Potentials of ribosomopathy gene as pharmaceutical targets for cancer treatment

Ribosomopathies encompass a spectrum of disorders arising from impaired ribosome biogenesis and reduced functionality.Mutation or dysexpression of the genes that disturb any finely regulated steps of ribosome biogenesis can result in different types of ribosomopathies in clinic,collectively known as ribosomopathy genes.Emerging data suggest that ribosomopathy patients exhibit a significantly heightened susceptibility to cancer.Abnormal ribosome biogenesis and dysregulation of some ribosomopathy genes have also been found to be intimately associated with cancer development.The correlation between ribosome biogenesis or ribosomopathy and the development of malignancies has been well established.This work aims to review the recent advances in the research of ribosomopathy genes among human cancers and meanwhile,to excavate the potential role of these genes,which have not or rarely been reported in cancer,in the disease development across cancers.We plan to establish a theoretical framework between the ribosomopathy gene and cancer development,to further facilitate the potential of these genes as diagnostic biomarker as well as pharmaceutical targets for cancer treatment.

Restoration of E-cadherin by compound 8J protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death

OBJECTIVE E-cadherin is a major component of tubular adherent proteins which maintain intercellular contacts and cell polarity in epithelial tissue,it is involved in the pathological process of renal cell carcinoma and fibrotic diseases via epithelial-mesenchymal transition.Although we and others found that expression of E-cadherin was significantly down-regulated in kidney suffered acute kidney injury(AKI),its function in AKI was still unknown,which was explored in the current study.METHODS We disrupted E-cadherin or restored E-cadherin with compound 8J in cisplatin-stimulated tubular epithelial cell lines,the cell damage and inflammation were evaluated,additionally,the therapeutic potential of E-cadherin restoration was also determined in vivo.RESULTS We found that cisplatin reduced E-cadherin expression both in mouse kidney and tubular epithelial cell lines(m TECs).Administration of compound 8J restored the level of E-cadherin,thereby increased cell viability while attenuating programmed cell death,which may be mediated by deactivation of RIPK/MLKL axis,reduced membrane translocation of phosphor-MLKL and decreased cleavage of caspase 3.Compound 8J also suppressed inflammatory response in cisplatin-treated m TECs,which was correlated with suppressed NF-κB phorsphorylation and promoter activity.In contrast,disruption of E-cadherin enhanced cell damage and inflammation.Treatment of compound 8J failed to further attenuate kidney damage in E-cadherin knockdown cells,indicating compound 8J protected against mT ECs mainly through restoring E-cadherin.We also found that peritoneal injection of compound 8J protected against renal function and tubular damage by preventing NF-κB-driven renal inflammation and RIPK/MLKL-regulated programmed cell death,which was led by restoration of E-cadherin in cisplatin nephropathy.CONCLUSION More than a victim degraded after kidney injury,E-cadherin also has functional role in controlling tubule integrity,programmed cel death and renal inflammation.In this regard,restoration of E-cadherin by compound 8J should be considered as a novel therapeutic strategy for acute kidney injury.

Alcohol promotes renal fibrosis by activating Nox-mediated DNA methylation of Smad7

OBJECTIVE Alcohol is mainly metabolized through liver and excreted by kidney in the body.Kidney damage has been considered as the secondary to liver injury and kidney dysfunction is common in hospitalized patients with severe alcoholic hepatitis.Both acute and chronic alcoholism accumulation can compromise kidney function,although alcoholic kidney disease has drawn much more attention recently,the methodology for establishing the in vivo and in vitro alcoholic renal fibrosis models are still lacking,and the underlying mechanisms are to be determined.METHODS and RESULTS Mice were feed with a liquid diet containing alcohol for 4 weeks,8 weeks and 12 weeks respectively,results of Masson′ s Trichrome staining showed that kidney fibrosis peaked in 8-week model group,which consistent with the results of albumin assay,Western blot,immunostaining and real-time PCR of collagen I and α-SMA.In vitro study also confirmed that ethanol upregulated the level of fibrotic index.es,including collagen I and α-SMA,in tubular epithelial cells(HK2 cells).Additionally,both in vivo and in vitro studies showed that Smad7 was decreased and Smad3 was highly activated.Then we further detected the underlying mechanisms by which alcohol induced the imbalance of Smad7 and Smad3.Results of Genome-wide methylation sequencing found DNA methylation of Smad7 in the alcoholic fibrosis kidney,which may be mainly mediated by DNA methyltransferase 1(DNMT1),because knock.down of DNMT1,but not DNMT2 and 3,largely restored Smad7 level in ethanol-treated HK2 cells.Con.sequently,we found that NADPH Oxidases(nox)-mediated oxidative stress is the major force upregu.lating DNMT1,since knockdown of Nox2 and 4 could both decrease DNMT1 while rebalancing Smad7/Smad3 axis,and thereby relieved ethanol-induced fibrotic response in HK2 cells.More importantly,intraperitoneal injection of apocynin,an inhibitor of NADPH oxidoreductase,attenuated renal fibrosis in alcoholic kidney fibrosis mouse model.CONCLUSION By establishing the novel in vivo and in vitro models,we found that through activating oxidative stress-induced DNA methylation of Smad7,alcohol induces renal fibrosis by breaking the balance between Smad7 and Smad3.Elimination of Nox-mediated oxidative stress may be a potential therapy for treatment of long-term alcohol abuse-induced kidney fibrosis.

Metabolomics Combined with Network Pharmacology Uncovers Effective Targets of Tao-Hong-Si-Wu Decoction for Its Protection from Sepsis-Associated Acute Lung Injury

Sepsis-induced acute lung injury(ALI)is a leading cause of death among septic complications.Tao-Hong-Si-Wu decoction(TSD),a classical recipe from traditional Chinese medicine used for treating ischemic stroke,has been recently reported to alleviate inflammation and inflammation-stimulated injuries related to the pathology of ALI.Here,we first observed the therapeutic effect of TSD on sepsis-induced ALI.Based on integrated metabolomics and network pharmacology analysis(NPA)techniques,we aim to understand the mechanism of TSD alleviating ALI.TSD’s effects were observed in rats modeled by cecal ligation and puncture(CLP)and rat macrophages stimulated by lipopolysaccharide(LPS).Metabolomics analyses were applied to determine the ingredients in the medicine and key metabolites correlated to the NPA for the prediction of TSD targets.Gene and protein expressions of the key predicted targets were evaluated in the lung tissue and macrophages of septic model rat by quantitative polymerase chain reaction(PCR)and enzyme-linked immunosorbent assays,respectively.TSD improved survival rate and protected against lung injury in CLP rats.Eleven endogenous metabolites were related to TSD’s actions.TSD significantly suppressed IL-6 and TNF-αsecretions and their gene expressions both in the lung tissue of the model rats and in LPS-stimulated macrophages.TSD also restored decreased lung protein expression of VEGFA in septic model rats.Targeted proteins and their affecting metabolites were finally validated in an external test set of rats.This study shows that metabolomics coupled with NPA is a promising approach to explore potential targets of medicine with complex compositions.

Application and progress of the detection technologies in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)has a very high incidence and fatality rate,and in most cases,it is already at an advanced stage when diagnosed.Therefore,early prevention and detection of HCC are two of the most effective strategies.However,the methods recommended in the practice guidelines for the detection of HCC cannot guarantee high sensitivity and specificity except for the liver biopsy,which is known as the“gold standard”.In this review,we divided the detection of HCC into pre-treatment diagnosis and post-treatment monitoring,and found that in addition to the traditional imaging detection and liver biopsy,alpha fetoprotein(AFP),lens culinaris-agglutinin-reactive fraction of AFP(AFP-L3),protein induced by vitamin K absence or antagonist-II(PIVKA-II)and other biomarkers are excellent biomarkers for HCC,especially when they are combined together.Most notably,the emerging liquid biopsy shows great promise in detecting HCC.In addition,lactic dehydrogenase(LDH),suppressor of cytokine signaling(SOCS)and other relevant biomarkers may become promising biomarkers for HCC post-treatment monitoring.Through the detailed introduction of the diagnostic technology of HCC,we can have a detailed understanding of its development process and then obtain some enlightenment from the diagnosis,to improve the diagnostic rate of HCC and reduce its mortality.

Decoding m^(6)A mRNA methylation by reader proteins in liver diseases

N6-methyladenosine(m^(6)A)is a dynamic and reversible epigenetic regulation.As the most prevalent internal post-transcriptional modification in eukaryotic RNA,it participates in the regulation of gene expression through various mechanisms,such as mRNA splicing,nuclear export,localization,translation efficiency,mRNA stability,and structural transformation.The involvement of m^(6)A in the regulation of gene expression depends on the specific recognition of m^(6)A-modified RNA by reader proteins.In the pathogenesis and treatment of liver disease,studies have found that the expression levels of key genes that promote or inhibit the development of liver disease are regulated by m^(6)A modification,in which abnormal expression of reader proteins determines the fate of these gene transcripts.In this review,we introduce m^(6)A readers,summarize the recognition and regulatory mechanisms of m^(6)A readers on mRNA,and focus on the biological functions and mechanisms of m^(6)A readers in liver cancer,viral hepatitis,non-alcoholic fatty liver disease(NAFLD),hepatic fibrosis(HF),acute liver injury(ALI),and other liver diseases.This information is expected to be of high value to researchers deciphering the links between m^(6)A readers and human liver diseases.

Driving role of macrophages in transition from acute kidney injury to chronic kidney disease

Acute kidney injury(AKI),characterized by acute renal dysfunction,is an increasingly common clinical problem and an important risk factor in the subsequent development of chronic kidney disease(CKD).Regardless of the initial insults,the progression of CKD after AKI involves multiple types of cells,including renal resident cells and immune cells such as macrophages.Recently,the involvements of macrophages in AKI-to-CKD transition have garnered significant attention.Furthermore,substantial progress has also been made in elucidating the pathophysiological functions of macrophages from the acute kidney to repair or fibrosis.In this review,we highlight current knowledge regarding the roles and mechanisms of macrophage activation and phenotypic polarization,and transdifferentiation in the development of AKI-to-CKD transition.In addition,the potential of macrophage-based therapy for preventing AKI-to-CKD transition is also discussed.

Hesperetin derivative-12 (HDND-12) regulates macrophage polarization by modulating JAK2/STAT3 signaling pathway

Macrophages show significant heterogeneity in function and phenotype, which could shift into different populations of cells in response to exposure to various micro-environmental signals. These changes, also termed as macrophage polarization, of which play an important role in the pathogenesis of many diseases. Numerous studies have proved that Hesperidin(HDN), a traditional Chinese medicine, extracted from fruit peels of the genus citrus, play key roles in anti-inflammation, anti-tumor, anti-oxidant and so on. However, the role of HDN in macrophage polarization has never been reported. Additional, because of its poor water solubility and bioavailability. Our laboratory had synthesized many hesperidin derivatives. Among them, hesperidin derivatives-12(HDND-12) has better water solubility and bioavailability. So, we evaluated the role of HDND-12 in macrophage polarization in the present study. The results showed that the expression of Arginase-1(Arg-1), interleukin-10(IL-10), transforming growth factor β(TGF-β) were up-regulated by HDND-12, whereas the expression of inducible Nitric Oxide Synthase(iNOS) was down-regulated in LPS-and IFN-γ-treated(M1) RAW264.7 cells. Moreover, the expression of p-JAK2 and p-STAT3 were significantly decreased after stimulation with HDND-12 in M1-like macrophages. More importantly, when we taken AG490(inhibitor of JAK2/STAT3 signaling), the protein levels of iNOS were significantly reduced in AG490 stimulation group compare with control in LPS, IFN-γ and HDND-12 stimulation cells. Taken together, these findings indicated that HDND-12 could prevent polarization toward M1-like macrophages, at least in part, through modulating JAK2/STAT3 pathway.

Potential targeted therapy and diagnosis based on novel insight into growth factors,receptors,and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression

Acute kidney injury(AKI)is defined as a rapid decline in renal function and is characterized by excessive renal inflammation and programmed death of resident cells.AKI shows high morbidity and mortality,and severe or repeated AKI can transition to chronic kidney disease(CKD)or even end-stage renal disease(ESRD);however,very few effective and specific therapies are available,except for supportive treatment.Growth factors,such as epidermal growth factor(EGF),insulin-like growth factor(IGF),and transforming growth factor-β(TGF-β),are significantly altered in AKI models and have been suggested to play critical roles in the repair process of AKI because of their roles in cell regeneration and renal repair.In recent years,a series of studies have shown evidence that growth factors,receptors,and downstream effectors may be highly involved in the mechanism of AKI and may function in the early stage of AKI in response to stimuli by regulating inflammation and programmed cell death.Moreover,certain growth factors or correlated proteins act as biomarkers for AKI due to their sensitivity and specificity.Furthermore,growth factors originating from mesenchymal stem cells(MSCs)via paracrine signaling or extracellular vesicles recruit leukocytes or repair intrinsic cells and may participate in AKI repair or the AKI-CKD transition.In addition,growth factor-modified MSCs show superior therapeutic potential compared to that of unmodified controls.In this review,we summarized the current therapeutic and diagnostic strategies targeting growth factors to treat AKI in clinical trials.We also evaluated the possibilities of other growth factorcorrelated molecules as therapeutic targets in the treatment of AKI and the AKI-CKD transition.

P2X7 Receptor in Alcoholic Steatohepatitis and Alcoholic Liver Fibrosis

Alcoholic liver disease is one of the most common chronic liver diseases in the world.It is a liver disease caused by prolonged heavy drinking and its main clinical features are nausea,vomiting,enlargement of the liver,and jaundice.Recent studies suggest that Kupffer cell-mediated inflam-matory response is a core driver in the development of alco-holic steatohepatitis and alcoholic liver fibrosis.As a danger signal,extracellular ATP activates the assembly of NLPR3 inflammasome by acting on purine P2X7 receptor,the ac-tivated NLRP3 inflammasome prompts ASC to cleave pro-cCaspase-1 into active caspase-1in KCs.Active caspase-1 promotes the conversion of pro-IL-1βto IL-1β,which fur-ther enhances the inflammatory response.Here,we briefly review the role of the P2X7R-NLRP3 inflammasome axis in the pathogenesis of alcoholic liver disease and the evolution of alcoholic steatohepatitis and alcoholic liver fibrosis.Reg-ulation of the inflammasome axis of P2X7R-NLRP3 may be a new approach for the treatment of alcoholic liver disease.