Antimicrobial carbon dots/pectin-based hydrogel for promoting healing processes in multidrug-resistant bacteria-infected wounds.

Multidrug-resistant (MDR) bacterial infections have become a significant threat to global healthcare systems. Here, we developed a highly efficient antimicrobial hydrogel using environmentally friendly garlic carbon dots, pectin, and acrylic acid. The hydrogel had a porous three-dimensional network structure, which endowed it with good mechanical properties and compression recovery performance. The hydrogel could adhere closely to skin tissues and had an equilibrium swelling ratio of 6.21, indicating its potential as a wound dressing. In particular, the bactericidal efficacy following 24-h contact against two MDR bacteria could exceed 99.99 %. When the hydrogel was applied to epidermal wounds infected with methicillin-resistant Staphylococcus aureus (MRSA) on mice, a remarkable healing rate of 93.29 % was observed after 10 days. This was better than the effectiveness of the traditionally used antibiotic kanamycin, which resulted in a healing rate of 70.36 %. In vitro cytotoxicity testing and hemolysis assay demonstrated a high biocompatibility. This was further proved by the in vivo assay where no toxic side effects were observed on the heart, liver, spleen, lung, or kidney of mice. This eco-friendly and easy-to-prepare food-inspired hydrogel provides an idea for the rational use of food and food by-products as a wound dressing to control MDR bacterial infections.

Cucurbitacin B Inhibits the Malignancy of Esophageal Carcinoma through the KIF20A/JAK/STAT3 Signaling Pathway.

This study intends to explore the effects of Cucurbitacin B (CuB) and KIF20A on esophageal carcinoma (ESCA). Data were downloaded from the Cancer Genome Atlas (TCGA) database. The expression properties of KIF20A have been confirmed by GEPIA and ualcan from TCGA. The expression of KIF20A was determined using western blotting in ECA109 and KYSE150 cells after transfection with KIF20A, KIF20A siRNA, or numerical control siRNA (si-NC). Then, different concentrations of CuB were used to treat ECA109 and KYSE150 cells. CCK-8 and colony formation assays were used to measure cell viability, and a Transwell assay was utilized to assess cell migration and invasion ability. N-cadherin, E-cadherin, snail, p-Janus kinase 2 (JAK2), JAK2, p-signal transducer and activator of transcription 3 (STAT3), and STAT3 expression levels were evaluated using western blot. KIF20A was higher expressed in ESCA than in normal cells, and its overexpression was associated with squamous cell carcinoma, TNM stage, and lymph nodal metastasis of ESCA patients. In ECA109 and KYSE150 cells, increased KIF20A facilitated cell proliferation, migration, and invasion, whereas the knockdown of KIF20A can reverse these effects with N-cadherin. Snail expression diminished and E-cadherin increased. Similarly, CuB treatment could inhibit cell proliferation, migration, and invasion concentration dependently. Furthermore, KIF20A accelerated the expression of p-JAK2 and p-STAT3, while the application of CuB inhibited KIF20A expression and attenuated the activation of the JAK/STAT3 pathway. These findings revealed that CuB could inhibit the growth, migration, and invasion of ESCA through downregulating the KIF20A/JAK/STAT3 signaling pathway, and CuB could serve as an essential medicine for therapeutic intervention.

Targeted screening of the synergistic components in Artemisia annua L. leading to enhanced antiplasmodial potency of artemisinin based on a "top down" PD-PK approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisinin (ART) showed enhanced antimalarial potency in the herb Artemisia annua L. (A. annua), from which ART is isolated. Increased absorption of ART with inhibited metabolism in the plant matrix is an underlying mechanism. Several synergistic components have been reported based on a "bottom-up" approach, i.e., traditional isolation followed by pharmacokinetic and/or pharmacodynamic evaluation. AIM OF THE STUDY: In this study, we employed a "top-down" approach based on in vivo antimalarial and pharmacokinetic studies to identify synergistic components in A. annua. MATERIALS AND METHODS: Two A. annua extracts in different chemical composition were obtained by extraction using ethyl acetate (EA) and petroleum ether (PE). The synergistic antimalarial activity of ART in two extracts was compared both in vitro (Plasmodium falciparum) and in vivo (murine Plasmodium yoelii). For the PD-PK correlation analysis, the pharmacokinetic profiles of ART and its major metabolite (ART-M) were investigated in healthy rats after a single oral administration of pure ART (20 mg/kg) or equivalent ART in each A. annua extract. A liquid chromatography-tandem high-resolution mass spectrometry (LC-HRMS)-based analytical strategy was then applied for efficient component classification and structural characterization of the differential components in the targeted extract with a higher antimalarial potency. Major components isolated from the targeted extract were then evaluated for their synergistic effect in the same proportion. RESULTS: Compared with pure ART (ED50, 5.6 mg/kg), ART showed enhanced antimalarial potency in two extracts in vivo (ED50 of EA, 2.9 mg/kg; ED50 of PE, 1.6 mg/kg), but not in vitro (IC50, 15.0-20.0 nM). A significant increase (1.7-fold) in ART absorption (AUC0-t) was found in rats after a single oral dose of equivalent ART in PE but not in EA; however, no significant change in the metabolic capability (AUCART-M/AUCART) was found for ART in either extract. The differential component analysis of the two extracts showed a higher composition of sesquiterpene compounds, especially component AB (3.0% in PE vs. 0.9% in EA) and component AA (14.1% in PE vs. 5.1% in EA). Two target sesquiterpenes were isolated and identified as arteannuin B (AB) and artemisinic acid (AA). The synergism between ART and AB/AA in the same proportion with PE extract (20:1.6:7.6, mg/kg) was verified by a pharmacokinetic study in rats. CONCLUSIONS: A "top-down" strategy based on PD-PK studies was successfully employed to identify synergistic components for ART in A. annua. Two sesquiterpene compounds (arteannuin B and artemisinic acid) could enhance the antimalarial potency of ART by increasing its absorption.

Photo-Triggered Cascade Therapy: A NIR-II AIE Luminogen Collaborating with Nitric Oxide Facilitates Efficient Collagen Depletion for Boosting Pancreatic Cancer Phototheranostics.

The dense extracellular matrix (ECM) in the pancreatic cancer severely hampers the penetration of nanodrugs, which causes inferior therapeutic efficacy. To address this issue, a multifunctional liposome, namely, Lip-DTI/NO, integrating a type-I photosensitizer DTITBT with glutathione (GSH) or heat-responsive nitric oxide (NO) donor S-nitroso-N-acetyl-D-penicillamine (SNAP) is constructed to deplete the tumor ECM, leading to enhanced drug delivery and consequently improved phototherapy. The loaded DTITBT possesses multiple functions including NIR-II fluorescence imaging, efficient superoxide radical (O2 •-) generation and excellent photothermal conversion efficiency, making it feasible for precisely pinpointing the tumor in the phototherapy process. Responding to the intracellular overexpressed glutathione or heat produced by photothermal effect of DTITBT, NO can be released from SNAP. Upon 808 nm laser irradiation, Lip-DTI/NO could selectively induce in situ generation of peroxynitrite anion (ONOO-) in tumor after cascade processes including O2 •- production, GSH or heat-triggered NO release, and rapid reaction between O2 •- and NO. The generated ONOO- could activate the expression of endogenous matrix metalloproteinases which could efficiently digest collagen of tumor ECM, thus facilitating enhanced penetration and accumulation of Lip-DTI/NO in tumor. In vivo evaluation demonstrates the notable therapeutic efficacy via ONOO--potentiated synergistic photodynamic-photothermal therapies on both subcutaneous and orthotopic pancreatic cancer model.

Inhibiting Quorum Sensing by Active Targeted pH-Sensitive Nanoparticles for Enhanced Antibiotic Therapy of Biofilm-Associated Bacterial Infections.

Inhibition of quorum sensing (QS) is considered as an effective strategy in combatting biofilm-associated bacterial infections. However, the application of quorum sensing inhibitors (QSI) is strongly restricted by poor water-solubility and low bioavailability. We herein fabricate pH-sensitive curcumin (Cur) loaded clustered nanoparticles with active targeting ability (denoted as anti-CD54@Cur-DA NPs) to inhibit QS for enhanced antibiotic therapy. Cur-DA NPs are first prepared through electrostatic interaction between Cur loaded amino-ended poly(amidoamine) dendrimer (PAMAM) and 2,3-dimethyl maleic anhydride (DA) modified biotin-poly(ethylene glycol)-polylysine (biotin-PEG-PLys). Anti-CD54@Cur-DA NPs are then obtained by the modification of Cur-DA NPs with anti-CD54. Cur loaded PAMAM can be released from Cur-DA NPs in acidic pH, leading to simultaneous charge reversal and size decrease, which is beneficial for biofilm penetration. Cur-DA NPs are hence much better in inhibiting QS than free Cur due to enhanced biofilm penetration. Compared to free Cur, Cur-DA NPs exhibit stronger capability in inhibiting the development of biofilm architecture and maturation, thus downregulating efflux pump-related genes and improving bactericidal performance of multiple antibiotics, including Penicillin G, ciprofloxacin, and tobramycin. Moreover, since anti-CD54 can selectively bind to inflamed endothelial cells, anti-CD54@Cur-DA NPs can be targeted accumulated in bacteria-infected tissues. The sequential treatment using anti-CD54@Cur-DA NPs and free antibiotics can effectively reduce bacterial burden and alleviate inflammation in a chronic lung infection model in vivo. This research provides an effective way to improve the therapeutic performance of QSI to enhance the anti-biofilm effects of antibiotics, which radiate a vitality of conventional antibiotics in treating biofilm-associated bacterial infections.

Screening immune adjuvants for an inactivated vaccine against Erysipelothrix rhusiopathiae.

In this study, we screened adjuvants for an inactivated vaccine against Erysipelothrix rhusiopathiae (E. rhusiopathiae). Inactivated cells of E. rhusiopathiae strain HG-1 were prepared as the antigen in five adjuvanted inactivated vaccines, including a mineral-oil-adjuvanted vaccine (Oli vaccine), aluminum-hydroxide-gel-adjuvanted vaccine (Alh vaccine), ISA201-biphasic-oil-emulsion-adjuvanted vaccine (ISA201 vaccine), GEL02-water-soluble-polymer-adjuvanted vaccine (GEL vaccine), and IMS1313-water-soluble-nanoparticle-adjuvanted vaccine (IMS1313 vaccine). The safety test results of subcutaneous inoculation in mice showed that Oli vaccine had the most severe side effects, with a combined score of 35, followed by the ISA201 vaccine (25 points), Alh vaccine (20 points), GEL vaccine (10 points), and IMS1313 vaccine (10 points). A dose of 1.5LD50 of strain HG-1 was used to challenge the mice intraperitoneally, 14 days after their second immunization. The protective efficacy of Oli vaccine and Alh vaccine was 100% (8/8), whereas that of the other three adjuvanted vaccines was 88% (7/8). Challenge with 2.5LD50 of strain HG-1 resulted in a 100% survival rate, demonstrating the 100% protective efficacy of the Oli vaccine, followed by the GEL vaccine (71%, 5/7), IMS1313 vaccine (57%, 4/7), ISA201 vaccine (43%, 3/7), and Alh vaccine (29%, 2/7). Challenge with 4LD50 of strain HG-1 showed 100% (7/7) protective efficacy of the Oli vaccine and 71% (5/7) protective efficacy of the GEL vaccine, whereas the protective efficacy of other three adjuvanted vaccine was 14% (1/7). The Alh and GEL vaccines were selected for comparative tests in piglets, and both caused minor side effects. A second immunization with these two adjuvanted vaccines conferred 60 and 100% protective efficacy, respectively, after the piglets were challenged via an ear vein with 8LD100 of strain HG-1. After challenge with 16LD100 of strain HG-1, the Alh and GEL vaccines showed 40% and 100% protective efficacy, respectively. Our results suggested that GEL is the optimal adjuvant for an inactivated vaccine against E. rhusiopathiae.

Effect and mechanism of glycerol monostearate dimer (GMS-D) and baking-treatment on the structure, in vitro digestion of gelatinized potato starch-GMS-D.

With the increasing progress of society and in-depth scientific research, dietary regulations, especially sustained glucose releases, are regarded as an effective and significant way to lighten or even cut the emergence of diabetes. In this research, the starch-lipid complex gelatinized potato starch-glycerol monostearate dimer (GPS-GMS-D) was developed to provide a low-glycemic index functional food component for type 2 diabetes. Briefly, the higher complexation index (CI, 71.02%), lower rapidly digestible starch (RDS, 35.57%), and lower estimated glycemic index (eGI, 52.34%) were referred to as GPS-GMS-D. It was assumed that the solid V-type crystal structure, induced with the helix between GMS-D and GPS due to high amylose, high saturation, and low steric hindrance, contributed to the lower digestibility. In addition, baking treatment for 5 min was systematically exerted to improve the flavor of GPS-GMS-D with a relatively high CI (59.98%) and low eGI (54.15%). It was believed that rapid dehydration and close interaction during baking treatment could slow down the decomposition of GPS-GMS-D and conversions of starch fractions. Therefore, these results suggested that the as-developed GPS-GMS-D was a promising low GI functional dietary food component for diabetes mellitus, and a suitable baking post-thermal treatment was successfully proposed to enhance the flavor of GPS-GMS-D. PRACTICAL APPLICATION: The higher amylose and solid V-type crystal structure in gelatinized potato starch-glycerol monostearate dimer (GPS-GMS-D) would induce the formation of slowly digestive starch (SDS) and resistant starch (RS) to suppress enzymatic hydrolysis. Moreover, the flavor of GPS-GMS-D was enhanced with appropriate and moderate thermal processing (baking), which was likely to improve the quality of life of a person with diabetes. Thus, we believe that GPS-GMS-D is a promising functional food component for diabetes mellitus.

A NIR-II emissive polymer AIEgen for imaging-guided photothermal elimination of bacterial infection.

The development of antibiotics resistance has made multidrug-resistant (MDR) bacterial infection one of the most serious global health issues. Photothermal therapy (PTT) is an emerging therapeutic mode which can be applied to bacterial infection without inducing resistance. Moreover, enhanced therapeutic efficacy and less tissue damage can be realized with NIR-II fluorescence imaging (FLI) guided PTT. Herein, a polymeric luminogen with aggregation-induced emission (AIEgens) characteristics, poly(dithieno[3,2-b:2',3'-d]pyrrole-benzo[1,2-c:4,5-c']bis([1,2,5]thiadiazole)) (PDTPTBT), was synthesized and used as a photothermal agent for PTT of bacterial infections. PDTPTBT was encapsulated into liposomes (L-PDTPTBT) for improved water dispersibility. Upon 808 nm NIR irradiation, L-PDTPTBT can eliminate multiple bacteria including the Gram-positive methicillin-resistant Staphylococcus aureus and Enterococcus faecalis, the Gram-negative Escherichia coli and Pseudomonas aeruginosa. Serious damage of bacterial membrane and leakage of cytoplasm is observed after photothermal treatment using L-PDTPTBT. The potential of the formulation has been demonstrated in two infected animal models: (i) a subcutaneous abscess model and (ii) a diabetic skin infection model. In the diabetic skin infection model, the death of mice is largely suppressed and the wounds can heal more quickly with treatment of L-PDTPTBT under NIR irradiation. The excellent photothermal bactericidal ability and low cytotoxicity make L-PDTPTBT potential candidate for treating MDR bacterial infections in the future.

Synchronously boosting type-I photodynamic and photothermal efficacies via molecular manipulation for pancreatic cancer theranostics in the NIR-II window.

In view of the fact that pancreatic cancer, called as the king of cancer, is one of the most lethal malignancies, exploring effective technologies for pancreatic cancer diagnosis and therapy remains an appealing yet significantly challenging task. Phototheranostics has recently received considerable attention by virtue of its various distinctive advantages. However, the limited penetration depth, strong oxygen-dependence and high heat shock protein-inhibition of conventional phototheranostic materials severely hamper their overall theranostic efficacy, especially for deep-seated hypoxia tumors, such as pancreatic tumor. In this study, an aggregation-induced emission (AIE)-featured photosensitizer, namely DCTBT, synchronously sharing NIR-II fluorescence imaging (FLI), diminished oxygen-dependent type-I photodynamic therapy (PDT) and high-efficiency photothermal therapy (PTT) functions was subtly constructed by molecular engineering. With the aid of an EGFR-targeting-peptide-modified amphiphilic polymer, the as-prepared DCTBT-loaded liposomes is capable of effectively accumulating at and visualizing pancreatic tumor, as well as significantly suppressing the tumor growth on both subcutaneous and orthotopic PANC-1 tumor mice models. This study thus brings useful insights into designing the next generation of cancer theranostic agents for potential clinical applications.

A Luminol-Based Self-Illuminating Nanocage as a Reactive Oxygen Species Amplifier to Enhance Deep Tumor Penetration and Synergistic Therapy.

The dense extracellular matrix (ECM) in tumor tissues resists drug diffusion into tumors and leads to a poor prognosis. To address this problem, glucose oxidase (GOx)-modified ferritin loaded with luminol-curcumin was fabricated. Once delivered to the tumor, this luminol-based self-illuminating nanocage could actively convert glucose to reactive oxygen species (ROS) to achieve starvation therapy. Then, excessive ROS were transmitted to luminol, thereby emitting 425 nm blue-violet light. Momentarily, light was further absorbed by curcumin and ROS production was amplified. Abundant ROS helps break down the ECM network to penetrate deep into tumors. In addition, ROS produced after cell internalization can induce apoptosis of tumor cells by decreasing the mitochondrial membrane potential and can promote ferroptosis by consuming reduced glutathione. Effective penetration and multiple pathways inducing tumor cell death contributed to the efficient antitumor effect (tumor inhibition rate of GOx-modified ferritin loaded with luminol-curcumin: 71.73%). This study developed a glucose-driven self-illuminating nanocage for active tumor penetration via ROS-mediated destruction of the ECM and provided the synergetic mechanism of apoptosis and ferroptosis.

Preemptive analgesic effectiveness of single dose intravenous ibuprofen in infants undergoing cleft palate repair: a randomized controlled trial.

BACKGROUND: Correction surgery for cleft palate is recommended between 9 and 18 months of age. Patients suffer from acute pain after palatoplasty. Clinicians are hesitant to use opioids for analgesia concerning the potential high risk of respiratory adverse events. Intravenous ibuprofen perhaps be a suitable adjuvant to pain relief. We try to assess whether preoperative administration of intravenous ibuprofen can decrease opioid requirements following cleft palate repair in infants. METHODS: This single center prospective randomized clinical trial was performed from February to April 2021 at Department of Anesthesiology in Shanghai Children's Medical Center. Forty patients ASA I-II, aged 9-24 months with isolated cleft palate and undergoing palatoplasty were randomized in a 1:1 ratio to receive either a single dose of 10 mg/kg ibuprofen intravenously or normal saline at induction. Children and infants postoperative pain scale (CHIPPS) was used for pain assessment. Those patients CHIPPS pain score equal or higher than 4 received analgesic rescue with titrating intravenous fentanyl 0.5 µg/kg and repeated in 10 min if required. The primary outcome was the amount of postoperative fentanyl used for rescue analgesia in postanesthesia care unit (PACU). RESULTS: Patients (n = 20 in each group) in IV-Ibuprofen group required less postoperative fentanyl than those in placebo group (p<0.001). There was no significant difference between two groups in first rescue analgesia time (p = 0.079) and surgical blood loss (p = 0.194). No incidence of obvious adverse events had been found within the first 24 h after surgery in both groups. CONCLUSIONS: Preemptive intravenous administration ibuprofen 10 mg/kg at induction had a significant opioid sparing effect in early postoperative period without obvious adverse effects in infants undergoing palatoplasty. TRIAL REGISTRATION: CHICTR, CTR2100043718, 27/02/2021 http://www.chictr.org.cn/showproj.aspx?proj=122187.

A Multicenter External Validation of a Score Model to Predict Risk of Events in Patients With Brugada Syndrome.

A multivariate risk score model was proposed by Sieira et al in 2017 for sudden death in Brugada syndrome; their validation in 150 patients was highly encouraging, with a C-index of 0.81; however, this score is yet to be validated by an independent group. A total of 192 records of patients with Brugada syndrome were collected from 2 centers in the United Kingdom and retrospectively scored according to a score model by Sieira et al. Data were compiled summatively over follow-up to mimic regular risk re-evaluation as per current guidelines. Sudden cardiac death survivor data were considered perievent to ascertain the utility of the score before cardiac arrest. Scores were compared with actual outcomes. Sensitivity in our cohort was 22.7%, specificity was 57.6%, and C-index was 0.58. In conclusion, up to 75% of cardiac arrest survivors in this cohort would not have been offered a defibrillator if evaluated before their event. This casts doubt on the utility of the score model for primary prevention of sudden death. Inherent issues with modern risk scoring strategies decrease the likelihood of success even in robustly designed tools such as the Sieira score model.

Polydopamine nanoparticles with different sizes for NIR-promoted gene delivery and synergistic photothermal therapy.

The combination of photothermal therapy and gene therapy has received increasing attention in tumor treatment. However, how to improve synergistic efficacy has become a new challenge. NIR light has a great potential in tumor treatment because of its considerable penetration depth and spatiotemporal controllability. Polydopamine is a popular photothermal conversion agent, which has desirable photothermal conversion ability and good biocompatibility. In this research, polydopamine-polyethyleneimine nanoparticles with diameters of 13 nm (SPPNPs) and 236 nm (LPPNPs) were prepared as gene carriers. The size of polydopamine nanoparticles had great effect on the complexes formation, photothermal conversion ability and gene transfection efficiency. After loading gene, the SPPNPs/gene and LPPNPs/gene complexes were about 60-80 nm and 240 nm respectively, indicating different styles of complexes formation. Both SPPNPs/gene and LPPNPs/gene complexes without NIR irradiation could achieve similar gene transfection efficiency as commercial lipofectamine 2000, while with lower cytotoxicity. Due to better photothermal conversion ability, the transfection level of LPPNPs/pGL-3 complexes increased to 4.5 times after NIR irradiation (2.6 W/cm2, 15 min), which ascribed to the quick escape of gene complexes from the endosome. The produced heat under NIR irradiation could also ablate tumor cells. So LPPNPs were chosen to deliver tumor suppressor gene p53 DNA to investigate the synergistic efficacy of gene/photothermal therapy. The tumor in KB tumor-bearing mice was almost eliminated after intratumoral injection, and the tumor inhibition efficacy of gene/photothermal synergistic therapy achieved to 99%. By combining NIR-promoted gene transfection and gene/photothermal synergistic therapy, the LPPNPs hold great promise in practical tumor treatment.

Aggregation-Induced Emission-Based Platforms for the Treatment of Bacteria, Fungi, and Viruses.

The prevention and control of pathogenic bacteria, fungi, and viruses is a herculean task for all the countries since they greatly threaten global public health. Rapid detection and effective elimination of these pathogens is crucial for the treatment of related diseases. It is urgently demanded to develop new diagnostic and therapeutic strategies to combat bacteria, fungi, and viruses-induced infections. The emergence of aggregation-induced emission (AIE) luminogens (AIEgens) is a revolutionary breakthrough for the treatment of many diseases, including pathogenic infections. In this review, the main focus is on the applications of AIEgens for theranostic treatment of pathogenic bacteria, fungi, and viruses. Due to the AIE characteristic, AIEgens are promising fluorescent probes for the detection of bacteria, fungi, and viruses with excellent sensitivity and photostability. Moreover, AIEgen-based theranostic platforms can be fabricated by introducing bactericidal moieties or designing AIE photosensitizers and AIE photothermal agents. The current strategies and ongoing developments of AIEgens for the treatment of pathogenic bacteria, fungi, and viruses will be discussed in detail.

Build an implanted "arsenal": detachable microneedles for NIR-triggered cancer photothermo-chemotherapy.

The current trend in tumor research is shifting from monotherapy to multimodal therapy. However, how to achieve on-demand drug delivery and minimize the invasiveness of treatment are still big challenges. Herein, we present a detachable microneedles (MNs) system, which consists of polycaprolactone (PCL) needles and polyvinylpyrrolidone/poly (vinyl alcohol) substrate, to build an implanted drug depot for on-demand photothermo-chemotherapy. Owing to the dissolvability of the substrate, detachable MNs can intradermally implant PCL needles loaded with photothermal conversion agent Prussian blue nanocubes (PB NCs) and chemotherapeutics doxorubicin hydrochloride (Dox·HCl). Once near-infrared light irradiates, PB NCs could translate light to local regional hyperthermia, which not only ablates cancer cells but also meltPCL to accelerate the diffusion of Dox·HCl. These MNs displayed a stable and repeatable photothermal effect under NIR irradiation. The ex vivo experiments using isolated swine skin demonstrated the as needed Dox·HCl delivery triggered by NIR light. Moreover, the robust antitumor efficacy of the MN system was proved in KB tumor-bearing nude mice under three timed NIR irradiation. Therefore, the developed detachable MNs which could build implanted "arsenal" for on-demand photothermo-chemotherapy have a bright future in tumor suppression.

Gu-Ben-Fang-Xiao decoction modulates lipid metabolism by activating the AMPK pathway in asthma remission.

Gu-Ben-Fang-Xiao decoction (GBFXD), derived from the traditional Chinese medicine Yu-Ping-Feng-San, is widely used in clinical settings and has obvious curative effects in respiratory diseases. GBFXD regulates cholesterol transport and lipid metabolism in chronic persistent asthma. There is evidence for its beneficial effects in the remission stage of asthma; however, its metabolic regulatory effects and underlying mechanisms during asthma remission are unclear. In the present study, we used liquid chromatography-mass spectrometry (LC-MS) to analyse the metabolic profile of mouse serum during asthma remission. The acquired LC-MS data were subjected to a multivariate analysis for identification of significantly altered metabolites. In total, 42 metabolites were significantly differentially expressed among the control, model, and GBFXD groups. In particular, levels of fatty acids, acylcarnitines, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, triglycerides, and diacylglycerols were altered during asthma remission. GBFXD may maintain lipid homeostasis on the lung surface by modulating lipid metabolism and may thereby alleviate asthma. We further quantified hypogeic acid (FA 16:1) based on targeted metabolomics and found that GBFXD may regulate fatty acid metabolism by activating the AMP-activated protein kinase (AMPK) pathway. These results support the use of GBFXD in patients with asthma remission.

[Modified Dihuang Decoction improves ovarian reserve in mice by regulating Bcl-2-related mitochondrial apoptosis pathway].

The present study investigated the effect of Modified Dihuang Decoction in improving ovarian reserve in mice through the Bcl-2-related mitochondrial apoptosis pathway. Forty-eight adult female BALB/c mice were randomly divided into the following six groups with eight mice in each group: a blank group, a model group, a femoston group(three cycles of treatment with 0.13 mg·kg~(-1) estradiol tablets for 2 days and 1.43 mg·kg~(-1) estradiol and dydrogesterone tablets for 3 days), and high(64.74 g·kg~(-1))-, medium(43.16 g·kg~(-1))-, and low-dose(21.58 g·kg~(-1)) Modified Dihuang Decoction groups. Mice in other groups except the blank group received a single intraperitoneal injection of 12 mg·kg~(-1) cyclophosphamide and 1.2 mg·kg~(-1) busulfan to induce a model of diminished ovarian reserve(DOR), while those in the blank group received an equal volume of normal saline. Mice were treated with corresponding drugs for 15 d from the 36 th day, once per day, and the mice in the blank group and the model group were treated with an equal volume of normal saline. The general condition and oestrous cycle were observed. The serum hormone levels were detected with the enzyme-linked immunosorbent assay(ELISA). The morphological changes of ovaries were observed by HE staining. Western blot was used to detect the protein expression of cysteinyl aspartate specific proteinase-9(caspase-9), cleaved caspase-3, Bcl-2 associated X protein(Bax), Bcl-2, superoxide dismutase-2(SOD-2), and glutathione peroxidase-1(GPx-1). The mRNA expression of Bax and Bcl-2 was detected by real-time fluorescence-based quantitative polymerase chain reaction(real-time PCR). The results showed that compared with the blank group, the model group showed body weight loss, disordered oestrous cycle, elevated serum levels of follicle-stimulating hormone(FSH) and luteinizing hormone(LH), reduced serum levels of estradiol(E_2), anti-mullerian hormone(AMH), and inhibin B(INHB), the declining number of ovarian follicles and granulosa layers, increased number of atretic follicles, up-regulated protein expression of caspase-9, cleaved caspase-3, and Bax and Bax mRNA expression in ovaries, and down-regulated protein expression of Bcl-2, SOD-2 and GPx-1, and Bcl-2 mRNA expression. Compared with the model group, the Modified Dihuang Decoction groups displayed restored body weight and oestrous cycle, decreased serum levels of FSH and LH, elevated serum levels of E_2, AMH, and INHB, increased number of ovarian follicles, thickened granulosa layers, and declining number of atretic follicles. Additionally, the protein expression of caspase-9, cleaved caspase-3, and Bax, and Bax mRNA expression was down-regulated, and the protein expression of Bcl-2, SOD-2, and GPx-1, and Bcl-2 mRNA expression was up-regulated. The results suggest that Modified Dihuang Decoction can regulate endocrine hormone, promote follicle growth and improve ovarian reserve by enhancing ovarian anti-oxidant capacity, inhibiting the Bcl-2-related mitochondrial apoptosis pathway, and further inhibiting cell apoptosis.

Imaging Changes and Clinical Complications After Drug-Eluting Bead Versus Conventional Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: Multicenter Study.

BACKGROUND. Drug-eluting bead transarterial chemoembolization (DEB-TACE) has emerged as an alternative to conventional TACE (cTACE) for treatment of hepatocellular carcinoma (HCC), although selection between the approaches remains controversial. OBJECTIVE. The purpose of this study was to compare DEB-TACE and cTACE in the treatment of patients with unresectable HCC in terms of hepatobiliary changes on imaging and clinical complications. METHODS. This retrospective study included 1002 patients (871 men, 131 women; mean age, 59 ± 12 years) from three centers who had previously untreated unresectable HCC and underwent DEB-TACE with epirubicin (780 procedures in 394 patients) or cTACE with ethiodized oil mixed with doxorubicin and oxaliplatin (1187 procedures in 608 patients) between May 2016 and November 2018. Among these patients 83.4% had hepatitis B-related liver disease, 57.6% had Barcelona Clinic Liver Cancer (BCLC) stage A or B HCC, and 42.4% had three or more nodules. Mean tumor size was 6.3 ± 4.2 cm. Hepatobiliary changes and tumor response were evaluated with CT or MRI 1 month after TACE. Clinical records were reviewed for adverse events. RESULTS. Bile duct dilatation (p < .001) and portal vein narrowing (p = .006) on imaging and liver failure (p = .03) and grade 3 abdominal pain (p < .001) in clinical follow-up occurred at higher frequency in the DEB-TACE group (15.5%, 4.6%, 2.3%, and 6.1%) than in the cTACE (7.4%, 1.6%, 0.7%, and 2.1%) group. Higher frequency of bile duct dilation in patients who underwent DEB-TACE was observed in subgroup analyses that included patients with BCLC stage A or B HCC (p = .001), with cirrhosis (p < .001), without cirrhosis (p = .04), and without main portal vein tumor thrombus (p = .002). Total bilirubin level 1 month after treatment was 1.5 ± 2.4 mg/dL (95% CI, 1.2-1.8 mg/dL) for DEB-TACE versus 1.3 ± 2.0 mg/dL (95% CI, 1.1-1.5 mg/dL) for cTACE (p = .02). The cTACE and DEB-TACE groups did not differ in other manifestations of postembolization syndrome or systemic toxicity (p > .05). Local tumor disease control rates did not differ between the cTACE and DEB-TACE groups (1 month, 96.7% vs 98.5%, p = .06; 3 months, 81.8% vs 82.4%, p = .87), but overall DCR was significantly higher in the cTACE than in the DEB-TACE group (1 month, 87.5% vs 80.0%, p = .001; 3 months, 78.5% vs 72.1%, p = .02). CONCLUSION. Compared with cTACE, DEB-TACE was associated with greater frequency of hepatobiliary injury and severe abdominal pain. CLINICAL IMPACT. Greater caution and closer follow-up are warranted for patients who undergo DEB-TACE for unresectable HCC than for those who undergo cTACE.

Gu-Ben-Fang-Xiao attenuates allergic airway inflammation by inhibiting BAFF-mediated B cell activation.

Allergic airway inflammation is one of the major pathological events involved in the development of asthma. The B cell-activating factor (BAFF)-mediated abnormal activation of B cells plays a key role in developing allergic airway inflammation. Here, we investigated the effects of Gu-Ben-Fang-Xiao decoction (GBFXD), a TCM decoction used in the prevention and treatment of allergic asthma, on allergic airway inflammation and BAFF-mediated B cell activation. A mouse model of OVA-Severe respiratory syncytial virus (RSV) induced asthma in the remission stage was administrated with GBFXD by gavage for four weeks, after which, the pulmonary function was evaluated. Pathological changes of the lung were observed by hematoxylin and eosin (HE) staining, and serum levels of IgE, BAFF, and inflammatory factors were detected by ELISA. The expression of BAFF, APRIL, and their related receptors in the lung and spleen was detected by Western blotting and RT-qPCR. Flow cytometry detected B cell subsets in the spleen, PBC, and monocyte subsets in bronchoalveolar lavage fluid (BALF). The results showed that GBFXD improved the lung function, alleviated the inflammatory changes of the lung tissue in OVA-RSV sensitized mice, and reduced levels of IL-6, TNF-α, IL1-ß, INOS, IL13 as well as IL-15, IgE, BAFF in the serum of OVA-RAV mice. Additionally, GBFXD significantly reduced the proportion of CD19+CD27+ B cell subpopulation and IgE + B cell subpopulation in the PBC and spleen cells of mice. Furthermore, the expression of BAFF, APRIL, BAFFR, TACI, and AID decreased in the lung and spleen of GBFXD-treated mice, as well as the proportion of CD11b + BAFF + cell subsets in BALF. In conclusion, GBFXD has an inhibitory effect on the secretion of BAFF by pulmonary macrophages and the expression of BAFF-related receptors, thereby reducing B cell activation and the release of IgE. This proposed mechanism contributes to the improvement of allergic airway inflammation and respiratory function in an asthmatic mouse model.

Colorectal adenocarcinoma patients with M1a diseases gain more clinical benefits from palliative primary tumor resection than those with M1b diseases: A propensity score matching analysis.

BACKGROUND: Surgical resection is regarded as the only potentially curative treatment option for patients with metastatic colorectal cancer (CRC). The National Comprehensive Cancer Network clinical practice guidelines do not recommend palliative surgery unless there is a risk of severe symptoms. However, accumulating evidence has shown that palliative surgery is associated with more favorable outcomes for patients with metastatic CRC. AIM: To investigate the separate role of palliative primary tumor resection for patients with stage IVA (M1a diseases) and stage IVB (M1b diseases) colorectal adenocarcinoma (CRA). METHODS: CRA patients diagnosed from 2010 to 2015 with definite M1a and M1b categories according to the 8th edition of American Joint Committee on Cancer staging system were selected from the Surveillance Epidemiology and End Results (SEER) database. To minimize potential selection bias, the data were adjusted by propensity score matching (PSM). Baseline characteristics, including gender, year of diagnosis, age, marital status, primary site, surgical information, race, grade, chemotherapy, and radiotherapy, were recorded and analyzed. Univariate and multivariate analyses were performed to explore the separate role of palliative surgery for patients with M1a and M1b diseases. RESULTS: A total of 19680 patients with metastatic CRA were collected from the SEER database, including 10399 cases of M1a diseases and 9281 cases of M1b diseases. Common independent prognostic factors for both M1a and M1b patients included year of diagnosis, age, race, marital status, primary site, grade, surgery, and chemotherapy. After PSM adjustment, 3732 and 3568 matched patients in the M1a and M1b groups were included, respectively. Patients receiving palliative primary tumor resection had longer survival time than those without surgery (P < 0.001). For patients with M1a diseases, palliative resection could increase the median survival time by 9 mo; for patients with M1b diseases, palliative resection could prolong the median survival time by 7 mo. For M1a diseases, patients with lung metastasis had more clinical benefit from palliative resection than those with liver metastasis (15 mo for lung metastasis vs 8 mo for liver metastasis, P < 0.001). CONCLUSION: CRA patients with M1a diseases gain more clinical benefits from palliative primary tumor resection than those with M1b diseases. Those patients with M1a (lung metastasis) have superior long-term outcomes after palliative primary tumor resection.