Research progress of nano-delivery systems for the active ingredients from traditional Chinese medicine.

INTRODUCTION: Traditional Chinese medicine (TCM) has been used for thousands of years in China, characterizing with novel pharmacological mechanisms, low toxicity, and limited side effects. However, the application of TCM active ingredients is often hindered by their physical and chemical properties, including poor solubility, low bioavailability, short half-life, toxic side effects within therapeutic doses, and instability in biological environments. Consequently, an increasing number of researchers are directing their attention towards the discovery of nano-delivery systems for TCM to overcome these clinical challenges. OBJECTIVES: This review aims to provide the latest knowledge and results concerning the studies on the nano-delivery systems for the active ingredients from TCM. MATERIALS AND METHODS: Recent literature relating to nano-delivery systems for the active ingredients from TCM is summarized to provide a fundamental understanding of how such systems can enhance the application of phytochemicals. RESULTS: The nano-delivery systems of six types of TCM monomers are summarized and categorized based on the skeletal structure of the natural compounds. These categories include terpenoids, flavonoids, alkaloids, quinones, polyphenols, and polysaccharides. The paper analyzes the characteristics, types, materials used, and the efficacy achieved by TCM-nano systems. Additionally, the advantages and disadvantages of nano-drug delivery systems for TCM are summarized in this paper. CONCLUSION: Nano-delivery systems represent a promising approach to overcoming clinical obstacles stemming from the physical and chemical properties of TCM active ingredients, thereby enhancing their clinical efficacy.

Enhanced external counterpulsation treatment improves multi-organ hemodynamics for postoperative liver transplantation patient. A case report.

INTRODUCTION: Post liver transplantation (LT) patients endure high morbidity rate of multi-organ ischemic symptoms following reperfusion. We hypothesize that enhanced external counterpulsation (EECP) as a typical non-invasive assisted circulation procedure, which can efficiently inhibit the relative ischemic symptoms via the systemic improvement of hemodynamics. CASE PRESENTATION: A 51-year-old male patient, 76 kg, 172 cm, received orthotopic LT surgery for viral hepatitis B induced acute-on-chronic liver failure hepatic failure. His medical records revealed ischemic symptoms in multi-organ at the time of hospital discharge, including headache, refractory insomnia, abdominal paralysis, and lower limb pain. The EECP treatment was introduced for assisted rehabilitation and to improve the postoperative quality of life. Doppler Ultrasound examination showed significant augmentation of blood flow volume in the carotid arteries, the hepatic artery, the portal vein and the femoral artery during EECP intervention. A standard 35-hour EECP treatment led to significant improvement in quality of life, e.g. sleep quality and walking ability. CONCLUSION: We report a case of multi-organ ischemic symptoms in a post LT patient. EECP treatment can significantly improve the quality of life via the systematic promotion of hemodynamics.

Onosma glomeratum Y. L. Liu polysaccharide alleviates LPS-induced pulmonary inflammation via NF-κB signal pathway.

As a traditional Chinese medicinal and edible homologous plant, Onosma glomeratum Y. L. Liu has been used for treating lung diseases in Tibet. In this study, a pectin polysaccharide, OGY-LLPA, with a molecular weight of 62,184 Da, was isolated and characterized by GC-MS and NMR analysis. It mainly consists of galacturonic acid (GalA), galactose (Gal), rhamnose (Rha), and arabinose (Ara), with a linear main chain of galacturonic acid (homogalacturonan, HG) inserted by part of rhamnose galacturonic acid (rhamnogalacturonan, RG), attaching with arabinogalactan (AG) branches at RG-I. Both in the LPS-induced A549 cell model and LPS-induced pneumonia mouse model, OGY-LLPA demonstrated strong anti-inflammatory effects, even comparable to DEX, indicating its potential as an anti-pneumonia candidate agent. Moreover, low-dose OGY-LLPA alleviated LPS-induced pulmonary inflammation by inhibiting the NF-κB signaling pathway. Overall, these findings could not only contribute to the utilization of Onosma glomeratum Y. L. Liu., but also provides a theoretical basis for the treatment of inflammation-related diseases.

False HbA1cValue due to a Rare Variant of Hemoglobin J-Cubujuqui.

BACKGROUND: Hemoglobin (Hb) J-Cubujuqui is a rare Hb variant, and reports about it are very limited. There are no descriptions that it affects the results of glycated Hb. METHODS: In this study, we describe a rare variant discovered during newborn screening. Both high-performance liquid chromatography (HPLC) and capillary electrophoresis for hemoglobin analysis displayed abnormal peaks. The Hb variant was confirmed by Sanger sequencing. RESULTS: The pedigree study shows the variant was inherited from the newborn's father. His fasting blood glucose (FBG) level was 5.5 mmol/L. HbA1c measured by HPLC was falsely low in her father (2.41%), whereas that measured by immunoassay was normal (5.11%). Sanger sequencing revealed a heterozygous mutation (CGT˃AGT) at amino acid position 141 of the α1 gene, corresponding to Hb J-Cubujuqui [α1 141(HC3) Arg→Ser (CGT˃AGT); HBA1:c.424C˃A (or HBA2)]. CONCLUSIONS: This is the first report that Hb J-Cubujuqui interferes with the measurement of HbA1cand prompts clinicians to pay attention to the accuracy of glycated Hb results.

Enhanced external counterpulsation treatment regulates blood flow and wall shear stress metrics in femoral artery: An in vivo study in healthy subjects.

As a non-invasive assisted circulation therapy, enhanced external counterpulsation (EECP) has demonstrated potential in treatment of lower-extremity arterial disease (LEAD). However, the underlying hemodynamic mechanism remains unclear. This study aimed to conduct the first prospective investigation of the EECP-induced responses of blood flow behavior and wall shear stress (WSS) metrics in the femoral artery. Twelve healthy male volunteers were enrolled. A Doppler ultrasound-basedapproach was introduced for the in vivo determination of blood flow in the common femoral artery (CFA) and superficial femoral artery (SFA) during EECP intervention, with incremental treatment pressures ranging from 10 to 40 kPa. Three-dimensional subject-specific numerical models were developed in 6 subjects to quantitatively assess variations in WSS-derived hemodynamic metrics in the femoral bifurcation. A mesh-independence analysis was performed. Our results indicated that, compared to the pre-EECP condition, both the antegrade and retrograde blood flow volumes in the CFA and SFA were significantly augmented during EECP intervention, while the heart rate remained constant. The time average shear stress (TAWSS) over the entire femoral bifurcation increased by 32.41%, 121.30%, 178.24%, and 214.81% during EECP with treatment pressures of 10 kPa, 20 kPa, 30 kPa, and 40 kPa, respectively. The mean relative resident time (RRT) decreased by 24.53%, 61.01%, 69.81%, and 77.99%, respectively. The percentage of area with low TAWSS in the femoral artery dropped to nearly zero during EECP with a treatment pressure greater than or equal to 30 kPa. We suggest that EECP is an effective and non-invasive approach for regulating blood flow and WSS in lower extremity arteries.

Structural and pharmacological diversity of 1,4-naphthoquinone glycosides in recent 20 years.

1,4-naphthoquinones are the most widespread naphthoquinone compounds. Recently, many 1,4-naphthoquinone glycosides with different structural features have been obtained from both nature and synthesis, which has led to an increasing variety of naphthoquinone glycosides. In this paper, the structure variety and biological activity in recent 20 years are reviewed, and classified them according to the source and structure characteristics. Meanwhile the synthetic methods of O-, S-, C- and N-naphthoquinone glycosides and their structure activity relationships are also described. It was referred that the presence of polar groups of C2 and C5 and non-polar groups attached to C3 on the naphthoquinone ring are beneficial for their biological activities. It will provide more comprehensive literature resources for the future research of 1, 4-naphthoquinone glycosides and lay a theoretical foundation.

Research progress on the structure and biological diversities of 2-phenylindole derivatives in recent 20 years.

The privileged structure binds to multiple receptors with high affinity, which is helpful to the development of new bioactive compounds. Indole is classified as a privileged structure, which may be one of the most important structural categories in drug discovery. As a special subset of indole compounds, 2-phenylindole seems to be one of most promising forerunners of drug development. In this paper, 106 articles were referenced to review the structural changes, biological activities and structure-activity relationship of compounds in recent 20 years, and classified them according to their pharmacological activities, from several aspects, including anticancer, antibacterial, anti-inflammatory, analgesic, antiviral, anti-parasite, the biological activities target to central nervous system, et al. It also points out the importance of artificial intelligence (AI) technology in discovery of new 2-phenylindole compounds in a broader prospect. This review will provide some ideas for researchers to develop new indole drugs.

Application opportunity of Doppler ultrasound combined with CT angiography in diabetic lower extremity arterial disease and the analysis of the risk factors.

Objective: This study examined the potential of combining Doppler ultrasound (DUS) and CT angiography (CTA) for early detection and intervention of lower extremity arterial disease (LEAD) in diabetes.Concurrently, risk factors influencing LEAD progression were analyzed. Methods: 106 Type-2 diabetes patients with LEAD, having undergone DUS and CTA, were divided into four stages according to Fontaine stage. Results of DUS and CTA were compared across stages and potential risk factors were analyzed. Results: Positive detection rates of LEAD differed between DUS and CTA for Fontaine stages I and II (P < 0.05), with no significant difference for stages III and IV (P > 0.05). CTA identified subgroups with mild to moderate stenosis and severe stenosis or occlusion, with positive rates on DUS of 17.95% and 89.9% respectively. Hypertension was found as an independent risk factor affecting LEAD progression. Conclusion: CTA should be performed early for LEAD in diabetes patients at Fontaine stages I and II, regardless of DUS results. For diabetes patients with LEAD, stringent blood pressure control is crucial to delay disease progression.

Tumor necrosis factor alpha delivers exogenous inflammation-related microRNAs to recipient cells with functional targeting capabilities.

Tumor necrosis factor alpha (TNF-α) is a critical pro-inflammatory cytokine in a wide range of tumors and infectious diseases. This study showed for the first time that TNF-α could specifically bind to certain intracellular or circulating inflammation-related microRNAs both in vitro and in vivo. The binding sites of TNF-α to microRNAs are located at the N-terminal of TNF-α and the 3'-GGUU motif of microRNAs. TNF-α could deliver exogenous unmodified single-stranded microRNAs into recipient cells through the TNF-α receptors (TNFRs) and stabilize them from being degraded by RNase in cells. Exogenous miR-146a or let-7c delivered into HCT116 cells by TNF-α could escape from lysosomes and specifically downregulate their target genes and then affect cell proliferation and migration in vitro, as well as tumorigenesis in vivo. Based on the above findings, the concept of "non-conjugated ligand-mediated RNA delivery (ncLMRD)" was proposed, which may serve as a promising strategy for therapeutic microRNA delivery in the future.

Sensitization of nerve cells to ultrasound stimulation through Piezo1-targeted microbubbles.

Neuromodulation by ultrasound (US) has recently drawn considerable attention due to its great advantages in noninvasiveness, high penetrability across the skull and highly focusable acoustic energy. However, the mechanisms and safety from US irradiation still remain less understood. Recently, documents revealed Piezo1, a mechanosensitive cation channel, plays key role in converting mechanical stimuli from US through its trimeric propeller-like structure. Here, we developed a Piezo1-targeted microbubble (PTMB) which can bind to the extracellular domains of Piezo1 channel. Due to the higher responsiveness of bubbles to mechanical stimuli from US, significantly lower US energy for these PTMB-binding cells may be needed to open these mechanosensitive channels. Our results showed US energy at 0.03 MPa of peak negative pressure can achieve an equivalent level of cytoplasmic Ca2+ transients which generally needs 0.17 MPa US intensity for the control cells. Cytoplasmic Ca2+ elevations were greatly reduced by chelating extracellular calcium ions or using the cationic ion channel inhibitors, confirming that US-mediated calcium influx are dependent on the Piezo1 channels. No bubble destruction and obvious temperature increase were observed during the US exposure, indicating cavitation and heating effects hardly participate in the process of Ca2+ transients. In conclusion, our study provides a novel strategy to sensitize the response of nerve cells to US stimulation, which makes it safer application for US-mediated neuromodulation in the future.

Compound Heterozygosity for a Novel Mutation Codon 104 (-A) (HBB: c.313delA) and Codons 41/42 (-CTTT) (HBB: c.126_129delCTTT) Leading to ß-Thalassemia Major in a Chinese Family.

ß-Thalassemia (ß-thal) is a hereditary blood disorder characterized by the reduced or absent synthesis of ß-globin chains. Here, we report a case of severe thalassemia with compound heterozygosity for a novel deletion mutation at codon 104 (-A) (HBB: c.313delA) and codons 41/42 (-CTTT) (HBB: c.126_129delCTTT) on the ß-globin gene (HBB), and a coinheritance of the -α4.2 (leftward) deletion on the α-globin gene cluster. The proband was a 12-year-old boy, and four other family members were involved in this study. This novel frameshift mutation caused classical ß-thal trait in the heterozygote and a transfusion-dependent form of ß-thal major (ß-TM) in compound heterozygosity with other ß0 mutations.

Effects of side-stream ratio on sludge reduction and microbial structures of anaerobic side-stream reactor coupled membrane bioreactors.

An anoxic/oxic membrane bioreactor (AO-MBR) and three anaerobic side-stream reactor (ASSR) coupled MBRs (ASSR-MBR) were operated to investigate effects of side-stream ratio (SR) on sludge reduction and microbial community structure of ASSR-MBRs. The ASSR-MBR achieved efficient COD and ammonium nitrogen removal. SR increased from 0.2 to 1.0 favored nitrogen removal, and increased sludge reduction from 6.0% to 49.7%. The total released COD in the ASSR increased with the rising SR and was inversely proportional to sludge yield of ASSR-MBR. Pyrosequencing analysis showed that phyla Chloroflexi and Armatimonadetes surviving in anaerobic conditions were enriched in the ASSR, while Nitrospirae was dominant in the MBR. Comparison at the genus level revealed that higher SR favored the growth of slow growers, while lower SR enriched hydrolytic and predatory bacteria. The results suggested that SR has a profound effect on nitrogen removal, sludge reduction and microbial community structure in the ASSR-MBR.

Species-specific mutual regulation of p53 and miR-138 between human, rat and mouse.

In recent years, p53 was identified to regulate the expression of many miRNAs and was also regulated by miRNAs. In this paper, we found that miR-138 showed a pronounced increase after p53 activation in human non-small cell lung cancer (NSCLC) cells, which is mediated by p53 binding sites in the promoter region of its host gene, but this did not happen with rat and mouse cells. More interestingly, we found that p53 could be also regulated by miR-138 in mouse and rat cells, but not in the human NSCLC cells. Our results suggest the existence of species-specific differences of the regulations of miRNA against its targets and the regulations of miRNA itself by other proteins.

Effects of dissolved oxygen on performance and microbial community structure in a micro-aerobic hydrolysis sludge in situ reduction process.

A sludge process reduction activated sludge (SPRAS), with a sludge process reduction module composed of a micro-aerobic tank and a settler positioned before conventional activated sludge process, showed good performance of pollutant removal and sludge reduction. Two SPRAS systems were operated to investigate effects of micro-aeration on sludge reduction performance and microbial community structure. When dissolved oxygen (DO) concentration in the micro-aerobic tank decreased from 2.5 (SPH) to 0.5 (SPL) mg/L, the sludge reduction efficiency increased from 42.9% to 68.3%. Compared to SPH, activated sludge in SPL showed higher contents of extracellular polymeric substances and dissolved organic matter. Destabilization of floc structure in the settler, and cell lysis in the sludge process reduction module were two major reasons for sludge reduction. Illumina-MiSeq sequencing showed that microbial diversity decreased under high DO concentration. Proteobacteria, Bacteroidetes and Chloroflexi were the most abundant phyla in the SPRAS. Specific comparisons down to the class and genus level showed that fermentative, predatory and slow-growing bacteria in SPL community were more abundant than in SPH. The results revealed that micro-aeration in the SPRAS improved hydrolysis efficiency and enriched fermentative and predatory bacteria responsible for sludge reduction.

Effects of alkalinity on membrane bioreactors for reject water treatment: Performance improvement, fouling mitigation and microbial structures.

Two submerged membrane bioreactors (MBRs) for reject water treatment were operated to investigate effects of sodium bicarbonate (SB) addition on enhancing process performance and mitigating membrane fouling. Results showed that SB addition enhanced average removal efficiencies of COD and NH4-N by 14.6% and 38.3%, respectively. With SB addition, the extracellular polymeric substances (EPS) content in activated sludge increased, but those in membrane foulants greatly decreased. Gel permeation chromatography analysis demonstrated that EPS in MBRs for reject water treatment had much larger molecular weight (MW) and broader MW distribution than those in MBRs for municipal wastewater treatment. The fouling mitigation by SB was attributed to a deprotonation mechanism reduced EPS adsorption on negatively charged membrane surfaces, and improvement of degradation efficiency of macromolecular organic matters. SB addition into MBRs for reject water treatment increased microbial abundance, enriched nitrifying bacteria, and converted predominant AOB genus from Nitrosomonas to Nitrosospira.

Exosomal transfer of vasorin expressed in hepatocellular carcinoma cells promotes migration of human umbilical vein endothelial cells.

Vasorin (VASN) is a type I transmembrane protein that plays important roles in tumor development and vasculogenesis. In this paper, we showed that VASN could be a key mediator of communication between tumor cells and endothelial cells. We confirmed for the first time that HepG2-derived VASN can be transferred to human umbilical vein endothelial cells (HUVECs) via receptor mediated endocytosis of exosomes, at least in part through HSPGs. The HepG2-derived VASN containing exosomes promote migration of recipient HUVECs cells. Our results identify a novel pathway by which a functional protein expressed in tumor cells affects the biological fate of endothelial cells via exosomes.

Nanoparticle-conjugated aptamer targeting hnRNP A2/B1 can recognize multiple tumor cells and inhibit their proliferation.

In this study, we further investigated a previously developed aptamer targeting ROS 17/2.8 (rat osteosarcoma) cells. We found that this C6-8 aptamer specifically binds to heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 and that it specifically labeled multiple tumor-cell lines as effectively as hnRNP A2/B1 monoclonal antibodies. When conjugated with fluorescent carbon nanodots (CDots) it could freely enter multiple living tumor cell lines (HepG2, MCF-7, H1299, and HeLa), whose growth it inhibited by targeting hnRNP A2/B1. Similar inhibitory effects were observed when the GFP-HepG2 hepatocarcinoma cells treated with C6-8-conjugated CDots were implanted in nude mice. Our work provides a new aptamer for targeting/labeling multiple tumor cell types, and its nanoparticle conjugates bring further advantages that increase its potential for use in cancer diagnosis and therapy.

Vasorin is a potential serum biomarker and drug target of hepatocarcinoma screened by subtractive-EMSA-SELEX to clinic patient serum.

UNLABELLED: We report a new biomarker of hepatocarcinoma, vasorin (VASN), screened by a subtractive EMSA-SELEX strategy from AFP negative serum of hepatocellular carcinoma (HCC) patients with extrahepatic metastases. VASN was verified to be highly expressed in sera of 100 cases of HCC patients compared with 97 cases of normal persons and 129 cases of hepatitis patients. Further validation by Q-PCR,IFA and Western blot showed higher expression of VASN at mRNA and protein levels in HCC cell lines and HCC tissues than in normal controls. RNA interference and forced overexpression assays verified that VASN promotes cell proliferation and migration and inhibits apoptosis. Down-regulation of microRNA miR145 and miR146a is an important mechanism leading to high expression of VASN. CONCLUSION: As a membrane protein and/or as free protein, VASN may be an effective target for biological treatment of liver cancer and is a potential biomarker for HCC diagnosis. Small molecular nucleotides targeting VASN are promising biological therapies to HCC.

A micro-aerobic hydrolysis process for sludge in situ reduction: performance and microbial community structure.

A sludge process reduction activated sludge (SPRAS) system by inserting a sludge process reduction (SPR) module, composed of a micro-aerobic tank and a settler, before activated sludge process was operated for sludge in situ reduction. The average removal efficiencies of COD and ammonium nitrogen were 86.6% and 87.9%, respectively. Compared to anoxic/aerobic (AO) process, SPRAS process reduced sludge production by 57.9% with observed sludge yield of 0.076 gVSS/gCOD. Pyrosequencing analyses revealed that the relative abundance and stability of microbial communities in SPRAS system were higher than AO system. Fermentative acidogenic classes Anaerolineae, Actinobacteria, Cytophagia and Caldilineae were enriched in the SPR module and responsible for sludge reduction. Specific comparison down to the genus level identified the enrichment of oxyanion-reducing bacteria (Sulfuritalea; Azospira; Ramlibacter), fermentative acidogenic bacteria (Propionivibrio; Opitutus; Caldilinea), slow growers (Ramlibacter) and predatory bacteria (Myxobacteria) in SPRAS system. Nitrifiers were also more abundant in SPRAS system than AO system.

Phosphonate removal from discharged circulating cooling water using iron-carbon micro-electrolysis.

Phosphonate is a commonly used corrosion and scale inhibitor for a circulating cooling water (CCW) system. Its discharge could cause eutrophication of receiving waters. The iron-carbon (Fe/C) micro-electrolysis technology was used to degrade and remove phosphonate from discharged CCW. The influences of initial pH, Fe/C ratio (FCR) and temperature on phosphonate removal were investigated in a series of batch tests and optimized by response surface methodology. The quadratic model of phosphonate removal was obtained with satisfactory degrees of fitness. The optimum conditions with total phosphorus removal efficiency of 95% were obtained at pH 7.0, FCR of 1.25, and temperature of 45 °C. The phosphonate removal mechanisms were also studied. Phosphonate removal occurred predominantly via two consecutive reactive phases: the degradation of phosphonate complexes (Ca-phosphonate) and the precipitation of Fe/C micro-electrolysis products (PO4(3-), Ca²âº and Fe³âº).