Role of extracellular vesicles in insulin resistance: Signaling pathways, bioactive substances, miRNAs, and therapeutic potential.

Extracellular vesicles are small lipid bilayer particles that resemble the structure of cells and range in size from 30 to 1000 nm. They transport a variety of physiologically active molecules, such as proteins, lipids, and miRNAs. Insulin resistance (IR) is a pathological disease in which insulin-responsive organs or components become less sensitive to insulin's physiological effects, resulting in decreased glucose metabolism in target organs such as the liver, muscle, and adipose tissue. Extracellular vesicles have received a lot of attention as essential intercellular communication mediators in the setting of IR. This review looks at extracellular vesicles' role in IR from three angles: signaling pathways, bioactive compounds, and miRNAs. Relevant publications are gathered to investigate the induction, inhibition, and bidirectional regulation of extracellular vesicles in IR, as well as their role in insulin-related illnesses. Furthermore, considering the critical function of extracellular vesicles in regulating IR, the study analyzes the practicality of employing extracellular vesicles for medication delivery and the promise of combination therapy for IR.

Analysis of China's PM2.5 and ozone coordinated control strategy based on the observation data from 2015 to 2020.

The coordinated control of PM2.5 and ozone has become the strategic goal of national air pollution control. Considering the gradual decline in PM2.5 concentration and the aggravation of ozone pollution, a better understanding of the coordinated control of PM2.5 and ozone is urgently needed. Here, we collected and sorted air pollutant data for 337 cities from 2015 to 2020 to explore the characteristics of PM2.5 and ozone pollution based on China's five major air pollution regions. The results show that it is necessary to continue to strengthen the emission reduction in PM2.5 and ozone precursors, and control NOx and VOCs while promoting a dramatic emission reduction in PM2.5. The primary method of curbing ozone pollution is to strengthen the emission control of VOCs, with a long-term strategy of achieving substantial emission reductions in NOx, because VOCs and NOx are also precursors to PM2.5; hence, their reductions also contribute to the reduction in PM2.5. Therefore, the implementation of a multipollutant emission reduction control strategy aimed at the prevention and control of PM2.5 and ozone pollution is the only means to realize the coordinated control of PM2.5 and ozone.

Insights into the Peroxide-Bicyclic Intermediate Pathway of Aromatic Photooxidation: Experimental Yields and NOx-Dependency of Ring-Opening and Ring-Retaining Products.

Aromatic hydrocarbons are important contributors to the formation of ozone and secondary organic aerosols in urban environments. The different parallel pathways in aromatic oxidation, however, remain inadequately understood. Here, we investigated the production yields and chemical distributions of gas-phase tracer products during the photooxidation of alkylbenzenes at atmospheric OH levels with NOx present using high-resolution mass spectrometers. The peroxide-bicyclic intermediate pathway emerged as the major pathway in aromatic oxidation, accounting for 52.1 ± 12.6%, 66.1 ± 16.6%, and 81.4 ± 24.3% of the total OH oxidation of toluene, m-xylene, and 1,3,5-trimethylbenzene, respectively. Notably, the yields of bicyclic nitrates produced from the reactions of bicyclic peroxy radicals (BPRs) with NO were considerably lower (3-5 times) than what the current mechanism predicted. Alongside traditional ring-opening products formed through the bicyclic pathway (dicarbonyls and furanones), we identified a significant proportion of carbonyl olefinic acids generated via the 1,5-aldehydic H-shift occurring in subsequent reactions of BPRs + NO, contributing 4-7% of the carbon flow in aromatic oxidation. Moreover, the observed NOx-dependencies of ring-opening and ring-retaining product yields provide insights into the competitive nature of reactions involving BPRs with NO, HO2, and RO2, which determine the refined product distributions and offer an explanation for the discrepancies between the experimental and model-based results.

Assessing the Ratios of Formaldehyde and Glyoxal to NO2 as Indicators of O3-NOx-VOC Sensitivity.

Ozone (O3) pollution has a negative effect on the public health and crop yields. Accurate diagnosis of O3 production sensitivity and targeted reduction of O3 precursors [i.e., nitrogen oxides (NOx) or volatile organic compounds (VOCs)] are effective for mitigating O3 pollution. This study assesses the indicative roles of the surface formaldehyde-to-NO2 ratio (FNR) and glyoxal-to-NO2 ratio (GNR) on surface O3-NOx-VOC sensitivity based on a meta-analysis consisting of multiple field observations and model simulations. Thresholds of the FNR and GNR are determined using the relationship between the relative change of the O3 production rate and the two indicators, which are 0.55 ± 0.16 and 1.0 ± 0.3 for the FNR and 0.009 ± 0.003 and 0.024 ± 0.007 for the GNR. The sensitivity analysis indicated that the surface FNR is likely to be affected by formaldehyde primary sources under certain conditions, whereas the GNR might not be. As glyoxal measurements are becoming increasingly available, using the FNR and GNR together as O3 sensitivity indicators has broad potential applications.

Immunomodulatory influences of sialylated lactuloses in mice.

The aim of this study was to investigate the immune modulatory influences of sialylated lactuloses in mice. The effects of the four sialylated lactuloses by gavage methods on the weight gain rate, organ, serum and spleen immunoglobulin of mice were investigated. Neu5Ac-α2,3-lactulose group and Kdn-α2,3-lactulose group had significantly higher weight gain rate than control group. The weight gain rate, thymus index and spleen index of Kdn-α2,3-lactulose group were significantly higher than control group and lactulose group. Liver and small intestine of Neu5Ac-α2,3-lactulose group, Neu5Ac-α2,6-lactulose group and Kdn-α2,6-lactulose group showed different degree of damage. IgG levels of serum and spleen in Neu5Ac-α2,6-lactulose group and Kdn-α2,6-lactulose group were significantly higher than control group and lactulose group. The contents of IgG in serum and spleen of Kdn-α2,3-lactulose group were significantly lower than that of control group, while the contents of IgA and IgM in serum were significantly higher than those of control group. The IgA level increased by 12.23% and 58.77% comparing with lactulose group and control group, respectively. The IgM level in serum of Kdn-α2,3-lactulose group mice increased by 43.88% and 8.05% comparing with control group and lactulose group, respectively. The IgA level and IgM level in spleen of Kdn-α2,3-lactulose group mice increased by 49.05% and 47.25% comparing with control group. In short, Kdn-α2,3-lactulose is relatively safe and superior to use as a food supplement or potential drug candidate. Our results also indicate that some other sialylated oligosaccharides are potentially harmful to organisms, they may cause some side effects.

Effects of sialylated lactulose on the mouse intestinal microbiome using Illumina high-throughput sequencing.

Sialylated oligosaccharides are known to have beneficial effects, such as increasing the level of bifidobacteria, reducing the levels of blood endotoxin and blood ammonia, and enhancing the body's immune system. However, it is unknown whether sialylated lactuloses have modulatory effects on the intestinal microbiota. In this study, 60 healthy mice were randomly divided into six groups, namely, a normal control group, a lactulose group, a Kdn-α2,3-lactulose group, a Kdn-α2,6-lactulose group, a Neu5Ac-α2,3-lactulose group, and a Neu5Ac-α2,6-lactulose group. After 14 days of lactulose administration, the feces of three mice from each group were collected, and the intestinal microbiota were detected by Illumina MiSeq high-throughput sequencing targeting the V3-V4 region of the 16S rDNA gene. At the phylum level, the relative abundance of Firmicutes was increased in the sialylated lactulose groups, while the abundance of Bacteroidetes was decreased. At the family level, sialylated lactulose intervention decreased the relative abundance of Bacteroidales S24-7 group and Helicobacteraceae and enhanced the abundance of Lactobacillaceae, which reflects the modulatory effect of sialylated lactulose on intestinal microbiota. Diversity analysis indicated that the index of Chao was higher in the sialylated lactulose groups than in the normal control group, and the Shannon and Simpson diversity indices were higher in the Kdnα-2,6-lactulose group and the Neu5Ac-α2,3-lactulose group than in the normal control group. The results of the intestinal microbiota sample composition indicated that there were differences between the sialylated lactulose groups and the normal control group. Thus, sialylated lactulose could be used as a functional food component with potential therapeutic applications in manipulating intestinal microbiota to exert beneficial effects on the host's health.

Insights into the phenomenon of an explosive growth and sharp decline in haze: A case study in Beijing.

A severe haze episode occurred in winter in the North China Plain (NCP), and the phenomenon of an explosive growth and sharp decline in PM2.5 (particulate matter with an aerodynamic diameter equal to or less than 2.5 µm) concentration was observed. To study the systematic causes for this phenomenon, comprehensive observations were conducted in Beijing from November 26 to December 2, 2015; during this period, meteorological parameters, LIDAR data, and the chemical compositions of aerosols were determined. The haze episode was characterized by rapidly varying PM2.5 concentration, and the highest PM2.5 concentration reached 667 µg/m3. During the haze episode, the NCP was dominated by a weak high-pressure system and continuously low PBL (planetary boundary layer) heights, which are unfavorable conditions for the diffusion of pollutants. The large increases in the concentrations of SNA (SO42-, NO3- and NH4+) during the haze implied that the formation of SNA was the largest contribution. Water vapor also played a vital role in the formation of haze by promoting the chemical transformation of secondary pollutants, which led to higher PM2.5 concentrations. The spatial distributions of PM2.5 in Beijing at different times and the backward trajectories of the air masses also indicated that pollutants from surrounding provinces in particular, contributed to the higher PM2.5 concentration.

Long-Acting Strategies for Antibody Drugs: Structural Modification, Controlling Release, and Changing the Administration Route.

Because of their high specificity, high affinity, and targeting, antibody drugs have been widely used in the treatment of many diseases and have become the most favored new drugs for research in the world. However, some antibody drugs (such as small-molecule antibody fragments) have a short half-life and need to be administered frequently, and are often associated with injection-site reactions and local toxicities during use. Increasing attention has been paid to the development of antibody drugs that are long-acting and have fewer side effects. This paper reviews existing strategies to achieve long-acting antibody drugs, including modification of the drug structure, the application of drug delivery systems, and changing their administration route. Among these, microspheres have been studied extensively regarding their excellent tolerance at the injection site, controllable loading and release of drugs, and good material safety. Subcutaneous injection is favored by most patients because it can be quickly self-administered. Subcutaneous injection of microspheres is expected to become the focus of developing long-lasting antibody drug strategies in the near future.

High-throughput single-microbe RNA sequencing reveals adaptive state heterogeneity and host-phage activity associations in human gut microbiome.

Microbial communities such as those residing in the human gut are highly diverse and complex, and many with important implications in health and diseases. The effects and functions of these microbial communities are determined not only by their species compositions and diversities but also by the dynamic intra- and inter-cellular states at the transcriptional level. Powerful and scalable technologies capable of acquiring single-microbe-resolution RNA sequencing information in order to achieve comprehensive understanding of complex microbial communities together with their hosts is therefore utterly needed. Here we report the development and utilization of a droplet-based smRNA-seq (single-microbe RNA sequencing) method capable of identifying large species varieties in human samples, which we name smRandom-seq2. Together with a triple-module computational pipeline designed for the bacteria and bacteriophage sequencing data by smRandom-seq2 in four human gut samples, we established a single-cell level bacterial transcriptional landscape of human gut microbiome, which included 29,742 single microbes and 329 unique species. Distinct adaptive responses states among species in Prevotella and Roseburia genus and intrinsic adaptive strategy heterogeneity in Phascolarctobacterium succinatutens were uncovered. Additionally, we identified hundreds of novel host-phage transcriptional activity associations in the human gut microbiome. Our results indicated the smRandom-seq2 is a high-throughput and high-resolution smRNA-seq technique that is highly adaptable to complex microbial communities in real-word situations and promises new perspectives in the understanding of human microbiomes.

Single-cell transcriptomics across 2,534 microbial species reveals functional heterogeneity in the rumen microbiome.

Deciphering the activity of individual microbes within complex communities and environments remains a challenge. Here we describe the development of microbiome single-cell transcriptomics using droplet-based single-cell RNA sequencing and pangenome-based computational analysis to characterize the functional heterogeneity of the rumen microbiome. We generated a microbial genome database (the Bovine Gastro Microbial Genome Map) as a functional reference map for the construction of a single-cell transcriptomic atlas of the rumen microbiome. The atlas includes 174,531 microbial cells and 2,534 species, of which 172 are core active species grouped into 12 functional clusters. We detected single-cell-level functional roles, including a key role for Basfia succiniciproducens in the carbohydrate metabolic niche of the rumen microbiome. Furthermore, we explored functional heterogeneity and reveal metabolic niche trajectories driven by biofilm formation pathway genes within B. succiniciproducens. Our results provide a resource for studying the rumen microbiome and illustrate the diverse functions of individual microbial cells that drive their ecological niche stability or adaptation within the ecosystem.

Nano-composite hydrogels of Cu-Apa micelles for anti-vasculogenic mimicry.

Vasculogenic mimicry (VM) describes the phenomenon whereby fluid-conducting vessels are formed by highly invasive tumour cells, which supply blood to tumours during their early growth stages. Single antiangiogenic agents have limited inhibitory effects on VM, therefore, a multi-pathway anti-VM strategy is required. In this study, Apatinib (Apa) was coordinated with Cu2+ to form a Cu-Apa copper complex. The latter was loaded into oligo-hyaluronic acid (HA) polymeric micelles (HA-Chol) and subsequently embedded in Astragalus polysaccharide-based in situ hydrogels (APsGels) to generate Cu-Apa/HA-Chol@APsGels. In this system, Cu-Apa exerts the combined effects of Cu2+ and Apa to inhibit VM; HA-Chol micelles achieve targeted drug delivery and enhance endocytosis efficiency; APsGels realise sustained release of the drugs to ensure an anti-VM effect. This system demonstrated improved VM inhibition with low cytotoxicity and high biocompatibility, wound healing, and transwell invasion in three-dimensional cell cultured VM. Moreover, this system significantly inhibited VM formation and melanoma growth in a mouse tumour transplantation model. This study provides an effective strategy for inhibiting VM.

A nano-targeted co-delivery system based on gene regulation and molecular blocking strategy for synergistic enhancement of platinum chemotherapy sensitivity in ovarian cancer.

Ovarian cancer (OC) has a low five-year survival rate, mainly because of its drug resistance to chemotherapy. It is the key to reverse drug resistance to combine multiple sensitization pathways to play a synergistic role. A nano scaled targeted co-delivery system (P123-PEI-G12, PPG) modified by bifunctional peptide tLyP-1-NLS (G12) was fabricated by using Pluronic P123 conjugated with low molecular weight polyethyleneimine (PEI). This delivery system can co-delivery Olaparib (Ola) and p53 plasmids to synergistically enhance the sensitivity of OC to platinum-based chemotherapy. P53@P123-PEI-G2/Ola (Co-PPGs) can achieve efficient tumor accumulation and cellular internalization through G12-mediated targeting. Co-PPGs then break down in the tumor cells, releasing the drug. Co-PPGs significantly enhanced the sensitivity of cisplatin (DDP) in platinum-resistant ovarian cancer (PROC) and synergistically inhibited the proliferation of PROC in vitro and in vivo. The sensitizing and synergistic effects of Co-PPGs were related to the activation of p53, inhibition of poly-ADP-ribose polymerase (PARP) and p-glycoprotein (P-gp) expression. This work provides a promising strategy for the effective treatment of PROC.

Applications and challenges of ultra-small particle size nanoparticles in tumor therapy.

With the development of nanotechnology, nanomedicines are widely used in tumor therapy. However, biological barriers in the delivery of nanoparticles still limit their application in tumor therapy. As one of the most fundamental properties of nanoparticles, particle size plays a crucial role in the process of the nanoparticles delivery process. It is difficult for large size nanoparticles with fixed size to achieve satisfactory outcomes in every process. In order to overcome the poor penetration of larger size, nanoparticles with ultra-small particle size are proposed, which are more conducive to deep tumor penetration and uniform drug distribution. In this review, the latest progresses and advantages of ultra-small nanoparticles are systematically summarized, the perspectives and challenges of ultra-small nanoparticles strategy for cancer treatment are also discussed.

Kiwi-derived extracellular vesicles for oral delivery of sorafenib.

Sorafenib is an oral treatment for hepatocellular carcinoma (HCC). However, poor water solubility, harsh gastrointestinal environment and off-target effects contribute to the low bioavailability of oral sorafenib. Plant-derived extracellular vesicles (PDEVs) are biological nanovesicles with various bioactive functions that offer significant advantages in the field of oral drug delivery: protection from degradation by gastrointestinal fluids; crossing the intestinal epithelial barrier; specific targeting; safety; and abundant yield. However, there are fewer studies applying PDEVs for anti-tumor drug delivery to extra-digestive tissues. In this study, kiwifruit-derived extracellular vesicles (KEVs) were isolated and purified from kiwifruit, and their natural hepatic accumulation properties were exploited for targeted delivery of sorafenib (KEVs-SFB). Evidence showed that encapsulation of KEVs reduced the leakage of sorafenib in the gastrointestinal environment and enhanced the ability to cross the intestinal epithelium; KEVs-SFB was able to achieve liver accumulation and was predominantly taken up by HepG2 cells; KEVs-SFB was effective in inhibiting 4T1 cell proliferation; in the orthotopic liver cancer model, oral administration of KEVs-SFB inhibited tumor growth and improved the side effects of SFB. This PDEVs-based oral drug delivery platform is important for improving oral bioavailability and reducing drug side effects.

Droplet-based high-throughput single microbe RNA sequencing by smRandom-seq.

Bacteria colonize almost all parts of the human body and can differ significantly. However, the population level transcriptomics measurements can only describe the average bacteria population behaviors, ignoring the heterogeneity among bacteria. Here, we report a droplet-based high-throughput single-microbe RNA-seq assay (smRandom-seq), using random primers for in situ cDNA generation, droplets for single-microbe barcoding, and CRISPR-based rRNA depletion for mRNA enrichment. smRandom-seq showed a high species specificity (99%), a minor doublet rate (1.6%), a reduced rRNA percentage (32%), and a sensitive gene detection (a median of ~1000 genes per single E. coli). Furthermore, smRandom-seq successfully captured transcriptome changes of thousands of individual E. coli and discovered a few antibiotic resistant subpopulations displaying distinct gene expression patterns of SOS response and metabolic pathways in E. coli population upon antibiotic stress. smRandom-seq provides a high-throughput single-microbe transcriptome profiling tool that will facilitate future discoveries in microbial resistance, persistence, microbe-host interaction, and microbiome research.

Therapeutic strategies to overcome cisplatin resistance in ovarian cancer.

Ovarian cancer (OC) is one of the most common gynecologic tumors worldwide and one with the highest mortality. Cisplatin (DDP) is the first platinum-based complex approved by the Food and Drug Administration (FDA) to treat patients with OC. Despite a good initial response rate, most patients receiving DDP treatment will ultimately develop resistance via various complicated mechanisms, leading to therapeutic failure and increased mortality. Multiple resistance pathways have been identified as potentially key areas of intervention. In this review, chemotherapeutic drugs and phytochemicals developed to overcome cisplatin-resistance ovarian cancer (CROC) were discussed. Targeted inhibition or specific drugs are effective against the DDP-resistance phenotype by inhibiting resistance or increasing cytotoxic efficacy. Phytochemicals as chemosensitizers offer novel treatment strategies for CROC patients by reducing chemoresistance and increasing drug efficacy. Due to the complexity of the DDP-resistance mechanism, the treatment of OC needs to improve specificity and effectiveness, and multi-path cooperative therapy is undoubtedly one of the best options. We discuss extensively the role of combination therapy in reversing DDP-resistance in OC and the significance of using a nanoparticle delivery system in this context. Suggestions for potential therapeutic strategies for CROC treatment will help discover more effective and specific regimens to overcome DDP-resistance.

Mitochondrial targeted hierarchical drug delivery system based on HA-modified liposomes for cancer therapy.

Chemotherapy targeting mitochondrial is a faster and more sensitive anti-tumor therapy strategy. In this study, a hierarchical drug delivery system HA-GDT-Lip was constructed by coupling glycyrrhetinic acid (GA), triphenylphosphine (TPP), and doxorubicin (DOX), encapsulating them in cationic liposomes (CLs), then coating the surface of CLs with HA. HA-GDT-Lip nanoparticles can be accumulated in tumor tissue through the EPR effect, then achieve tumor cell-specific endocytosis mediated by the CD44 receptor, DOX can be successfully delivered into mitochondria through the combined action of GA and TPP. Physicochemical properties analysis showed that HA-GDT-Lip nanoparticles were uniform in size and spherical in shape. In vitro cell experiments showed that HA-GDT-Lip had high cell uptake efficiency and mitochondrial targeting ability. In addition, HA-GDT-Lip could induce MPTP opening and accelerate cell apoptosis. Meanwhile, HA-GDT-Lip showed excellent antitumor activity and in vivo safety in tumor-bearing nude mice. In conclusion, HA-GDT-Lip may serve as a promising mitochondrial delivery system to reduce the side effects of anticancer drugs and improve their antitumor efficacy.

Advanced research on extracellular vesicles based oral drug delivery systems.

The oral route is the most convenient and simplest mode of administration. Nevertheless, orally administration of some commonly used therapeutic drugs, such as polypeptides, therapeutic proteins, small-molecule drugs, and nucleic acids, remains a major challenge due to the harsh gastrointestinal environment and the limited oral bioavailability. Extracellular vesicles (EVs) are diverse, nanoscale phospholipid vesicles that are actively released by cells and play crucial roles in intercellular communications. Some EVs have been shown to survive with the gastrointestinal tract (GIT) and can cross biological barriers. The potential of EVs to cross the GIT barrier makes them promising natural delivery carriers for orally administered drugs. Here, we introduce the uniqueness of EVs and their feasibility as oral drug delivery vehicles (ODDVs). Then we provide a general description of the different cellular EVs based oral drug delivery systems (ODDSs) currently under study and emphasize the contribution of endogenous features and multifunctional properties of EVs to the delivery performance. The current obstacles of moving EVs based ODDSs from bench to bedside are also discussed.

Phragmites rhizoma polysaccharide-based nanocarriers for synergistic treatment of ulcerative colitis.

The purpose of this study was to construct Phragmites rhizoma polysaccharide-based nano-drug delivery systems (PRP2-SeNPs-H/Aza-Lips) for synergistically alleviating ulcerative colitis and to investigate the important roles of Phragmites rhizoma polysaccharide-based nanocarriers in PRP2-SeNPs-H/Aza-Lips. Phragmites rhizoma polysaccharide (PRP2) was isolated and used for the preparation of Phragmites rhizoma polysaccharide selenium nanoparticles with low selenium content (PRP2-SeNPs-L) and high selenium content (PRP2-SeNPs-H). Based on the electrostatic attraction between PRP2-SeNPs-H and azathioprine liposomes (Aza-Lips), PRP2-SeNPs-H/Aza-Lips were constructed for precise delivery of the model drug azathioprine (Aza) to colon lesions. Results showed that PRP2 significantly alleviated the clinical symptoms and colon tissue damage and down-regulated the levels of inflammatory factors in serum and colon, demonstrating beneficial effects on mice with ulcerative colitis. PRP2-SeNPs-L had better relieving effects on ulcerative colitis. Phragmites rhizoma polysaccharide-based nanocarriers may protect azathioprine liposomes against gastrointestinal digestion, enhance the therapeutic effects on ulcerative colitis, and significantly reduce liver damage from azathioprine, which helps to improve the efficacy and toxicity of clinical drugs.

A cancer cell membrane coated nanoparticles-based gene delivery system for enhancing cancer therapy.

Gene therapy is a superior therapeutic means in cancer therapy. However, the instability of nucleic acid and the lack of suitable delivery carrier greatly restricts its further development and application. Herein, we coupled low molecular weight polyethyleneimine (LMW PEI) through disulfide bonds, then modified it with manganese dioxide (MnO2) nanosheets and nuclear localization signal peptide (NLS), as a p53 gene carrier, and finally coated it with B16F10 cell membrane to construct a novel gene-carrier system CM@MnO2-PEI-NLS-ss/p53 (M@MPNs/p53). Tumor cell membrane coating endows nanoparticles with homotypic targeting and immune escape capabilities, disulfide-crosslinked LMW-PEI has high transfection efficiency and low toxicity, and NLS peptides enhance nuclear delivery and improve p53 gene delivery efficiency; meanwhile, MnO2 nanosheets oxidize high intracellular concentration of glutathione (GSH), sensitizing p53 gene-mediated antitumor therapy. The results showed that the novel biofilm-camouflaged M@MPNs/p53 nanoparticles had a highly specific targeting effect on homologous cancer cells and could effectively inhibit tumor growth in vitro and in vivo. Besides, MnO2 loading improved p53-mediated tumor regression. This novel gene delivery platform is of great significance in improving gene delivery efficiency and enhancing anti-tumor therapy.