[Identification of key genes and functions in lung metastasis of osteosarcoma based on bioinformatics].

OBJECTIVE: To screen the differentially expressed genes of lung metastasis of osteosarcoma by bioinformatics, and explore their functions and regulatory networks. METHODS: The data set of GSE14359 was screened from GEO database(http://www.ncbi.nlm.nih.gov/gds) and the differentially expressed gene(DEG) was identified using GEO2R online tool. Download osteosarcoma disease related miRNAs from the online HMMD database(http://www.cuilab.cn/hmdd) and then FunRich software was used to predict the target gene, intersects with DEG to obtains the target gene. The miRNA-mRNA relationship pairs were formed according to the targeted joints, then the data was imported into Cytoscape for visualization, DAVID was used to performe GO and KEGG analysis on target genes, STRING was used to construct PPI network, Cytoscape visualization, CytoHubba plug-in screening central genes and online website for expression and survival analysis. RESULTS: Total 704 DEGs were identified, consisting of 477 up-regulated genes and 227 down regulated genes. FunRich predicted 7 888 mRNAs and 343 target genes were obtained through intersection of the two. KEGG analysis showed that it was mainly involved in focal adhesion, ECM receptor interaction, TNF signal pathway, PI3K-Akt signal pathway, IL-17 signal pathway and MAPK signal pathway. Ten central genes (CCNB1, CHEK1, AURKA, DTL, RRM2, MELK, CEP55, FEN1, KPNA2, TYMS) were identified as potential key genes. Among them, CCNB1, DTL, MELK were highly correlated with poor prognosis. CONCLUSION: The key genes and functional pathways identified in this study may be helpful to understand the molecular mechanism of the occurrence and progression of lung metastases from osteosarcoma, and provide potential therapeutic targets.

Assessment of heavy metal(oid) pollution and related health risks in agricultural soils surrounding a coal gangue dump from an abandoned coal mine in Chongqing, Southwest China.

The coal gangue dump may introduce heavy metal(oid)s (HMs) into surrounding agricultural soils, posing potential health risks to nearby communities. This study evaluated heavy metal(oid) pollution in agricultural soils adjacent to a gangue dump at an abandoned coal mine in Chongqing, Southwest China. The concentrations of HMs (As, Cd, Cr, Cu, Ni, Pb, and Zn) were quantified using ICP-MS, and the contamination status was assessed using the Geoaccumulation Index (Igeo), Contamination Factor (CF), Pollution Load Index (PLI), and Potential Ecological Risk Index (RI). Heavy metal(oid) contamination was detected in soils across a depth of 0-30 cm, particularly pronounced in the topsoil layer (0-10 cm and 10-20 cm depths). Cu emerged as the predominant contaminant across all examined depths, with average Igeo values of 1.20, 1.21, and 1.16 for the 0-10 cm, 10-20 cm, and 20-30 cm depths, respectively, indicating moderate contamination. The CF for Cu was 3.55, 3.55, and 3.50 for these respective depths, classifying it as considerable contamination. The PLI values ranged from 1.61 to 2.50, with a mean value of 2.12, indicating overall contamination. The ecological risk assessment indicated that the soil's ecological risk was low at all depths. Cd was the major contributor to the RI, accounting for 48%, 47%, and 42% at 0-10 cm, 10-20 cm, and 20-30 cm depths, respectively. Health risk assessments revealed significant non-carcinogenic risks to children (mean HI = 1.30) and unacceptable carcinogenic risks to both adults and children (mean TCR = 3.26 × 10-4 and 1.53 × 10-3, respectively). This study underscores the critical need for comprehensive risk assessments using multiple indicators to prioritize remediation efforts for HMs, providing a scientific basis for effective environmental management and public health protection in the Three Gorges Reservoir Area.

Evaluation of chemical components and quality in Xinhui Chenpi (Citrus reticulata 'Chachi') with two different storage times by GC-MS and UPLC.

Xinhui Chenpi (XHCP) is a well-known type of Chenpi (CP) widely used as both a Chinese herb and a food ingredient. While previous studies have explored how the quality of CP changes over time, there has been limited research specifically on XHCP. This study aims to assess the chemical components and quality of XHCP based on total flavonoid content (TF), antioxidant activity (AA), and color value (CV) at two stages: freshly harvested (XHCP-0Y) and after 3 years of storage (XHCP-3Y). Thirty-eight common volatile compounds were identified, and the content of 17 compounds among them, nine nonvolatile compounds, which included one alkaloid (synephrine), three phenolic acids (PA, protocatechuic acid, vanillic acid, and ferulic acid), and five flavonoids (narirutin, hesperidin, sinensetin, nobiletin, and tangeretin), were firstly detected by the newly developed gas chromatograph-mass spectrometer (GC-MS) and ultra-performance liquid chromatography (UPLC) methods. Compared to XHCP-0Y, the content of 17 volatile compounds and synephrine decreased in XHCP-3Y to varying degrees, while the content of PA, five flavonoids, TF, AA, and CV increased. The reduction of dryness caused by volatile compounds and the enhancement of efficacy related to PA, flavonoids, and AA suggested improved quality of XHCP after 3 years of storage. The methods developed in this study show promise for evaluating the quality of XHCP during the aging process.

Relationship between dietary fiber intake and chronic diarrhea in adults.

BACKGROUND: Dietary fiber is essential for human health and can help reduce the symptoms of constipation. However, the relationship between dietary fiber and diarrhea is, poorly understood. AIM: To evaluate the relationship between dietary fiber and chronic diarrhea. METHODS: This retrospective study was conducted using data from the United States National Health and Nutrition Examination Survey, conducted between 2005 and 2010. Participants over the age of 20 were included. To measure dietary fiber consumption, two 24-hour meal recall interviews were conducted. The independent relationship between the total amount of dietary fiber and chronic diarrhea was evaluated with multiple logistic regression and interaction analysis. RESULTS: Data from 12829 participants were analyzed. Participants without chronic diarrhea consumed more dietary fiber than participants with chronic diarrhea (29.7 vs 28.5, P = 0.004). Additionally, in participants with chronic diarrhea, a correlation between sex and dietary fiber intake was present: Women who consume more than 25 g of dietary fiber daily can reduce the occurrence of chronic diarrhea. CONCLUSION: Dietary fiber can reduce the occurrence of chronic diarrhea.

Space-Like Irradiation Exacerbated Cognitive Deficits and Amyloid Pathology in CRND8 Mouse Model of Alzheimer's Disease.

Background: Space radiation was linked to neurological damage and behavioral deficits which raised concerns of increased degenerative risk on the brain and development of Alzheimer's disease following space travel. Objective: In this study, we investigated the effects of irradiation by 56Fe and 28Si in CRND8 mice, an Alzheimer's disease mouse model. Methods: Six-month-old CRND8 mice were exposed to whole body irradiation by 56Fe and 28Si at 0.5 Gy and 2 Gy doses. Behavior tests were administered 1-month to 3-months post-irradiation. Amyloid deposition and other pathological changes were analyzed 3-months and/or 6-months post-irradiatio. Results: The Novel Object Recognition test showed some decline in 8-month-old mice compared to non-irradiated CRND8 mice. Male mice also showed a loss of freezing behavior in the fear conditioning contextual test following irradiation. Golgi staining revealed a loss of spines in hippocampal neurons after irradiation. Total amyloid immunohistochemistry showed a robust increase in 3-months post-irradiation 56Fe groups which became normalized to non-irradiated group by 6-months post-irradiation. However, 2 Gy 28Si caused a trend towards increased plaque load at 3-months post-irradiation which became significant at 6-months post irradiation only in male CRND8 mice. While 0.5 Gy Fe did not induce obvious changes in the total number of iba-1 positive microglia, more hippocampal microglia were found to express PCNA after 0.5 Gy Fe treatment, suggesting potential involvement of microglial dysfunction. Conclusions: Overall, our study provides new evidence of gender-specific and ion-dependent effects of space radiation on cognition and amyloid pathology in AD models.

Plant-Derived Exosomes as Novel Nanotherapeutics Contrive Glycolysis Reprogramming-Mediated Angiogenesis for Diabetic Ulcer Healing.

Reversal of endothelial cell (EC) dysfunction under high-glucose (HG) conditions to achieve angiogenesis has remained a big challenge in diabetic ulcers. Herein, exosomes derived from medicinal plant ginseng (GExos) were shown as excellent nanotherapeutics with biomimetic cell membrane-like structures to be able to efficiently transfer the encapsulated active substances to ECs, resulting in a marked reprogramming of glycolysis by up-regulating anaerobic glycolysis and down-regulating oxidative stress, which further restore the proliferation, migration, and tubule formation abilities of ECs under HG conditions. In vivo, GExos enhance the angiogenesis and nascent vessel network reconstruction in full-thickness diabetic complicated skin ulcer wounds in mice with high biosafety. GExos were shown as promising nanotherapeutics in stimulating glycolysis reprogramming-mediated angiogenesis in diabetic ulcers, possessing wide application potential for reversing hyperglycemic dysangiogenesis and stimulating vascular regeneration.

Advances in the isolation, cultivation, and identification of gut microbes.

The gut microbiome is closely associated with human health and the development of diseases. Isolating, characterizing, and identifying gut microbes are crucial for research on the gut microbiome and essential for advancing our understanding and utilization of it. Although culture-independent approaches have been developed, a pure culture is required for in-depth analysis of disease mechanisms and the development of biotherapy strategies. Currently, microbiome research faces the challenge of expanding the existing database of culturable gut microbiota and rapidly isolating target microorganisms. This review examines the advancements in gut microbe isolation and cultivation techniques, such as culturomics, droplet microfluidics, phenotypic and genomics selection, and membrane diffusion. Furthermore, we evaluate the progress made in technology for identifying gut microbes considering both non-targeted and targeted strategies. The focus of future research in gut microbial culturomics is expected to be on high-throughput, automation, and integration. Advancements in this field may facilitate strain-level investigation into the mechanisms underlying diseases related to gut microbiota.

Incoherent partial superposition modeling for single-shot angle-resolved ellipsometry measurement of thin films on transparent substrates.

Ellipsometric measurement of transparent samples suffers from substrate backside reflection challenges, including incoherent and partial superposition issues. The recently developed angle-resolved ellipsometry (ARE) can naturally eliminate the backside reflections of substrates with a micro-spot equivalent thickness or thicker; however, for thinner substrates, ARE working with general incoherent backside reflection models shows significant inaccuracy or measurement failure. In this paper, an incoherent partial superposition (IPS) model is proposed to characterize the optical superposition effect between the frontside and uncertain backside reflections from an unknown substrate. IPS introduces a cosine-like correction of the backside reflection, corresponding to the overlapping-area change of backside and frontside reflections along with incident angles. Benefiting from ARE's wide-angle spectral imaging capability, IPS achieves single-shot measurement of thin film thicknesses on transparent substrates of unknown thickness. An ARE system was built and calibrated regarding the linear relationship between the cosine-corrected angular frequencies and substrate thicknesses. Then, commercial ITO films on glasses of different thicknesses ranging from 200 to 1000 µm were measured. Experimental results show that IPS-ARE results in a root-mean-square accuracy error of ∼1 nm in film thickness measurement and provides a ∼77% error reduction from general incoherent backside reflection models.

Siderophore-harboring gut bacteria and fecal siderophore genes for predicting the responsiveness of fecal microbiota transplantation for active ulcerative colitis.

BACKGROUND: Predictive markers for fecal microbiota transplantation (FMT) outcomes in patients with active ulcerative colitis (UC) are poorly defined. We aimed to investigate changes in gut microbiota pre- and post-FMT and to assess the potential value in determining the total copy number of fecal bacterial siderophore genes in predicting FMT responsiveness. METHODS: Patients with active UC (Mayo score ≥ 3) who had undergone two FMT procedures were enrolled. Fecal samples were collected before and 8 weeks after each FMT session. Patients were classified into clinical response and non-response groups, based on their Mayo scores. The fecal microbiota profile was accessed using metagenomic sequencing, and the total siderophore genes copy number via quantitative real-time polymerase chain reaction. Additionally, we examined the association between the total siderophore genes copy number and FMT efficacy. RESULTS: Seventy patients with UC had undergone FMT. The clinical response and remission rates were 50% and 10% after the first FMT procedure, increasing to 72.41% and 27.59% after the second FMT. The cumulative clinical response and clinical remission rates were 72.86% and 25.71%. Compared with baseline, the response group showed a significant increase in Faecalibacterium, and decrease in Enterobacteriaceae, consisted with the changes of the total bacterial siderophore genes copy number after the second FMT (1889.14 vs. 98.73 copies/ng, P < 0.01). Virulence factor analysis showed an enriched iron uptake system, especially bacterial siderophores, in the pre-FMT response group, with a greater contribution from Escherichia coli. The total baseline copy number was significantly higher in the response group than non-response group (1889.14 vs. 94.86 copies/ng, P < 0.01). A total baseline copy number cutoff value of 755.88 copies/ng showed 94.7% specificity and 72.5% sensitivity in predicting FMT responsiveness. CONCLUSIONS: A significant increase in Faecalibacterium, and decrease in Enterobacteriaceae and the total fecal siderophore genes copy number were observed in responders after FMT. The siderophore genes and its encoding bacteria may be of predictive value for the clinical responsiveness of FMT to active ulcerative colitis.

Bacterial c-di-GMP triggers metamorphosis of mussel larvae through a STING receptor.

Bacteria induced metamorphosis observed in nearly all marine invertebrates. However, the mechanism of bacteria regulating the larvae-juvenile metamorphosis remains unknown. Here, we test the hypothesis that c-di-GMP, a ubiquitous bacterial second-messenger molecule, directly triggers the mollusc Mytilus coruscus larval metamorphosis via the stimulator of interferon genes (STING) receptor. We determined that the deletion of c-di-GMP synthesis genes resulted in reduced c-di-GMP levels and biofilm-inducing activity on larval metamorphosis, accompanied by alterations in extracellular polymeric substances. Additionally, c-di-GMP extracted from tested varying marine bacteria all exhibited inducing activity on larval metamorphosis. Simultaneously, through pharmacological and molecular experiments, we demonstrated that M. coruscus STING (McSTING) participates in larval metamorphosis by binding with c-di-GMP. Our findings reveal that new role of bacterial c-di-GMP that triggers mussel larval metamorphosis transition, and extend knowledge in the interaction of bacteria and host development in marine ecosystems.

Fecal microbiota transplantation significantly improved respiratory failure of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to respiratory failure, and eventually death. However, there is a lack of effective treatments for ALS. Here we report the results of fecal microbiota transplantation (FMT) in two patients with late-onset classic ALS with a Japan ALS severity classification of grade 5 who required tracheostomy and mechanical ventilation. In both patients, significant improvements in respiratory function were observed following two rounds of FMT, leading to weaning off mechanical ventilation. Their muscle strength improved, allowing for assisted standing and mobility. Other notable treatment responses included improved swallowing function and reduced muscle fasciculations. Metagenomic and metabolomic analysis revealed an increase in beneficial Bacteroides species (Bacteroides stercoris, Bacteroides uniformis, Bacteroides vulgatus), and Faecalibacterium prausnitzii after FMT, as well as elevated levels of metabolites involved in arginine biosynthesis and decreased levels of metabolites involved in branched-chain amino acid biosynthesis. These findings offer a potential rescue therapy for ALS with respiratory failure and provide new insights into ALS in general.

Intestinal microecological transplantation for a patient with chronic radiation enteritis: A case report.

BACKGROUND: The gut microbiota is strongly associated with radiation-induced gut damage. This study aimed to assess the effectiveness and safety of intestinal microecological transplantation for treating patients with chronic radiation enteritis. CASE SUMMARY: A 64-year-old female with cervical cancer developed abdominal pain, diarrhea, and blood in the stool 1 year after radiotherapy. An electronic colonoscopy was performed to diagnose chronic radiation enteritis. Two courses of intestinal microecological transplantation and full-length 16S rRNA microbiological analysis were performed. The patient experienced short- and long-term relief from symptoms without adverse effects. Whole 16S rRNA sequencing revealed significant differences in the intestinal flora's composition between patient and healthy donors. Pathogenic bacteria, such as Escherichia fergusonii and Romboutsia timonensis, were more in the patient. Beneficial bacteria such as Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans, Ruminococcus bromii, and Bifidobacterium longum were more in the healthy donors. Intestinal microbiota transplantation resulted in a significant change in the patient's intestinal flora composition. The composition converged with the donor's flora, with an increase in core beneficial intestinal bacteria, such as Eubacterium rectale, and a decrease in pathogenic bacteria. Changes in the intestinal flora corresponded with the patients' alleviating clinical symptoms. CONCLUSION: Intestinal microecological transplantation is an effective treatment for relieving the clinical symptoms of chronic radiation enteritis by altering the composition of the intestinal flora. This study provides a new approach for treating patients with chronic radiation enteritis.

Bacterial c-di-GMP signaling gene affects mussel larval metamorphosis through outer membrane vesicles and lipopolysaccharides.

Biofilms serve as crucial cues for settlement and metamorphosis in marine invertebrates. Within bacterial systems, c-di-GMP functions as a pivotal signaling molecule regulating both biofilm formation and dispersion. However, the molecular mechanism of how c-di-GMP modulates biofilm-induced larval metamorphosis remains elusive. Our study reveals that the deletion of a c-di-GMP related gene in Pseudoalteromonas marina led to an increase in the level of bacterial c-di-GMP by knockout technique, and the mutant strain had an enhanced ability to produce more outer membrane vesicles (OMVs) and lipopolysaccharides (LPS). The mutant biofilms had higher induction activity for larval metamorphosis in mussels Mytilus coruscus, and OMVs play a major role in the induction activity. We further explored the function of LPS in OMVs. Extracted LPS induced high larval metamorphosis rate, and LPS content were subject to c-di-GMP and LPS-biosynthesis gene. Thus, we postulate that the impact of c-di-GMP on biofilm-induced metamorphosis is mediated through OMVs and LPS.

Consensus statement on research and application of Chinese herbal medicine derived extracellular vesicles-like particles (2023 edition).

To promote the development of extracellular vesicles of herbal medicine especially the establishment of standardization, led by the National Expert Committee on Research and Application of Chinese Herbal Vesicles, research experts in the field of herbal medicine and extracellular vesicles were invited nationwide with the support of the Expert Committee on Research and Application of Chinese Herbal Vesicles, Professional Committee on Extracellular Vesicle Research and Application, Chinese Society of Research Hospitals and the Guangdong Engineering Research Center of Chinese Herbal Vesicles. Based on the collation of relevant literature, we have adopted the Delphi method, the consensus meeting method combined with the nominal group method to form a discussion draft of "Consensus statement on research and application of Chinese herbal medicine derived extracellular vesicles-like particles (2023)". The first draft was discussed in online and offline meetings on October 12, 14, November 2, 2022 and April and May 2023 on the current status of research, nomenclature, isolation methods, quality standards and research applications of extracellular vesicles of Chinese herbal medicines, and 13 consensus opinions were finally formed. At the Third Academic Conference on Research and Application of Chinese Herbal Vesicles, held on May 26, 2023, Kewei Zhao, convenor of the consensus, presented and read the consensus to the experts of the Expert Committee on Research and Application of Chinese Herbal Vesicles. The consensus highlights the characteristics and advantages of Chinese medicine, inherits the essence, and keeps the righteousness and innovation, aiming to provide a reference for colleagues engaged in research and application of Chinese herbal vesicles at home and abroad, decode the mystery behind Chinese herbal vesicles together, establish a safe, effective and controllable accurate Chinese herbal vesicle prevention and treatment system, and build a bridge for Chinese medicine to the world.

Sleep deprivation-induced anxiety-like behaviors are associated with alterations in the gut microbiota and metabolites.

The present study aimed to characterize the gut microbiota and serum metabolome changes associated with sleep deprivation (SD) as well as to explore the potential benefits of multi-probiotic supplementation in alleviating SD-related mental health disorders. Rats were subjected to 7 days of SD, followed by 14 days of multi-probiotics or saline administration. Open-field tests were conducted at baseline, end of SD (day 7), and after 14 days of saline or multi-probiotic gavage (day 21). Metagenomic sequencing was conducted on fecal samples, and serum metabolites were measured by untargeted liquid chromatography tandem-mass spectrometry. At day 7, anxiety-like behaviors, including significant decreases in total movement distance (P = 0.0002) and staying time in the central zone (P = 0.021), were observed. In addition, increased levels of lipopolysaccharide (LPS; P = 0.028) and decreased levels of uridine (P = 0.018) and tryptophan (P = 0.01) were detected in rats after 7 days of SD. After SD, the richness of the gut bacterial community increased, and the levels of Akkermansia muciniphila, Muribaculum intestinale, and Bacteroides caecimuris decreased. The changes in the host metabolism and gut microbiota composition were strongly associated with the anxiety-like behaviors caused by SD. In addition, multi-probiotic supplementation for 14 days modestly improved the anxiety-like behaviors in SD rats but significantly reduced the serum level of LPS (P = 0.045). In conclusion, SD induces changes in the gut microbiota and serum metabolites, which may contribute to the development of chronic inflammatory responses and affect the gut-brain axis, causing anxiety-like behaviors. Probiotic supplementation significantly reduces serum LPS, which may alleviate the influence of chronic inflammation. IMPORTANCE: The disturbance in the gut microbiome and serum metabolome induced by SD may be involved in anxiety-like behaviors. Probiotic supplementation decreases serum levels of LPS, but this reduction may be insufficient for alleviating SD-induced anxiety-like behaviors.

Brucea javanica derived exosome-like nanovesicles deliver miRNAs for cancer therapy.

Triple-negative breast cancer (TNBC) is characterized by complex heterogeneity, high recurrence and metastasis rates, and short overall survival, owing to the lack of endocrine and targeted receptors, which necessitates chemotherapy as the major treatment regimen. Exosome-like nanovesicles derived from medicinal plants have shown great potential as novel biotherapeutics for cancer therapy by delivering their incorporated nucleic acids, especially microRNAs (miRNAs), to mammalian cells. In this study, we isolated exosome-like nanovesicles derived from B. javanica (BF-Exos) and investigated their influence and underlying molecular mechanisms in TNBC. We found that BF-Exos delivered 10 functional miRNAs to 4T1 cells, significantly retarding the growth and metastasis of 4T1 cells by regulating the PI3K/Akt/mTOR signaling pathway and promoting ROS/caspase-mediated apoptosis. Moreover, BF-Exos were shown to inhibit the secretion of vascular endothelial growth factor, contributing to anti-angiogenesis in the tumor microenvironment. In vivo, BF-Exos inhibited tumor growth, metastasis, and angiogenesis in breast tumor mouse models, while maintaining high biosafety. Overall, BF-Exos are considered promising nanoplatforms for the delivery of medicinal plant-derived nucleic acids, with great potential to be developed into novel biotherapeutics for the treatment of TNBC.

The influence of maternal diet on offspring's gut microbiota in early life.

BACKGROUND: The influence of maternal diet on offspring's health is an area of study that is linked to epigenetics. Maternal diet contributes to determining the health status of offspring and maternally linked mechanisms and is a global health challenge that requires attention. The impact of gut microbiota on host metabolism and offspring health is still not established. OBJECTIVE: In this review, we intend to discuss the evidence on the impact of maternal diet and the health of offspring gut microbiota. The paper focuses on the gut microbiome of animal models. It captures the maternal diet and its influence on the offspring's gut microbiota, behavior that is supported by cell experimental results. Both inflammation and immune status of offspring induced by maternal diet are discussed. Finally, this review used predicted biological pathways involved in maternal diet and offspring health, and the influence of maternal diet on gut microbiota and offspring behavior. Obesity, diabetes, asthma and allergies, and neurodegenerative disorders and prospects for maternal diet, and microbiota and offspring health were discussed. CONCLUSION: The review was able to gather that a high-fat diet during pregnancy created a long-lasting metabolic signature on the infant's innate immune system, altering inflammation in the offspring microbiota, which predisposed offspring to obesity and metabolic diseases in adulthood.

Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma.

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.

Challenges and progress of neurodrug: bioactivities, production and delivery strategies of nerve growth factor protein.

Nerve growth factor (NGF) is a vital cytokine that plays a crucial role in the development and regeneration of the nervous system. It has been extensively studied for its potential therapeutic applications in various neural diseases. However, as a protein drug, limited natural source seriously hinders its translation and clinical applications. Conventional extraction of NGF from mouse submandibular glands has a very high cost and potentially induces immunogenicity; total synthesis and semi-synthesis methods are alternatives, but have difficulty in obtaining correct protein structure; gene engineering of plant cells is thought to be non-immunogenic, bioactive and economical. Meanwhile, large molecular weight, high polarity, and negative electrical charge make it difficult for NGF to cross the blood brain barrier to reach therapeutic targets. Current delivery strategies mainly depend on the adenovirus and cell biodelivery, but the safety and efficacy remain to be improved. New materials are widely investigated for the controllable, safe and precise delivery of NGF. This review illustrates physiological and therapeutic effects of NGF for various diseases. Moreover, new progress in production and delivery technologies for NGF are summarized. Bottlenecks encountered in the development of NGF as therapeutics are also discussed with the countermeasures proposed.

Progress and challenges of plant-derived nucleic acids as therapeutics in macrophage-mediated RNA therapy.

Plant-derived nucleic acids, especially small RNAs have been proved by increasing evidence in the pharmacological activities and disease treatment values in macrophage meditated anti-tumor performance, immune regulating functions and antiviral activities. But the uptake, application and delivery strategies of RNAs as biodrugs are different from the small molecules and recombinant protein drugs. This article summarizes the reported evidence for cross-kingdom regulation by plant derived functional mRNAs and miRNAs. Based on that, their involvement and potentials in macrophage-mediated anti-tumor/inflammatory therapies are mainly discussed, as well as the load prospect of plant RNAs in viruses and natural exosome vehicles, and their delivery to mammalian cells through macrophage were also summarized. This review is to provide evidence and views for the plant derived RNAs as next generation of drugs with application potential in nucleic acid-based bio-therapy.