owing to its indispensable role in cell division. Herein, starting from previously identified effective compound CZS-034, based on rational drug design strategies, tyrosine kinase receptor A (TRKA) selectivity- and metabolic stability-guided structure-activity relationship (SAR) exploration were carried out to discover a highly potent (IC50 = 2.6 nM) and selective (SF = 1054.4 over TRKA) PLK4 inhibitor B43 (CZS-241) with acceptable human liver microsome stability (t1/2 = 31.5 min). Moreover, compound B43 effectively inhibited leukemia cells in 29 tested cell lines, especially chronic myeloid leukemia (CML) cell lines K562 and KU-812. Pharmacokinetic characteristics revealed that compound B43 possessed over 4 h of half-life and 70.8% bioavailability in mice. In the K562 cells xenograft mouse model, a 20 mg/kg/day dosage treatment obviously suppressed tumor progression. As a potential and novel PLK4-targeted candidate drug for CML, compound B43 is undergoing extensive preclinical safety evaluation.