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• Modest efficacy, toxicity, and poor effectiveness against brain metastasis are common limitations of multi-targeted novel molecular inhibitors. • A promising prospect was shown recently in selective RET inhibitors. • The development of multitarget agents and specific inhibitors has been evaluated in clinical trials. • More studies need to be conducted on the targeted therapies against RET arrangement cancer. Genomic profiling has revolutionized treatment options for patients with oncogene-driven cancers, such as epidermal growth factor receptor (EGFR) mutant carcinoma. Rearranged during transfection (RET) rearrangement, as one of the main activated oncogenes, has been well studied and found to be involved in the malignant behavior of carcinogenesis, resulting in acquired resistance to EGFR tyrosine kinase inhibitors and inducing an intrinsic resistance to immunotherapy. Thus, targeted therapies have been investigated against RET arrangement cancers, including several multi-kinase inhibitors and selective RET inhibitors. However, modest efficacy, a relatively high rate of toxicity, and poor effectiveness against brain metastasis are common limitations of multi-targeted novel molecular inhibitors. A promising prospect was shown recently in selective RET inhibitors in several ongoing clinical trials. In this review, we reviewed the concurrent dilemmas of targeted therapies against RET arrangement cancer from preclinical and clinical studies and proposed several clinical considerations for clinical practice prospectively. [ABSTRACT FROM AUTHOR]

Highlights • IL-2 promotes sorafenib-mediated apoptosis in Huh7 cells. • IL-2 in combination with sorafenib interrupts mitochondrial metabolism. • Mitochondrial fragmentation is augmented by IL-2 in the presence of sorafenib. Abstract Sorafenib is a standard targeted drug used to treat hepatocellular carcinoma (HCC). Notably, cytokine has been found to further enhance the therapeutic effectiveness of the targeted drug. Thereby, the aim of this study is to verify whether cytokine IL-2 could increase the anti-cancer effects of sorafenib on liver cancer in vitro. Huh7 cells were used in the present study and the cell apoptosis and migration were determined in response to sorafenib treatment. Then, siRNA and pathway blocker were used to determine the molecular mechanisms by which IL-2 enhance the therapeutic effectiveness of Huh7 liver cancer cell in vitro. The data in our study illustrated that sorafenib treatment induced apoptosis in Huh7 liver cancer cell in vitro, an effect that was accompanied with a drop in cell proliferation and migration. Biological investigation demonstrated that IL-2 supplementation further augmented the pro-apoptotic effects of sorafenib in vitro. At the molecular levels, the combination of IL-2 and sorafenib impaired mitochondrial respiratory function, reduced mitochondrial potential, promoted mitochondrial ROS overloading and activated mitochondrial apoptotic pathway. Meanwhile, we found that IL-2 supplementation induced mitochondrial stress via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. Blockade of the JNK signalling pathway and/or knockdown of TAZ could abrogate the inhibitor effects of IL-2/sorafenib on liver cancer survival, growth and mobility. Collectively, these data indicated that IL-2 supplementation could further augment the anti-cancer effectiveness of sorafenib via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. This finding identifies mitochondrial stress and the JNK-Hippo pathway as the potential targets to treat liver cancer. [ABSTRACT FROM AUTHOR]

The goal of this study was to examine the role of sodium butyrate in preserving the intestinal mucosal barrier and reducing hyperuricemia (HUA). First, we established a mouse model of HUA via intraperitoneal injection of potassium oxonate together with a yeast-rich diet to detect the levels of serum uric acid (UA) and fecal short-chain fatty acids (SCFAs). Then, in vitro, different concentrations of UA and sodium butyrate (NaB) were used to treat LS174T and Caco2 cells. The effects of UA and NaB on the gut barrier were determined based on the expression levels of MUC2, ZO-1, and Occludin.Finally, C57BL/6 mice were used to model HUA, and these mice were administered 200 mg·kg−1·d−1 NaB by gavage to counter the HUA. The effect of NaB on HUA in the intestinal tract was elucidated by determining serum UA levels, inflammatory parameters, epithelial barrier integrity, and via histological analysis. The data showed that the content of fecal SCFAs in HUA mice decreased. Additionally, in LS174T and Caco2 cells, NaB reversed the decrease of ZO-1, Occludin, and MUC2 protein expression caused by high UA levels. Furthermore, NaB decreased serum UA of HUA mice, and reversed both the decreased expression of MUC2, ZO-1, Occludin, and ABCG2 proteins and the increased level of inflammatory factors in the intestinal tissues of these mice. The HUA mouse model showed intestinal barrier damage. NaB protected the intestinal barrier of HUA mice and reduced the serum UA level. • The HUA model mice showed intestinal barrier damage. • NaB reversed the damage of intestinal barrier in HUA model mice. • NaB reduces serum UA level in HUA model mice. • NaB may reduce the serum UA level of HUA model mice by up-regulating the expression level of intestinal ABCG2 protein. [ABSTRACT FROM AUTHOR]

Noncoding RNAs (ncRNAs) do not participate in protein-coding. Ferroptosis is a newly discovered form of cell death mediated by reactive oxygen species and lipid peroxidation. Recent studies have shown that ncRNAs such as microRNAs, long noncoding RNAs, circular RNAs, and ferroptosis are involved in the occurrence and development of osteosarcoma (OS). Studies have confirmed that ncRNAs participate in the development of OS by regulating the ferroptosis. However, systematic summary on this topic are still lacking. This review summarises the potential role of ncRNAs in the diagnosis, treatment, drug resistance, and prognosis of OS and the basis for diagnosing, preventing, and treating clinical OS and developing effective drugs. This review summarises the latest research progress on ncRNAs that regulate ferroptosis in OS, attempts to clarify the molecular mechanisms by which ncRNAs regulate ferroptosis in the pathogenesis of OS, and elaborates on the involvement of ferroptosis in OS from the perspective of ncRNAs. [Display omitted] • NcRNAs play an important role in the treatment, diagnosis, prognosis, and drug resistance of osteosarcoma. • Ferroptosis involving ncRNAs provides a new direction for the pathogenesis of osteosarcoma. • NcRNAs may act as a hub for regulating the ferroptosis of osteosarcoma with other forms of cell metabolism and death. • The expression of ncRNAs related with ferroptosis is correlated with immune checkpoint, which can be explored as a new idea of immunotherapy for osteosarcoma. [ABSTRACT FROM AUTHOR]

Large tumor suppressor 2 (LATS2), an important mediator of the cell apoptotic response pathway, has been linked to the progression of several cancers. Here, we described the molecular feature of LATS2 as a novel antitumor factor in liver cancer cells in vitro. Western blotting was used to detect the expression of LATS2 and its downstream factors. ELISA, immunofluorescence, and flow cytometry were used to evaluate the alterations of mitochondrial function in response to LATS2 overexpression. Adenovirus-loaded LATS2 and siRNA against DRP1 were transfected into liver cancer cells to overexpress LATS2 and knockdown DRP1 expression, respectively. The results of the present study demonstrated that overexpression of LATS2 was closely associated with more liver cancer cell death. Mechanistically, LATS2 overexpression increased the expression of DRP1, and DRP1 elevated mitochondrial division, an effect that was accompanied by mitochondrial dysfunction, including mitochondrial membrane potential reduction, mitochondrial respiratory complex downregulation, mitochondrial cyt-c release into the nucleus and mitochondrial oxidative injury. Moreover, LATS2 overexpression also initiated mitochondrial apoptosis, and this process was highly dependent on DRP1-related mitochondrial division. Molecular investigations demonstrated that LATS2 modulated DRP1 expression via the Wnt/β-catenin pathway. Inhibition of the Wnt/β-catenin pathway pregented LATS2-mediated DRP1 upregulation, ultimately sustaining mitochondrial function and cell viability in the presence of LATS2 overexpression. Altogether, the above data identify LATS2-Wnt/β-catenin/DRP1/mitochondrial division as a novel anticancer signaling pathway promoting cancer cell death, which might be an attractive therapeutic target for the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Ginseng polysaccharide (GP) is one of the most abundant components in Panax ginseng. However, the absorption pathways and mechanisms of GPs have not been investigated systematically due to the challenges of their detection. The fluorescein isothiocyanate derivative (FITC) was employed to label GP and ginseng acidic polysaccharide (GAP) to obtain target samples. HPLC-MS/MS assay was used to determine the pharmacokinetics of GP and GAP in rats. The Caco-2 cell model was used to investigate the uptake and transport mechanisms of GP and GAP in rats. Our results demonstrated that the absorption of GAP was more than that of GP in rats after gavage administration, while there was no significant difference between both after intravenous administration. In addition, we found that GAP and GP were more distributed in the kidney, liver and genitalia, suggesting that GAP and GP are highly targeted to the liver, kidney and genitalia. Importantly, we explored the uptake mechanism of GAP and GP. GAP and GP are endocytosed into the cell via lattice proteins or niche proteins. Both are transported lysosomally mediated to the endoplasmic reticulum (ER) and then enter the nucleus through the ER, thus completing the process of intracellular uptake and transportation. Our results confirm that the uptake of GPs by small intestinal epithelial cells is primarily mediated via lattice proteins and the cytosolic cellar. The discovery of important pharmacokinetic properties and the uncovering of the absorption mechanism provide a research rationale for the research of GP formulation and clinical promotion. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) is an abrupt loss of kidney function. MicroRNA-30b (miR-30b) has been reported to be involved in the inflammatory reaction of a variety of diseases. However, the role of miR-30b in AKI remains unknown. In this research, we aimed to investigate the role of miR-30b in lipopolysaccharide (LPS)-induced kindey inflammatory injury in vitro and in vivo . Methods In vitro, after miR-30b mimic/inhibitor transfection and/or LPS treatment, the viability, apoptosis, autophagy and inflammatory cytokines releases, as well as activation of c-Jun-N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) pathways were detected by cell counting kit-8 (CCK-8) assay, flow cytometry, qRT-PCR, enzyme-linked immunosorbent assay (ELISA) and western blot, respectively. In vivo , after LPS treatment and/or anti-miR-30b administration, the levels of creatinine, the activities of alanine aminotransferase (ALT) and histologic scores, as well as concentrations of inflammatory cytokines were assessed by creatinine assay kit, ALT assay kit and ELISA, respectively. Results LPS inhibited HK-2 cell viability and induced HK-2 cell apoptosis, autophagy and the releases of inflammatory cytokines. Overexpression of miR-30b promoted LPS-induced HK-2 cell viability inhibition, cell inflammatory cytokines releases, cell apoptosis induction and activation of JNK and NF-κB signaling pathways, but inhibited LPS-induced HK-2 cell autophagy. Suppression of miR-30b had opposite effects. Moreover, suppression of miR-30b alleviated the LPS-induced kidney injury in mice model by decreasing creatinine level, ALT activity and histologic scores, as well as concentrations of inflammatory cytokines. Conclusion miR-30b participated in the LPS-induced kindey inflammatory injury in vitro and in vivo . [ABSTRACT FROM AUTHOR]

Silica nanoparticles (SiNPs) are composed of silicon dioxide, the most abundant compound on Earth, and are used widely in many applications including the food industry, synthetic processes, medical diagnosis, and drug delivery due to their controllable particle size, large surface area, and great biocompatibility. Building on basic synthetic methods, convenient and economical strategies have been developed for the synthesis of SiNPs. Numerous studies have assessed the biomedical applications of SiNPs, including the surface and structural modification of SiNPs to target various cancers and diagnose diseases. However, studies on the in vitro and in vivo toxicity of SiNPs remain in the exploratory stage, and the toxicity mechanisms of SiNPs are poorly understood. This review covers recent studies on the biomedical applications of SiNPs, including their uses in drug delivery systems to diagnose and treat various diseases in the human body. SiNP toxicity is discussed in terms of the different systems of the human body and the individual organs in those systems. This comprehensive review includes both fundamental discoveries and exploratory progress in SiNP research that may lead to practical developments in the future. [Display omitted] • This review summarizes the current status of SiNPs, focusing on synthesis, biomedical applications, and toxicity. • We discuss the applications of SiNPs in medical fields by classifying the main systems of the human body. • We discuss the toxicity and possible mechanisms of SiNPs in various organs. [ABSTRACT FROM AUTHOR]

There are multiple pathways for communication of gut microbes with human organs. Trimethylamine N-oxide (TMAO) is generated via a metaorganismal pathway, which begins with the conversion of dietary phosphatidyl choline into trimethylamine in the gut of microbes, followed by liver oxidation of TMAO by flavin monooxygenases in the host. The gut-liver axis that links the liver metabolism and the gut microbiota plays an important role in the mechanisms of liver diseases. Translocated lipopolysaccharide (LPS) enters the liver through hepatic portal vein and causes damage to the liver function. Changes in the gut microbiota can affect the function of central nervous system through multiple signaling pathways, including the hypothalamus-pituitary-adrenal axis, immune regulation, serotonin metabolism, and production of neuroactive compounds. Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; GABA, gamma-aminobutyric acid; HPA, hypothalamic–pituitary–adrenal; LPS, lipopolysaccharide; SCFAs, short-chain fatty acids; 5-HT, serotonin; TMA, trimethylamine; TMAO, trimethylamine oxide. • Dysbiosis of intestinal microbiota is related to various diseases. • A. muciniphila is a new target for treating diabetes, obesity, intestinal diseases, liver diseases and neuropsychiatric diseases. • Herbal medicine are widely accepted for treating diseases by regulating intestinal microbiota and microbial metabolites. • Herbal medicine exert a prebiotic effect on A. muciniphila in the treatment of various ailments. There are trillions and trillions of microorganisms in the human gut, and these microorganisms and their metabolites are closely related to human health. Recent studies have found that the abundance of Akkermansia muciniphila is decreased in many diseases. Supplementation of A. muciniphila is used to treat many diseases, suggesting it as a probiotic. Herbal medicines are considered as valuable asset of traditional Chinese medicine. Recent studies have revealed traditional Chinese medicine as a potential prebiotic agent for the treatment of many diseases. Hence, in this review, we aimed to provide a plausible mechanistic basis for the interactions between herbal medicines and A. muciniphila , and therapeutic benefits on this interaction in various illnesses. [ABSTRACT FROM AUTHOR]

Retraction notice to "MicroRNA-30b promotes lipopolysaccharide-induced inflammatory injury and alleviates autophagy through JNK and NF- B pathways in HK-2 cells" [Biomed. The journal was initially contacted by the first author to request the retraction as they reported that results were not reproducible post publication. Given the comments of Dr Elisabeth Bik https://scienceintegritydigest.com/2020/02/21/the-tadpole-paper-mill / regarding this article, the journal requested the author to provide the raw data. [Extracted from the article]

• Aurora kinase A and B inhibitors suppress the proliferation of t(8;21) AML by inducing G2/M accumulation. • The t(8;21) AML cells are more sensitive to Aurora B inhibition compared with Aurora A. • This study provide novel approach to t(8;21) AML target therapy. The fusion gene AML1-ETO initially dysregulates various cell cycle molecules in t(8;21) acute myeloid leukemia. Aurora kinases have shown great promise in treating tumors. However, the efficacy of Aurora kinase (AURK) A and B inhibition in t(8;21) AML remains unclear. We found that AURK-A inhibitor Alisertib and AURK-B inhibitor Barasertib strongly inhibited the growth and proliferation of t(8;21) AML cells. The quantity and size of cell colonies were markedly decreased after a 14-d drug exposure. The cell cycle distribution was blocked at the G2/M phase in both dose- and time-dependent manner. The expression of p53 family and cdc2-p34 significantly changed as well. Notably, we found that t(8;21) AML cells are more sensitive to Aurora B inhibition. In each set of experiments, Barasertib took less time or a lower concentration to achieve similar efficacy. Taken together, our data highlighted the potential role of Aurora kinases as promising cell cycle targets for the treatment of t(8;21) AML and hereby provided a theoretical basis to guide relevant clinical trials. [ABSTRACT FROM AUTHOR]