Microbiome-liver crosstalk:A multihit therapeutic target for liver disease

Liver disease has become a leading cause of death,particularly in the West,where it is attributed to more than two million deaths annually.The correlation between gut microbiota and liver disease is still not fully understood.However,it is well known that gut dysbiosis accompanied by a leaky gut causes an increase in lipopolysaccharides in circulation,which in turn evoke massive hepatic inflammation promoting liver cirrhosis.Microbial dysbiosis also leads to poor bile acid metabolism and low short-chain fatty acids,all of which exacerbate the inflammatory response of liver cells.Gut microbial homeostasis is maintained through intricate processes that ensure that commensal microbes adapt to the low oxygen potential of the gut and that they rapidly occupy all the intestinal niches,thus outcompeting any potential pathogens for available nutrients.The crosstalk between the gut microbiota and its metabolites also guarantee an intact gut barrier.These processes that protect against destabilization of gut microbes by potential entry of pathogenic bacteria are collectively called colonization resistance and are equally essential for liver health.In this review,we shall investigate how the mechanisms of colonization resistance influence the liver in health and disease and the microbial-liver crosstalk potential as therapeutic target areas.

Whole exome sequencing identifies risk variants associated with intracranial epidermoid cyst deterioration:A case report

BACKGROUND Intracranial epidermoid cyst(IEC)transformation to malignant squamous cell carcinoma(SCC)is extremely rare,and its etiology is yet unknown.Currently,SCC is treated by performing surgery,followed by a combination of radiotherapy and chemotherapy.It is crucial to identify efficient and trustworthy therapeutic targets for SCC to improve its diagnosis,prognosis,and treatment.CASE SUMMARY In this study,we report the case of a 47-year-old female patient with SCC,which progressed from IEC in the left internal capsule region.The patient was sought treatment at our hospital for severe diplopic vision,accompanied with speech disorder and memory loss.Based on the clinical and postoperative pathology,this patient was finally diagnosed with SCC.To identify disease-causing variants,whole exome sequencing(WES)was performed on the proband.WES revealed two pathogenic missense mutations on Gap junction protein beta 2(GJB2)(c.257C>T)and Toll-like receptor 2(TLR2)(c.1039A>G),respectively.CONCLUSION This study provided the first clinical evidence for demonstrating the role of GJB2 and TLR2 in IEC development and treatment.We further confirmed WES as a robust and reliable technique for underlying rare and complex disease-related genetic factor identification.

Mechanism Prediction of Monotropein for the Treatment of Colorectal Cancer by Network Pharmacology Analysis

Objective To discover the pharmacological mechanisms of monotropein in colorectal cancer by network pharmacology methods.Methods The main-candidate-target network was constructed by the prediction of targets of monotropein, collection of therapeutic targets of colorectal cancer drugs, and construction of the target network and layers of screening. The data were interpreted by pathway enrichment and target score calculation.Results This study:(1) Demonstrated the potential of monotropein to be a multi-target drug against colorectal cancer using a computational approach;(2) Discovered 10 candidate targets of monotropein, among which protein kinase B(AKT1)exhibited the highest relevance and importance to colorectal cancer and proto-oncogene tyrosine-protein kinase Src(SRC),Bruton’s tyrosine kinase(BTK), and heat shock protein HSP 90-alpha(HSP90 AA1) also exhibited high relevance;(3) Observed 32 possible pathways related to the effects of monotropein on colorectal cancer, which might explain the mechanism of its action;and(4) Established a method to assess the importance of targets in the network.Conclusions This study offered clues for the mechanism of the bioactivities of monotropein against colorectal cancer by network analysis. Monotropein has the potential to be a multi-target drug against colorectal cancer, which lays the foundation for its clinical applications and further study.

YM155 Inhibits Neuroblastoma Cell Migration and Survival <i>in Vitro</i>and Tumor Growth and Metastatic Burden in a Pre-Clinical Model

Background: Neuroblastoma exhibits a high incidence of chromosomal translocations, the most common being the gain of a portion of the long arm of chromosome 17. This region includes the gene BIRC5/survivin, which is highly upregulated in neuroblastoma and correlates with poor prognosis. Survivin is a member of the inhibitor of apoptosis family of proteins and is involved in tumor cell survival and migration. YM155 is a small molecule inhibitor of survivin transcription and has shown efficacy in several cancer model systems both?in vitro?and?in vivo. Procedure: Cells were treated with YM155 and effects on migration, invasion, and apoptosis signaling were investigated?in vitro. Tumor burden was assessed in xenografted mice by measuring tumor volume and liver metastases. Results: Treatment with YM155 caused a dose-dependent decrease in survivin expression and induction of apoptosis. Lower concentrations of YM155 reduced cell migration and invasion by 15% - 50% which varied by cell line. In a xenograft model, YM155 treatment inhibited tumor growth by 25% - 70%, reduced metastatic burden in the liver by 50%, and prolonged animal survival. Conclusion: The data suggest YM155 as a possible therapeutic agent for metastatic neuroblastoma.

Metabolic regulation of microglial phagocytosis:Implications for Alzheimer’s disease therapeutics

Microglia,the resident immune cells of the brain,are increasingly implicated in the regulation of brain health and disease.Microglia perform multiple functions in the central nervous system,including surveillance,phagocytosis and release of a variety of soluble factors.Importantly,a majority of their functions are closely related to changes in their metabolism.This natural inter-dependency between core microglial properties and metabolism offers a unique opportunity to modulate microglial activities via nutritional or metabolic interventions.In this review,we examine the existing scientific literature to synthesize the hypothesis that microglial phagocytosis of amyloid beta(Aβ)aggregates in Alzheimer’s disease(AD)can be selectively enhanced via metabolic interventions.We first review the basics of microglial metabolism and the effects of common metabolites,such as glucose,lipids,ketone bodies,glutamine,pyruvate and lactate,on microglial inflammatory and phagocytic properties.Next,we examine the evidence for dysregulation of microglial metabolism in AD.This is followed by a review of in vivo studies on metabolic manipulation of microglial functions to ascertain their therapeutic potential in AD.Finally,we discuss the effects of metabolic factors on microglial phagocytosis of healthy synapses,a pathological process that also contributes to the progression of AD.We conclude by enlisting the current challenges that need to be addressed before strategies to harness microglial phagocytosis to clear pathological protein deposits in AD and other neurodegenerative disorders can be widely adopted.

Mitochondria-targeted carrier-free nanoparticles based on dihydroartemisinin against hepatocellular carcinoma

Hepatocellular carcinoma is a common and fatal malignancy for which there is no effective systemic therapeutic strategy.Dihydroartemisinin(DHA),a derivative of artemisinin,has been shown to exert anti-tumor effects through the production of reactive oxygen species(ROS)and resultant mitochondrial damage.However,clinical translation is limited by several drawbacks,such as insolubility,instability and low bioavailability.Here,based on a nanomedicine-based delivery strategy,we fabricated mitochondria-targeted carrier-free nanoparticles coupling DHA and triphenylphosphonium(TPP),aiming to improve bioavailability and mitochondrial targeting.DHA-TPP nanoparticles can be passively delivered to the tumor site by enhanced penetration and retention and then internalized.Flow cytometry and Western blot analysis showed that DHA-TPP nanoparticles increased intracellular ROS,which increased mitochondrial stress and in turn upregulated the downstream Bcl-2 pathway,leading to apoptosis.In vivo experiments showed that DHA-TPP nanoparticles exhibited anti-tumor effects in a mouse model of hepatocellular carcinoma.These findings suggest carrier-free DHA-TPP nanoparticles as a potential therapeutic strategy for hepatocellular carcinoma.

Effects of plants-associated microbiota on cultivation and quality of Chinese herbal medicines

Microbial resource influences the life activities of medicinal plants from several perspectives.Endophytes,rhizosphere microorganisms,and other environmental microorganisms play essential roles in medicinal plant growth and development,plant yield,and clinical efficacy.The microbiota can influence the biosynthesis of active compounds in medicinal plants by stimulating specific metabolic pathways.They induce host plants to improve their resistance to environmental stresses by accumulating secondary metabolites.Microorganisms can interact with their host plants to produce long-term,targeted selection results and improve their ability to adapt to the environment.Due to the interdependence and interaction between microorganisms and medicinal plants,Chinese herbal medicines(CHMs)quality is closely related to the associated microorganisms.This review summarizes the relationship between medicinal plants and their associated microorganisms,including their species,distribution,life activities,and metabolites.Microorganisms can aid in quality control,improve the efficacy of medicinal plants,and provide markers for identifying the origin and storage time of CHMs.Therefore,a comprehensive understanding of the relationship between microorganisms and medicinal plants will help to control the quality of CHMs from different perspectives.

Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells

Many monoclonal antibodies(mAbs)have been extensively used in the clinic,such as rituximab to treat lymphoma.However,resistance and non-responsiveness to mAb treatment have been challenging for this line of therapy.Complement is one of the main mediators of antibody-based cancer therapy via the complement-dependent cytolysis(CDC)effect.CD59 plays a critical role in resistance to mAbs through the CDC effect.In this paper,we attempted to investigate whether the novel CD59 inhibitor,recombinant ILYd4,was effective in enhancing the rituximab-mediated CDC effect on rituximab-sensitive RL-7 lymphoma cells and rituximab-induced resistant RR51.2 cells.Meanwhile,the CDC effects,which were mediated by rituximab and anti-CD24 mAb,on the refractory multiple myeloma(MM)cell line ARH-77 and the solid tumor osteosarcoma cell line Saos-2,were respectively investigated.We found that rILYd4 rendered the refractory cells sensitive to the mAb-mediated CDC effect and that rILYd4 exhibited a synergistic effect with the mAb that resulted in tumor cells lysis.This effect on tumor cell lysis was apparent on both hematological tumors and solid tumors.Therefore,rILYd4 may serve as an adjuvant for mAb mediated-tumor immunotherapy.

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy:advances and perspectives

Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers.Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996,SAR405838,NVP-CGM097,MK-8242,RG7112,RG7388,DS-3032 b,and AMG232 currently undergo clinical evaluation for cancer therapy.This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera(PROTAC)degraders with a particular focus on how these inhibitors or degraders are identified from starting points,strategies employed,structure-activity relationship(SAR)studies,binding modes or co-crystal structures,biochemical data,mechanistic studies,and preclinical/clinical studies.Moreover,we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition,acquired resistance and toxicity of P53 activation as well as future directions.

Novel SNP markers on ginsenosides biosynthesis functional gene for authentication of ginseng herbs and commercial products

Panax ginseng and Panax quinquefolius have similar bioactive components and morphological characteristics, but they are known to have different medicinal values, high-sensitive and accurate method is expected to identify the sources of ginseng products and evaluate the quality, but with a huge challenge. Our established UHPLC-TOF/MS method coupled with orthogonal partial least squares discriminant analysis(OPLS-DA) model based on 18 ginsenosides was applied to discriminate the sources of raw medicinal materials in ginseng products, and nested PCR strategy was used to discover 6 novel single nucleotide polymorphism(SNP)sites in functional dammarenediol synthase(DS) gene for genetic authentication of P. ginseng and P. quinquefolius for the first time.OPLS-DA model could identify the sources of raw ginseng materials are real or not. SNP markers were applied to identify ginseng fresh samples as well as commercial products, and proved to be successful. This established molecular method can tell exact source information of adulterants, and it was highly sensitive and specific even when total DNA amount was only 0.1 ng and the adulteration was as low as 1%. Therefore, this study made an attempt at the exploration of new type SNP marker for variety authentication and function regulation at the same time, and the combination of chemical and molecular discrimination methods provided the comprehensive evaluation and authentication for the sources of ginseng herbs and products.

Natural products as LSD1 inhibitors for cancer therapy

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase1(LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.

Peptidomic Analysis Reveals that Novel Peptide LDP2 Protects Against Hepatic Ischemia/Reperfusion Injury

Background and Aims:Hepatic ischemia/reperfusion(I/R)injury has become an inevitable issue during liver transplantation,with no effective treatments available.However,peptide drugs provide promising regimens for the treatment of this injury and peptidomics has gradually attracted increasing attention.This study was designed to analyze the spectrum of peptides in injured livers and explore the potential beneficial peptides involved in I/R injury.Methods:C57BL/6 mice were used to establish a liver I/R injury animal model.Changes in peptide profiles in I/R-injured livers were analyzed by mass spectrometry,and the functions of the identified peptides were predicted by bioinformatics.AML12 cells were used to simulate hepatic I/R injury in vitro.After treatment with candidate liver-derived peptides(LDPs)1–10,the cells were collected at various reperfusion times for further study.Results:Our preliminary study demonstrated that 6 h of reperfusion caused the most liver I/R injury.Peptidomic results suggested that 10 down-regulated peptides were most likely to alleviate I/R injury by supporting mitochondrial function.Most importantly,a novel peptide,LDP2,was identified that alleviated I/R injury of AML12 cells.It increased cell viability and reduced the expression of inflammation-and apoptosis-related proteins.In addition,LDP2 inhibited the expression of proteins related to autophagy.Conclusions:Investigation of changes in the profiles of peptides in I/R-injured livers led to identification of a novel peptide,LDP2 with potential function in liver protection by inhibiting inflammation,apoptosis,and autophagy.

The Complement System in Liver Diseases

The complement system plays an important role in mediating both acquired and innate responses to defend against microbial infection, and in disposing immunoglobins and apoptotic cells. The liver （mainly hepatocytes） is responsible for biosynthesis of about 80-90% of plasma complement components and expresses a variety of complement receptors. Recent evidence from several studies suggests that the complement system is also involved in the pathogenesis of a variety of liver disorders including liver injury and repair, fibrosis, viral hepatitis, alcoholic liver disease, and liver ischemia/reperfusion injury. In this review, we will discuss the potential role of the complement system in the pathogenesis of liver diseases. Cellular ＆ Molecular Immunology.

The good and evil of complement activation in HIV-1 infection

The complement system,a key component of innate immunity,is a first-line defender against foreign pathogens such as HIV-1.The role of the complement system in HIV-1 pathogenesis appears to be multifaceted.Although the complement system plays critical roles in clearing and neutralizing HIV-1 virions,it also represents a critical factor for the spread and maintenance of the virus in the infected host.In addition,complement regulators such as human CD59 present in the envelope of HIV-1 prevent complement-mediated lysis of HIV-1.Some novel approaches are proposed to combat HIV-1 infection through the enhancement of antibody-dependent complement activity against HIV-1.In this paper,we will review these diverse roles of complement in HIV-1 infection.

3, 4-seco-Labdane diterpenoids from the leaves of Callicarpa nudiflora with anti-inflammatory effects

Four new 3,4-seco-labdane diterpenoids,nudiflopenes J-M,were isolated from the leaves of Callicarpa nudiflora along with six known compounds.The structures of these diterpenoids were determined by comprehensive spectroscopic analysis.All the isolated compounds were evaluated for their inhibitory effects on NO production in LPS-stimulated RPMs and RAW264.7 cells.The results suggest that nudiflopenes J-M and other four known compounds showed significant inhibitory effects against NO production comparable to the positive control dexamethasone.

Non-covalent glycosylated gold nanoparticles/peptides nanovaccine as potential cancer vaccines

Herein,we firstly developed a non-covalent glycosylated gold nanoparticles/peptides nanovaccine which is assembled byβ-cyclodextrin(β-CD)based host-guest recognitions.This nanovaccine can generate significant titers of antibodies and improve the therapeutic effect against melanoma,suggesting the immunogenicity of peptide antigens can be improved by loading with this carrier.The novel vaccine carrier provides a platform for the transport of various antigens especially T cell-independent antigens.

miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis

Acidosis,regardless of hypoxia involvement,is recognized as a chronic and harsh tumor microenvironment(TME)that educates malignant cells to thrive and metastasize.Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression,the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy.Here,chemical-induced and transgenic mouse models for colon,liver and lung cancer were established,respectively.miR-7 and TGF-β2 expressions were examined in clinical tissues(n=184).RNA-seq,miRNA-seq,proteomics,biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis.Our data show that lung cancer is sensitive to the increased acidification of TME,and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5 p.TGF-β2 is a direct target of miR-7-5 p.The reduced expression of miR-7-5 p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer.Indeed,overexpression of miR-7-5 p reduces the acidic p H-enhanced lung cancer metastasis.Furthermore,the human lung tumor samples also show a reduced miR-7-5 p expression but an elevated level of activated TGF-β2;the expressions of both miR-7-5 p and TGF-β2 are correlated with patients’survival.We are the first to identify the role of the miR-7/TGF-β2 axis in acidic p H-enhanced lung cancer metastasis.Our study not only delineates how acidification directly affects tumorigenesis,but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer(NSCLC)treatment.Our study opens an avenue to explore the p H-sensitive subcellular components as novel therapeutic targets for cancer treatment.

Full synthesis and bioactivity evaluation of Tn-RC-529 derivative conjugates as self-adjuvanting cancer vaccines

A facile and efficient strategy was established for the construction of RC-529 and its derivatives.Four conjugates of RC-529 derivatives with Tn antigen were synthesized and all elicited strong and T celldependent immune responses in mice without requiring external adjuvants.In addition,all antisera induced by these conjugates could specifically recognize,bind to and kill Tn-overexpressing cancer cells.Thus,RC-529 shows promise as a useful platform for the development of new vaccine carriers with self-adjuvanting properties for the treatment of cancer.Moreover,preliminary structure-activity relationship analysis provides convincing support for further optimization of,and additional investigation into RC-529.

IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα

Inhibitor of nuclear factor kappa-B kinase subunit beta(IKKβ)is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B(IκBα)and then activate nuclear factor kappa-B(NF-κB).Inhibition of IKKβhas been a therapeutic strategy for inflammatory and autoimmune diseases.Here we report that IKKβis constitutively activated in healthy donors and healthy Ikkβ^(C46A)(cysteine 46 mutated to alanine)knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation.These indicate that IKKβactivation probably plays homeostatic role instead of causing inflammation.Compared to IkkβWTlittermates,lipopolysaccharides(LPS)could induce high mortality rate in Ikkβ^(C46A) mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5’adenosine monophosphate-activated protein kinase(p-AMPK)expression.We then demonstrated that IKKβkinase domain(KD)phosphorylates AMPKa1 via interacting with residues Thr183,Ser184,and Thr388,while IKKβhelix-loop-helix motifs is essential to phosphorylate IκBαaccording to the previous reports.Kinase assay further demonstrated that IKKβsimultaneously catalyzes phosphorylation of AMPK and IκBαto mediate homeostasis.Accordingly,activation of AMPK rather than inhibition of IKKβcould substantially rescue LPS-induced mortality in Ikkβ^(C46A) mice by rebuilding the homeostasis.We conclude that IKKβactivates AMPK to restrict inflammation and IKKβmediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.

TCP1 regulates Wnt7b/β-catenin pathway through P53 to influence the proliferation and migration of hepatocellular carcinoma cells

Dear Editor,Molecular chaperones are critical mediators of oncogenesis and necessary for cell survival.1 The cytoplasmic chaperone TRiC(Tcomplex protein-1 ring complex,also known as CCT)comprises two back-to-back stacked rings,with each ring containing eight subunits(CCT1–CCT8).2 And the effects of CCT subunits on tumors may be different.However,the roles of the CCT1 subunit(also known as TCP1)in hepatocellular carcinoma(HCC)and its molecular mechanism have not been investigated thoroughly.Understanding these details can provide new ideas and strategies for treating HCC.