Mesenchymal stem cell-derived exosome:The likely game-changer in stem cell research

Stem cell research is a promising area of transplantation and regenerative medicine with tremendous potential for improving the clinical treatment and diagnostic options across a variety of conditions and enhancing understanding of human development.Over the past few decades,mesenchymal stem cell(MSCs)studies have exponentially increased with a promising outcome.However,regardless of the huge investment and the research attention given to stem cell research,FDA approval for clinical use is still lacking.Amid the challenges confronting stem cell research as a cellbased product,there appears to be evidence of superior effect and heightened potential success in its expressed vesicles,exosomes,as cell-free products.In addition to their highly desirable intrinsic biologically unique structural,compositional,and morphological characteristics,as well as predominant physiochemical stability and biocompatibility properties,exosomes can also be altered to enhance their therapeutic capability or diagnostic imaging potential via physical,chemical,and biological modification approaches.More importantly,the powerful therapeutic potential and superior biological functions of exosomes,particularly,regarding engineered exosomes as cell-free products,and their utilization in a new generation of nanomedicine treatment,vaccination,and diagnosis platforms,brings hope of a change in the near future.This viewpoint discusses the trend of stem cell research and why stem cell-derived exosomes could be the game-changer.

Retrieving Soil Moisture in Hebei by Using Temperature Vegetation Dryness Index

The temperature-vegetation index space coupled with information of surface temperature and vegetation, is an important method to realize soil moisture estimation and agricultural drought monitoring. In order to estimate the soil moisture in the study area, we collected soil relative humidity of Agricultural meteorological station and downloaded Moderate Resolution Imaging Spectrometer (MODIS) image data. Then, the temperature vegetation dryness index was calculated based on the MODIS Normalized difference vegetation index (NDVI) and land surface temperature (LST). A correlation analysis of TVDI and soil relative humidity at depth of 10 cm was carried out and an empirical model of moisture estimation was established. Finally, another set of data was used to validate the accuracy of model. The results show that the TVDI method can be used to achieve the soil moisture in the study area. The empirical model has certain universality in the study area, and obtains a high accuracy of soil moisture estimation with an R2 of 0.374 and RMSE of 11.73%.

Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent

Chemotherapy-induced complications,particularly lethal cardiovascular diseases,pose significant challenges for cancer survivors.The intertwined adverse effects,brought by cancer and its complication,further complicate anticancer therapy and lead to diminished clinical outcomes.Simple supplementation of cardioprotective agents falls short in addressing these challenges.Developing bifunctional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously.Drug repurposing was naturally endowed with co-therapeutic potential of two indications,implying a unique chance in the development of bi-functional agents.Herein,we further proposed a novel“trilogy of drug repurposing”strategy that comprises function-based,targetfocused,and scaffold-driven repurposing approaches,aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent.Through function-based repurposing,a cardioprotective agent,carvedilol(CAR),was identified as a potential neddylation inhibitor to suppress lung cancer growth.Employing target-focused SAR studies and scaffold-driven drug design,we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection.Remarkably,optimal derivative 43 displayed promising bi-functional effects,especially in various self-established heart failure mice models with and without tumor-bearing.Collectively,the present study validated the practicability of the“trilogy of drug repurposing”strategy in the development of bi-functional cotherapy agents.

Repurposing antimycotic ciclopirox olamine as a promising anti-ischemic stroke agent

Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis.Here we demonstrated that post-ischemic treatment with ciclopirox olamine(CPX),a potent antifungal clinical drug,alleviated brain infarction,neurological deficits and brain edema in a classic rat model of ischemic stroke.Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect,which can be further enhanced by multiple doses administration of CPX.CPX also effectively reversed ischemia-induced neuronal loss,glial activation as well as blood-brain barrier(BBB)damage.Employing quantitative phosphoproteomic analysis,130 phosphosites in 122 proteins were identified to be significantly regulated by CPX treatment in oxygen glucose deprivation(OGD)-exposed SH-SY5 Y cells,which revealed that phosphokinases and cell cycle-related phosphoproteins were largely influenced.Subsequently,we demonstrated that CPX markedly enhanced the AKT(protein kinase B,PKB/AKT)and GSK3β(glycogen synthase kinase 3β)phosphorylation in OGD-exposed SH-SY5 Y cells,and regulated the cell cycle progression and nitric oxide(NO)release in lipopolysaccharide(LPS)-induced B V-2 cells,which may contribute to its ameliorative effects against ischemia-associated neuronal death and microglial inflammation.Our study suggests that CPX could be a promising compound to reduce multiple ischemic injuries;however,further studies will be needed to clarify the molecular mechanisms involved.

The Features and Regulation of Co-transcriptional Splicing in Arabidopsis

Precursor mRNA(pre-mRNA)splicing is essential for gene expression in most eukaryotic organisms.Previous studies from mammals,Drosophila,and yeast show that the majority of splicing events occurs co-transcriptionally.In plants,however,the features of co-transcriptional splicing(CTS)and its regulation still remain largely unknown.Here,we used chromatin-bound RNA sequencing to study CTS in Arabidopsis thaliana.We found that CTS is widespread in Arabidopsis seedlings,with a large proportion of alternative splicing events determined co-transcriptionally.CTS efficiency correlated with gene expression level,the chromatin landscape and,most surprisingly,the number of introns and exons of individual genes,but is independent of gene length.In combination with enhanced crosslinking and immunoprecipitation sequencing analysis,we further showed that the hnRNP-like proteins RZ-1B and RZ-1C promote efficient CTS globally through direct binding,frequently to exonic sequences.Notably,this general effect of RZ-1B/1C on splicing promotion is mainly observed at the chromatin level,not at the mRNA level.RZ-1C promotes CTS of multiple-exon genes in association with its binding to regions both proximal and distal to the regulated introns.We propose that RZ-1C promotes efficient CTS of genes with multiple exons through cooperative interactions with many exons,introns,and splicing factors.Our work thus reveals important features of CTS in plants and provides methodologies for the investigation of CTS and RNA-binding proteins in plants.

Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer’s disease

Drug repurposing is an efficient strategy for new drug discovery.Our latest study found that nitazoxanide(NTZ),an approved anti-parasite drug,was an autophagy activator and could alleviate the symptom of Alzheimer’s disease(AD).In order to further improve the efficacy and discover new chemical entities,a series of NTZ-based derivatives were designed,synthesized,and evaluated as autophagy activator against AD.All compounds were screened by the inhibition of phosphorylation of p70S6K,which was the direct substrate of mammalian target of rapamycin(mTOR)and its phosphorylation level could reflect the mTOR-dependent autophagy level.Among these analogs,compound 22 exhibited excellent potency in promotingβ-amyloid(Aβ)clearance,inhibiting tau phosphorylation,as well as stimulating autophagy both in vitro and in vivo.What’s more,22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice.These results demonstrated that 22 was a potential candidate for the treatment of AD.

General Reductive Amination of Aldehydes and Ketones with Amines and Nitroaromatics under H2 by Recyclable Iridium Catalysts

Heterogeneous iridium catalysts were prepared and applied for the reductive amination of aldehydes and ketones with nitroaromatics and amines using H2. The iridium catalysts were prepared by pyrolysis of ionic liquid 1-methyl-3-cyanomethylimidazoulium chloride （[MCNI]C1） with iridium chloride （IrC13） in activated carbons. Iridium particles were well dispersed and stable in the N-doped carbon materials from [MCNI]C1 with activated carbon. The Ir@NC（600-2h） catalyst was found to be highly active and selective for the reductive amination of aldehydes and ketones using H2 and a variety of nitrobenzenes and amines were selectively converted into the corresponding secondary and tertiary amines. The Ir@NC（600-2h） catalyst can be reusable several times without evident deactivation.

Comparison of hepatic gene expression profiles between three mouse models of Nonalcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder worldwide. Murine models of NAFLD have been widely used to explore its pathogenesis. In this study, we performed a systematic evaluation of hepatic genome-wide mRNA expression by RNA-Sequencing using three mouse models of NAFLD: leptin receptor deficient db/db mice, high-fat high-sugar diet (HSHF)-induced obese mice, and dexamethasone (DEX)-induced NAFLD mice. As a result, we found both distinct and common pathways in the regulation of lipid metabolism from transcriptomes of three mouse models. Moreover, only a total of 12 differentially expressed genes (DEGs) were commonly detected among all three mouse groups, indicating very little overlap among all three models. Therefore, our results suggest that NAFLD is a heterogeneous disease with highly variable molecular mechanisms.

Cucurbitacin B-induced G2/M cell cycle arrest of conjunctival melanoma cells mediated by GRP78-FOXM1-KIF20A pathway

Conjunctival melanoma(CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B(CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16,CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a Kdvalue of0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78-FOXM1-KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway.

Emerging role of protein modification in inflammatory bowel disease

The onset of inflammatory bowel disease(IBD)involves many factors,including environmental parameters,microorganisms,and the immune system.Although research on IBD continues to expand,the specific pathogenesis mechanism is still unclear.Protein modification refers to chemical modification after protein biosynthesis,also known as post-translational modification(PTM),which causes changes in the properties and functions of proteins.Since proteins can be modified in different ways,such as acetylation,methylation,and phosphorylation,the functions of proteins in different modified states will also be different.Transitions between different states of protein or changes in modification sites can regulate protein properties and functions.Such modifications like neddylation,sumoylation,glycosylation,and acetylation can activate or inhibit various signaling pathways(e.g.,nuclear factor-κB(NF-κB),extracellular signal-regulated kinase(ERK),and protein kinase B(AKT))by changing the intestinal flora,regulating immune cells,modulating the release of cytokines such as interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and interferon-γ(IFN-γ),and ultimately leading to the maintenance of the stability of the intestinal epithelial barrier.In this review,we focus on the current understanding of PTM and describe its regulatory role in the pathogenesis of IBD.

Discovery of synergistic activity of fluoroquinolones in combination with antimicrobial peptides against clinical polymyxin-resistant Pseudomonas aeruginosa DK2

Polymyxin B(PB),as the last-line of defense against multidrug-resistant Gram-negative bacteria,has caused resistance to P.aeruginosa recently.Fortunately,synergistic treatment could preserve the last class of antibiotics and reduce the emergency of drug resistance.Here,we performed a screen of 970 approved drugs synergized with PB against the P.aeruginosa DK2,which is severely resistant to PB,MIC=512μg/mL.Encouragingly,we found fluoroquinolones could synergy with PB and achieved an obvious reduction in MIC of PB below the clinical susceptible breakpoint(2 μg/mL).Especially,gemifloxacin achieved the highest synergistic effect with PB,leading to a 4096-fold MIC reduction(reduced from512 μg/mL to 0.125 μg/mL).Furthermore,synergistic effect was also observed in the combination of gemifloxacin and colistin.Finally,outer membrane permeabilization assay showed that gemifloxacin could increase the permeability of bacterial cell membranes for P.aeruginosa which partly explained the synergy mechanism.These results indicate that fluoroquinolones represent attractive synergists to address the emerging threat of polymyxin-resistant infections.

HucMSC-Ex alleviates inflammatory bowel disease via the lnc78583-mediated miR3202/HOXB13 pathway

As a group of nonspecific inflammatory diseases affecting the intestine,inflammatory bowel disease(IBD)exhibits the characteristics of chronic recurring inflammation,and was proven to be increasing in incidence(Kaplan,2015).IBD induced by genetic background,environmental changes,immune functions,microbial composition,and toxin exposures(Sasson et al.,2021)primarily includes ulcerative colitis(UC)and Crohn's disease(CD)with complicated clinical symptoms featured by abdominal pain,diarrhea,and even blood in stools(Fan et al.,2021;Huang et al.,2021).

Pro-senescence neddylation inhibitor combined with a senescence activated β-galactosidase prodrug to selectively target cancer cells

Dear Editor,Targeting senescence therapy is a promising anticancer strategy by arresting the cell-cycle and inducing cellular senescence.However,senescent cells can promote malignancy and drug resistance.1,2 Thus,with the induction of senescence emerged as a viable therapeutic concept,it is important to consider how to eliminate those senescent cancer cells.

Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation

Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2(FP-2) and Plasmodium falciparum dihydrofolate reductase(PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme(IC_(50)= 6.8 + 1.8 mmol/L and IC_(50)= 8.8 + 0.3 mmol/L) and P. falciparum 3D7 strain(IC50= 2.9mmol/L).Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P.falciparum Dd2 strain(IC_(50)= 1.1 mmol/L) than pyrimethamine(IC_(50)>10 mmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9(IC_(50)= 2.6 mmol/L) and GB4(IC_(50)= 1.0 mmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria.

Repurposing of antitumor drug candidate Quisinostat lead to novel spirocyclic antimalarial agents

Antimalarial chemotherapies endowed with effectiveness against drug-resistant parasites and good safety are urgently required in clinical.Our previous research revealed that clinical phaseⅡantitumor drug Quisinostat was a promising antimalarial prototype by inhibiting the activity of Plasmodium falciparum(P.falciparum)histone deacetylase(PfHDAC).Herein,30 novel spirocyclic linker derivatives were designed and synthesized based on Quisinostat as lead compound,and then their antimalarial activities and cytotoxicity were systematically evaluated.Among them,compounds 8 and 27 could effectively eliminate wild-type and multi-drug resistant P.falciparum parasites,and display weakened cytotoxicity and good metabolic stability.Western blot assay demonstrated that they could inhibit PfHDAC activity like Quisinostat.In addition,both 8 and 27 showed certain antimalarial efficacy in rodent malaria model,and the animal toxicity of 8 was significantly improved compared with Quisinostat.Overall,8 and 27 were structurally novel PfHDAC inhibitors and provided prospective prototype for further antimalarial drug research.

Promotion of nonalcoholic steatohepatitis by RNA N^(6)-methyladenosine reader IGF2BP2 in mice

Nonalcoholic steatohepatitis(NASH)has emerged as the major cause of end-stage liver diseases.However,an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies.In the present study,through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis,we identified IGF2BP2,an N6-methyladenosine modification reader,as a key regulator that promotes NASH progression in mice.Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis,inflammation,and fibrosis in mice,at least in part,by increasing Tab2 mRNA stability.Besides,hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers.Of potential clinical significance,IGF2BP2 expression is significantly upregulated in the livers of NASH patients.Moreover,knockdown of IGF2BP2 substantially alleviated liver injury,inflammation,and fibrosis in diet-induced NASH mice.Taken together,our findings reveal an important role of IGF2BP2 in NASH,which may provide a new therapeutic target for the treatment of NASH.

Intergenerational hyperglycemia through epigenetic alterations of gametes

In a recent study published in Nature,Chen et al.reported a mechanism through which hyperglycemia is transmitted from female mice to their offspring through their eggs and DNA methylation of the paternal-derived pancreatic Gck promoter is increased due to a decrease of maternal effector TET3 dioxygenase.