Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer

Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.

Metformin:A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation

The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological disease.However,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear.Here,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH patients.As the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive relationship with the clinical characteristics of BPH patients.Activation of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)heterodimers.Met’s anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 cells.Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

Neonatal Exposure to Propofol Interferes with the Proliferation and Differentiation of Hippocampal Neural Stem Cells and the Neurocognitive Function of Rats in Adulthood via the Akt/p27 Signaling Pathway

Objective Neonatal exposure to propofol has been reported to cause neurotoxicity and neurocognitive decline in adulthood;however,the underlying mechanism has not been established.Methods SD rats were exposed to propofol on postnatal day 7(PND-7).Double-immunofluorescence staining was used to assess neurogenesis in the hippocampal dentate gyrus(DG).The expression of pAkt and p27 were measured by western blotting.The Morris water maze,novel object recognition test,and object location test were used to evaluate neurocognitive function 2-month-old rats.Results Phosphorylation of Akt was inhibited,while p27 expression was enhanced after neonatal exposure to propofol.Propofol also inhibited proliferation of neural stem cells(NSCs)and decreased differentiation to neurons and astroglia.Moreover,the neurocognitive function in 2-month-old rats was weakened.Of significance,intra-hippocampal injection of the Akt activator,SC79,attenuated the inhibition of p-AKT and increase of p27 expression.SC79 also rescued the propofol-induced inhibition of NSC proliferation and differentiation.The propofol-induced neurocognition deficit was also partially reversed by SC79.Conclusion Taken together,these results suggest that neurogenesis is hindered by neonatal propofol exposure.Specifically,neonatal propofol exposure was shown to suppress the proliferation and differentiation of NSCs by inhibiting Akt/p27 signaling pathway.

Connexin 40-formed GJIC increases the phototoxicity of photodynamic therapy through ROS-and calcium-mediated pathways

OBJECTIVE To explore the effect of connexin(Cx)40-formed gap junctional intercellular communication(GJIC)on Photofrin-photodynamic therapy(PDT)phototoxicity in Cx40-transfected He La cells and its potential mechanisms.METHODS He La cell line stably transfected to express Cx40 was seeded at high and low cell density,respectively,to assess in vitro photosensitivity using CCK8 assay.Western blot assay was performed to detect the expression of Cx40.The intracellular ROS and Ca^(2+) concentrations were determined using flow cytometer.4-HNE and ceramide were measured using ELISA assay.RESULTS Cx40-composed GJ formation at high density enhances the phototoxicity of PhotofrinPDT.When the Cx40 is not expressed or Cx40 channels are blocked,the phototoxicity in high-density cultures substantially reduces,indicating that the enhanced PDT phototoxicity at high density is mediated by Cx40-composed GJIC.The GJIC-mediated increase in PDT phototoxicity was associated with ROS and calcium-mediated stress signaling pathways.CONCLUSION The work uniquely presents the ability of Cx40-composed GJIC to enhance the sensitivity of malignant cells to PDT,and indicates that maintenance or increase of Cx40-formed GJIC may be a profitable strategy towards the enhancement of PDT therapeutic efficiency.

New opportunities and challenges of natural products research:When target identification meets single-cell multiomics

Natural products, and especially the active ingredients found in traditional Chinese medicine(TCM), have a thousand-year-long history of clinical use and a strong theoretical basis in TCM. As such,traditional remedies provide shortcuts for the development of original new drugs in China, and increasing numbers of natural products are showing great therapeutic potential in various diseases. This paper reviews the molecular mechanisms of action of natural products from different sources used in the treatment of inflammatory diseases and cancer, introduces the methods and newly emerging technologies used to identify and validate the targets of natural active ingredients, enumerates the expansive list of TCM used to treat inflammatory diseases and cancer, and summarizes the patterns of action of emerging technologies such as single-cell multiomics, network pharmacology, and artificial intelligence in the pharmacological studies of natural products to provide insights for the development of innovative natural product-based drugs. Our hope is that we can make use of advances in target identification and singlecell multiomics to obtain a deeper understanding of actions of mechanisms of natural products that will allow innovation and revitalization of TCM and its swift industrialization and internationalization.

Necrostatin-1 protection of dopaminergic neurons

Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson＇s disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before exposure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death process of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range（5–30 μM） elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Parkinson＇s disease.

Identification of Potential Therapeutic Targets of Alzheimer's Disease By Weighted Gene Co-Expression Network Analysis

Objective Alzheimer's disease(AD)is the most common cause of dementia.The pathophysiology of the disease mostly remains unearthed,thereby challenging drug development for AD.This study aims to screen high throughput gene expression data using weighted co-expression network analysis(WGCNA)to explore the potential therapeutic targets.Methods The dataset of GSE36980 was obtained from the Gene Expression Omnibus(GEO)database.Normalization,quality control,filtration,and soft-threshold calculation were carried out before clustering the co-expressed genes into different modules.Furthermore,the correlation coefiidents between the modules and clinical traits were computed to identify the key modules.Gene ontology and pathway enrichment analyses were performed on the key module genes.The STRING database was used to construct the protein-protein interaction(PPI)networks,which were further analyzed by Cytoscape app(MCODE).Finally,validation of hub genes was conducted by external GEO datasets of GSE 1297 and GSE 28146.Results Co-expressed genes were clustered into 27 modules,among which 6 modules were identified as the key module relating to AD occurrence.These key modules are primarily involved in chemical synaptic transmission(G0:0007268),the tricarboxylic acid(TCA)cycle and respiratory electron transport(R-HSA-1428517).WDR47,OXCT1,C3orfl4,ATP6V1A,SLC25A14,NAPB were found as the hub genes and their expression were validated by external datasets.Conclusions Through modules co-expression network analyses and PPI network analyses,we identified the hub genes of AD,including WDR47,0XCT1,C3orfl4i ATP6V1A,SLC25A14 and NAPB.Among them,three hub genes(ATP6V1A,SLC25A14,OXCT1)might contribute to AD pathogenesis through pathway of TCA cycle.

Neuroprotection of quercetin on central neurons against chronic high glucose through enhancement of Nrf2/Glo-1 mediated by phosphorylation regulation

OBJECTIVE To investigate the neuroprotective effects of quercetin on central neurons against chronic high glucose in central neurons,in relation to Nrf2/ARE/Glo-1 activation.METHODS SH-SY5Y cells were cultured with high glucose(HG,70 mmol·L^(-1)),4-fold of the normal glucose(17.5 mmol·L^(-1)).Quercetin was set three concentrations(5,10,20μmol·L^(-1)),with Nrf2 activator sulforaphane(SFN)as a positive group(2.5μmol·L^(-1)).After 72 h,cells were collected for glyoxalase 1(Glo-1)activity and GSH level were by spectrophotometry;advanced glycation end-products(AGEs)as well as nuclear Nrf2 and p-Nrf2 levels by immunofluorescence;Glo-1,γ-glutamycysteine synthase(γ-GCS),Nrf2 and p-Nrf2 protein levels by Western blotting,and Glo-1 andγ-GCS m RNA levels by real-time qP CR.RESULTS Quercetin increased the cell viability of SH-SY5Y cells,and upregulated the levels of Glo-1 activity,protein,and m RNA in SH-SY5Y cells cultured with HG,accompanied by the elevated levels of glutathione,a cofactor of Glo-1 activity,and the reduced levels of AGEs.Meanwhile,quercetin could increase p-Nrf2 and Nrf2 levels in nucleus as well as p-Nrf2 levels in cytosol of SH-SY5Y cells exposed to chronic HG,accompanied by the elevated protein expression and m RNA levels ofγ-GCS,a known target gene of Nrf2/ARE signaling.Moreover,a PKC activator or a p38MAPK inhibitor pretreatment could significantly increase the protein expression ofγ-GCS in HG condition,but an alkylating agent for sulfydryl of cysteine in Keap 1,a negative regulator of Nrf2,pretreatment only showed an increased tendency ofγ-GCS protein,compared with without pretreatment;however,after pretreatment with those tool drugs,co-treatment with quercetin and HG had similar results to those of single tool drug pretreatment followed by HG exposure.CONCLUSION Firstly,quercetin can enhance Glo-1 function in central neurons,which is mediated by activation of Nrf2/ARE pathway,then exerts the neuroprotection against HG induced damage;moreover,PKC and p38 MAPK pathways may be involved in Nrf2 inactivation in chronic HG condition.

Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus

Background:Hippocampal damage caused by status epilepticus(SE)can bring about cognitive decline and emotional disorders,which are common clinical comorbidities in patients with epilepsy.It is therefore imperative to develop a novel therapeutic strat-egy for protecting hippocampal damage after SE.Mitochondrial dysfunction is one of contributing factors in epilepsy.Given the therapeutic benefits of mitochondrial replenishment by exogenous mitochondria,we hypothesized that transplantation of mitochondria would be capable of ameliorating hippocampal damage following SE.Methods:Pilocarpine was used to induced SE in mice.SE-generated cognitive de-cline and emotional disorders were determined using novel object recognition,the tail suspension test,and the open field test.SE-induced hippocampal pathology was assessed by quantifying loss of neurons and activation of microglia and astrocytes.The metabolites underlying mitochondrial transplantation were determined using metabonomics.Results:The results showed that peripheral administration of isolated mitochon-dria could improve cognitive deficits and depressive and anxiety-like behaviors.Exogenous mitochondria blunted the production of reactive oxygen species,pro-liferation of microglia and astrocytes,and loss of neurons in the hippocampus.The metabonomic profiles showed that mitochondrial transplantation altered multiple metabolic pathways such as sphingolipid signaling pathway and carbon metabolism.Among potential affected metabolites,mitochondrial transplantation decreased levels of sphingolipid(d18:1/18:0)and methylmalonic acid,and elevated levels of D-fructose-1,6-bisphosphate.Conclusion:To the best of our knowledge,these findings provide the first direct ex-perimental evidence that artificial mitochondrial transplantation is capable of amelio-rating hippocampal damage following SE.These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy-associated psychiat-ric and cognitive disorders.

Divergent defluorocarboxylation of α-CF_(3) alkenes with formate via photocatalyzed selective mono-or triple C-F bond cleavage

Unprecedented divergent synthesis of gem-difluorovinylacetic acid and glutaric acid derivatives fromα-CF_(3)alkenes with formate as the carbonyl source was disclosed.The reaction can undergo selective mono-or triple C-F bond cleavage by simply switching the photocatalyst and hydrogen atom transfer(HAT)catalyst under visible-light-induced conditions at room temperature.Foramte acts as both the C1 source and the reductant through the generation of CO_(2)^(·-)species,which underwent Giese radical addition to electron-deficient alkenes to trigger the consecutive C-F bond cleavage and carboxylation process.

High-throughput fluorescent screening of thioredoxin reductase inhibitors to inhibit Mycobacterium tuberculosis

Tuberculosis(TB)is a chronic infectious disease,which is caused by the pathogen Mycobacterium tuberculosis(Mtb)and reemerged as a global health risk with a significant proportion of multi-drug resistant and extensively drug resistant TB cases.It is very urgent to find some novel high-confidence drug targets in Mtb for discovering the effective anti-TB agents.Thioredoxin reductase(TrxR)has been identified to be a highly viable target for anti-TB drugs for its important role in protecting the pathogen from thiol-specific oxidizing stress,regulating intracellular dithiol/disulfide homeostasis and DNA replication and repair.In the present work,a near-infrared(NIR)fluorescent probe DDAT was developed for the detection of TrxR activity and used to high-throughput screen the TrxR inhibitors from natural products.Two screened TrxR inhibitors from Sappan Lignum and microbial metabolites that were further used to inhibit Mycobacterium tuberculosis.All the results indicate that DDAT is a practical fluorescent molecular tool for the discovery of potential anti-TB drugs.

A NIR fluorescent probe for Vanin-1 and its applications in imaging, kidney injury diagnosis,and the development of inhibitor

Vanin-1 is an amidohydrolase that catalyses the conversion of pantetheine into the aminothiol cysteamine and pantothenic acid(coenzyme A precursor), which plays a vital role in multiple physiological and pathological processes. In this study, an enzyme-activated near-infrared(NIR) fluorescent probe(DDAV) has been constructed for sensitively detecting Vanin-1 activity in complicated biosamples on the basis of its catalytic characteristics. DDAV exhibited a high selectivity and sensitivity toward Vanin-1 and was successfully applied to the early diagnosis of kidney injury in cisplatin-induced kidney injury model. In addition, DDAV could serve as a visual tool for in situ imaging endogenous Vanin-1 in vivo. More importantly, Enterococcus faecalis 20247 which possessed high expression of Vanin-1 was screened out from intestinal bacteria using DDAV, provided useful guidance for the rational use of NSAIDs in clinic. Finally, oleuropein as a potent natural inhibitor for Vanin-1 was discovered fromherbal medicines library using a high-throughput screening method using DDAV, which held great promise for clinical therapy of inflammatory bowel disease.

Conditional Deletion of Foxg1 Alleviates Demyelination and Facilitates Remyelination via the Wnt Signaling Pathway in Cuprizone-Induced Demyelinated Mice

The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells(OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone(CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type(WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3 b, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.

Hesperetin induces glyoxalase 1 enhancement in SH-SY5Y cells cultured with high glucose via Nrf2/ARE activation

OBJECTIVE To investigate the neuroprotective effects of hesperetin on central neurons under chronic high glucose,and the relationship to glyoxalase 1(Glo-1),a cytoprotective enzyme.METHODS The human neuroblas⁃toma SH-SY5Y cells were divided into 5 groups:normal glucose,high glucose(HG),HG plus low,middle,or high concentra⁃tion of hesperetin(1,5,25μmol·L^-1).After treatment for 72 h,neuron damages,Glo-1 expressions and functions,as well as Nrf2/ARE pathway and its regulating mechanisms were examined.RESULTS Hesperetin increased cell viability and decreased lactate dehydrogenase release,which was accompanied by the elevated activity,protein,and mRNA levels of Glo-1 as well as the enhanced Glo-1 functions in SH-SY5Y cells cultured with HG.Moreover,hesperetin activated Nrf2/ARE pathway as evidenced by the raised Nrf2 and p-Nrf2 levels in nucleus and up-regulation of γ-glutamycysteine synthase(γ-GCS),a well-known target gene of Nrf2/ARE pathway.Nevertheless,pretreatment with a PKC inhibitor(Go 6983)or an Akt inhibitor(MK-22062HCl,reflecting GSK-3β activation)abolished the effect of hesperetin on protein expressions of Glo-1 and γ-GCS.CONCLUSION Hesperetin exerted the neuroprotection by promoting Glo-1 function in central neurons in long-term HG condition,which was mediated by activation of Nrf2/ARE pathway;moreover,the increased Nrf2 phosphorylation and nuclear translocation mediated by PKC activation and/or GSK-3β inhibition were involved in the activation of Nrf2/ARE pathway by hesperetin.

Chiral Br?nsted acid-catalyzed asymmetric intermolecular[4+2]annulation of ynamides with para-quinone methides

Catalytic asymmetric transformations of ynamides have attracted considerable attention in recent years.However,most of them were limited to intramolecular reactions or required metal catalysts.Herein,a chiral Br?nsted acid-catalyzed asymmetric intermolecular[4+2]annulation of ynamides with para-quinone methides(p-QMs)is disclosed,which not only represents the first metal-free protocol for catalytic asymmetric nucleophilic addition of ynamides to electrophiles,but also constitutes the first enantioselective annulation between p-QMs and alkynes.This methodology leads to the practical synthesis of biologically important chiral 4-aryl-3,4-dihydrocoumarins and 4-aryl-coumarins.Preliminary control experiments indicate that the orthohydroxyphenyl substituted p-QMs could isomerize into ortho-quinone methides(o-QMs)in the presence of chiral catalyst,which further react with ynamides via enantioselective[4+2]annulation,to generate the chiral product.

Allosterically activating SHP2 by oleanolic acid inhibits STAT3-Th17 axis for ameliorating colitis

Src homology 2 domain-containing tyrosine phosphatase 2(SHP2)is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth,differentiation,and survival.The activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's disease.Thus,the identification of SHP2 activators and a complete understanding of their mechanism is required.We used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open conformation.Oleanolic acid was identified as a suitable candidate.By binding to R362,K364,and K366 in the active center of the PTP domain,oleanolic acid maintained the active open state of SHP2,which facilitated the binding between SHP2 and its substrate.This oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rαand inhibiting the activation of STAT3.Furthermore,via the activation of SHP2 and subsequent attenuation of the STAT3-Th17 axis,oleanolic acid effectively mitigated colitis in mice.This protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor SHP099.These findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

A hepatoprotection study of Radix Bupleuri on acetaminophen-induced liver injury based on CYP450 inhibition

We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serum aspartate transaminase(AST) and alanine transaminase(ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine(APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione(GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2 E1 and CYP3 A activity. Further investigation revealed the increasing of CYP2 E1 and CYP3 A protein was significantly inhibited in pretreatment group,while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.

Electrospun Core-Shell Fibrous 2D Scaffold with Biocompatible Poly(Glycerol Sebacate) and Poly-l-Lactic Acid for Wound Healing

Biomimetic scaffolds made by synthetic materials are usually used to replace the natural tissues aimed at speeding up the skin regeneration.In this study,a flexible and cytocompatible poly(glycerol sebacate)@poly-l-lactic acid(PGS@PLLA)fibrous scaffold with a core-shell structure was fabricated by coaxial electrospinning,where the shell PLLA was used to be a skeleton with pores on the fibrous surface.The fibrous morphology with pores on the surface of the prepared fibers was observed by SEM.The core-shell microstructure of PGS@PLLA fibers was confirmed by TEM and Laser Scanning Confocal Microscopy(LSCM).In addition,the prepared fibers exhibited a strong ability to repair tissues of the skin wound,where the stability of cell security and proliferation,and the lower inflammatory response were all superior to those of pure PLLA scaffold.It’s worth noting that the percentage of skin tissue was regenerated by 95%within 14 days,which suggests the potential application for electrospun-based synthetic fibrous scaffolds on wound healing.

Real-time identification of gut microbiota with aminopeptidase N using an activable NIR fluorescent probe

A NIR fluorescent probe(DDAA) derived from fluorophore DDAO with alanine as the recognition group was developed for sensing aminopeptidase N(APN) in gut microbiota.Using DDAA as the real-time guidance tool for the fluorescence imaging of intestinal microorganism,target bacteria and saccharomycete possessing active APN were identified successfully from human feces.

Characterization of a small-molecule inhibitor targeting NEMO/IKKβto suppress colorectal cancer growth

NEMO/IKKβcomplex is a central regulator of NF-κB signaling pathway,its dissociation has been considered to be an attractive therapeutic target.Herein,using a combined strategy of molecular pharmacological phenotyping,proteomics and bioinformatics analysis,Shikonin(SHK)is identified as a potential inhibitor of the IKKβ/NEMO complex.It destabilizes IKKβ/NEMO complex with IC_(50) of 174 nM,thereby significantly impairing the proliferation of colorectal cancer cells by suppressing the NF-κB pathway in vitro and in vivo.In addition,we also elucidated the potential target sites of SHK in the NEMO/IKKβcomplex.Our study provides some new insights for the development of potent small-molecule PPI inhibitors.