pH-Responsive NIR-II phototheranostic agents for in situ tumor vascular monitoring and combined anti-vascular/photothermal therapy.

Developing nanoplatforms integrating superior fluorescence imaging ability in second near-infrared (NIR-II) window and tumor microenvironment responsive multi-modal therapy holds great potential for real-time feedback of therapeutic efficacy and optimizing tumor inhibition. Herein, we developed a pH-sensitive pyrrolopyrrole aza-BODIPY-based amphiphilic molecule (PTG), which has a balanced NIR-II fluorescence brightness and photothermal effect. PTG is further co-assembled with a vascular disrupting agent (known as DMXAA) to prepare PTDG nanoparticles for combined anti-vascular/photothermal therapy and real-time monitoring of the tumor vascular disruption. Each PTG molecule has an active PT-3 core which is linked to two PEG chains via pH-sensitive ester bonds. The cleavage of ester bonds in the acidic tumor environment would tricker releases of DMXAA for anti-vascular therapy and further assemble PT-3 cores into micrometer particles for long term monitoring of the tumor progression. Furthermore, benefiting from the high brightness in the NIR-II region (119.61 M-1 cm-1) and long blood circulation time (t1/2 = 235.6 min) of PTDG nanoparticles, the tumor vascular disrupting process can be in situ visualized in real time during treatment. Overall, this study demonstrates a self-assembly strategy to build a pH-responsive NIR-II nanoplatform for real-time monitoring of tumor vascular disruption, long-term tracking tumor progression and combined anti-vascular/photothermal therapy.

Lipid droplet targeting-guided hypoxic photodynamic therapy with curcumin analogs.

Two photosensitizers (CCOH and CCN) were designed and synthesized by introducing coumarin into the curcumin (CUR) structure. Compared with CUR, more reactive oxygen species (ROS) were generated by CCOH and CCN in type I and II synergy upon light irradiation. Cell experiments indicated that CCN with an excellent LD-targeting effect could be used to monitor the changes in the morphology and number of LDs in tumor cells during PDT.

Anti-Quenching NIR-II J-Aggregates of Benzo[c]thiophene Fluorophore for Highly Efficient Bioimaging and Phototheranostics.

Molecular fluorophores with the second near-infrared (NIR-II) emission hold great potential for deep-tissue bioimaging owing to their excellent biocompatibility and high resolution. Recently, J-aggregates are used to construct long-wavelength NIR-II emitters as their optical bands show remarkable red shifts upon forming water-dispersible nano-aggregates. However, their wide applications in the NIR-II fluorescence imaging are impeded by the limited varieties of J-type backbone and serious fluorescence quenching. Herein, a bright benzo[c]thiophene (BT) J-aggregate fluorophore (BT6) with anti-quenching effect is reported for highly efficient NIR-II bioimaging and phototheranostics. The BT fluorophores are manipulated to have Stokes shift over 400 nm and aggregation-induced emission (AIE) property for conquering the self-quenching issue of the J-type fluorophores. Upon forming BT6 assemblies in an aqueous environment, the absorption over 800 nm and NIR-II emission over 1000 nm are boosted for more than 41 and 26 folds, respectively. In vivo visualization of the whole-body blood vessel and imaging-guided phototherapy results verify that BT6 NPs are excellent agent for NIR-II fluorescence imaging and cancer phototheranostics. This work develops a strategy to construct bright NIR-II J-aggregates with precisely manipulated anti-quenching properties for highly efficient biomedical applications.

Near-Infrared Hypocrellin Derivatives for Synergistic Photodynamic and Photothermal Therapy.

Hypocrellin B (HB) derived from naturally produced hypocrellins has attracted considerable attention in photodynamic therapy (PDT) because of its excellent photosensitive properties. However, the weak absorption within a "phototherapy window" (600-900 nm) and poor water solubility of HB have limited its clinical application. In this study, two HB derivatives (i. e., HE and HF) were designed and synthesized for the first time by introducing two different substituent groups into the HB structure. The obtained derivatives showed a broad absorption band covering the near-infrared (NIR) region, NIR emission (peaked at 805 nm), and singlet oxygen quantum yields of 0.27/0.31. HE-PEG-NPs were also prepared using 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000) to achieve excellent dispersion in water and further explored their practical applications. HE-PEG-NPs not only retained their 1 O2 -generating ability, but also exhibited a photothermal conversion efficiency of 25.9%. In vitro and in vivo therapeutic results revealed that the synergetic effect of HE-PEG-NPs on PDT and photothermal therapy (PTT) could achieve a good performance. Therefore, HE-PEG-NPs could be regarded as a promising phototheranostic agent.

Meta-analysis of influences of Biejiajian Pill combined with entecavir on serum liver fibrosis markers of compensatory period of hepatitis b cirrhosis: Protocol of systematic review and meta-analysis.

BACKGROUND: Chronic viral hepatitis b and its related complications have caused serious harm to human health and become a worldwide public health problem. Hepatitis b cirrhosis is one of the most common complications in Asia. Traditional Chinese medicine combined with antiviral therapy has become the first choice for clinical treatment of hepatitis b Cirrhosis. Biejia Pill is an effective prescription of traditional Chinese medicine in treating Compensatory period of cirrhosis, and there are more and more clinical reports about its validity in treating Compensatory period of cirrhosis. Therefore, we designed this study protocol to evaluate the adjuvant role of Biejia Pill in the treatment of Compensatory period of cirrhosis. METHOD: Electronic Databases, PubMed, EMBASE database, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang, Chinese Scientific Journals Database (VIP) and China Biology Medicine disc, (CBM), will be systematically searched from inception to July 2019. Randomized controlled trials (RCTs) on Biejiajian Pill combined with Entecavir and Entecavir alone against Compensatory period of hepatitis b cirrhosis will be included; inclusion and exclusion criteria will be used to screen the trials. liver fibrosis biomarkers including ECM or its metabolites (serum hyaluronic acid (HA), laminin (LN), procollagen type III (PC-III), and type IV collagen (IV-C)) will be measured as primary outcomes. Liver function, including alanine aminotransferase (ALT) and aspartarte aminotransferase (AST), and improvement of related clinical symptoms will be measured as secondary outcomes. RevMan5 software will be used for literature quality evaluation and data synthesis and analysis. RESULT: To evaluate the efficacy and safety of Biejiajian Pill in combination therapy by observing the outcomes of serum liver fibrosis markers, adverse reactions and liver function. CONCLUSION: This study protocol will be used to evaluate the efficacy and safety of Biejia Pill in combination with entecavir in the treatment of Compensatory period of hepatitis b cirrhosis, as well as the adjuvant treatment of Biejia Pill in combination.PROSPERO registration number: CRD42019135402.

Natural-Origin Hypocrellin-HSA Assembly for Highly Efficient NIR Light-Responsive Phototheranostics against Hypoxic Tumors.

Tumor hypoxia severely limits the therapeutic efficacy of solid tumors in photodynamic therapy. One strategy is to develop photosensitizers with simultaneously high efficiency in photodynamic (PDT) and photothermal therapies (PTT) in a single natural-origin phototheranostic agent to overcome this problem. However, less attention has been paid to the natural-origin phototheranostic agent with high PDT and PTT efficiencies even though they have negligible side effects and are environmentally sustainable in comparison with many reported phototheranostic agents. In addition, almost all clinical applied photosensitizers are of natural origin so far. Herein, we synthesized a natural product-based hypocrellin derivative (AETHB), with a high singlet oxygen quantum yield of 0.64 as an efficient photosensitizer different from commercially available porphyrin-based photosensitizers. AETHB is further assembled with human serum albumin to construct nanoparticles (HSA-AETHB NPs) with a high photothermal conversion efficiency (more than 50%). As-prepared HSA-AETHB NPs have shown good water solubility and biocompatibility, pH and light stability, wide absorption (400-750 nm), and NIR emission centered at 710 nm. More importantly, HSA-AETHB NPs can be applied for fluorescent/photoacoustic dual-mode imaging and simultaneously highly efficient PDT/PTT in hypoxic solid tumors. Therefore, this natural-origin multifunctional phototheranostic agent is showing very promising for effective, precise, and safe cancer therapy in clinical applications.

Adjuvant treatment with Xiaoqinglong formula for bronchial asthma: Protocol of systematic review and meta-analysis.

BACKGROUND: Bronchial asthma is one of the most common chronic diseases in the world and has become a serious public health problem. Combination therapy has become the first choice for clinical treatment of bronchial asthma. In addition to the combined use of routine medication, traditional Chinese medicine as an adjuvant therapy is also considered. Xiaoqinglong Decoction (XQLD) is an effective prescription of traditional Chinese medicine in treating asthma, and there are more and more clinical reports about its combination with western medicine in treating asthma. Therefore, we designed this study protocol to evaluate the adjuvant role of XQLD in the treatment of bronchial asthma. METHOD: The following electronic databases will be systematically searched from inception to April 2019: PubMed, EMBASE database, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang, Chinese Scientific Journals Database (VIP), and China Biology Medicine disc, (CBM). And the following primary outcomes will be tested, including effective rate (ER), pulmonary function (FEV1, PEF, FEV1/FVC), adverse reactions (AR). RevMan5 software will be used for literature quality evaluation and stata14.0 software will be used for data synthesis and analysis. RESULT: To evaluate the efficacy and safety of Xiaoqinglong decoction in combination therapy by observing the outcomes of efficacy, adverse reactions and pulmonary function. CONCLUSION: This study protocol will be used to evaluate the efficacy and safety of XQLD in combination with conventional drugs in the treatment of bronchial asthma, as well as the adjuvant role of XQLD in combination. PROSPERO REGISTRATION NUMBER: CRD42019133549.

Pheophytin Derived Near-Infrared-Light Responsive Carbon Dot Assembly as a New Phototheranotic Agent for Bioimaging and Photodynamic Therapy.

Carbon dots (CDs), a kind of phototheranostic agent with the capability of simultaneous bioimaging and phototherapy [i.e., photodynamic therapy (PDT) or photothermal therapy (PTT)], have received considerable attention because of their remarkable properties, including flexibility for surface modification, high biocompatibility, low toxicity and photo-induced activity for malignant tumor cells. Among numerous carbon sources, it has been found that natural biomass are good candidates for the preparation of CD phototheranostic agents. In this study, pheophytin, a type of Mg-free chlorophyll derivative and also a natural product with low toxicity, was used as a raw carbon source for the synthesis of CDs by using a microwave method. The obtained hydrophobic CDs exhibited a maximum near-infrared (NIR) emission peak at approximately 680 nm, and high singlet oxygen (1 O2 ) generation with a quantum yield of 0.62. The self-assembled CDs from the as-prepared CDs with DSPE-mPEG2000 retained efficient 1 O2 generation. The obtained carbon dot assembly was not only an efficient fluorescence (FL) imaging agent but also a smart PDT agent. Our studies indicated that the obtained hydrophilic CD assembly holds great potential as a new phototheranostic agent for cancer therapy. This work provides a new route for synthesis of CDs and proposes a readily available candidate for tumor treatment.

Epigenetic differences of chronic hepatitis B in different TCM syndromes: Protocol for a case-control, non-interventional, observational clinical study.

INTRODUCTION: Chronic hepatitis B is a serious disease causing serious harm to the human health. Chinese medicine has its unique advantages in the clinical prevention and treatment, while the syndrome of Chinese medicine lacks the understanding at the micro level. There are some theoretical commonalities between the epigenetics and traditional Chinese medicine (TCM) syndromes. The biological basis of chronic hepatitis B (CHB) syndrome differentiation from the perspective of epigenetics is of great significance to diagnose and prevent the diseases. METHODS: This protocol is a case-control, noninterventional, observational clinical study. Patients with CHB for spleen-stomach damp heat and liver depression and spleen deficiency, with 12 each and 11 healthy volunteers were recruited. Peripheral venous blood was collected from the participants. DNA methylated transferase, genomic DNA methylated spectrum, methylated DNA binding protein MeCP2, chronic infection of hepatitis B virus with methylated related proteins, and miRNA target genes were analyzed. OBJECTIVES: From the perspective of DNA methylation epigenetics, "DNA methylation-miRNA-Target gene" is the main line, which further reveals the essence of TCM syndrome. To improve the level of TCM clinical syndrome differentiation and the clinical efficacy of TCM, especially in the study of TCM syndromes of CHB, discovering its underlying biological signature is necessary. TRIAL REGISTRATION: Clinical Trials Registration: ChiCTR1800017365, registered 26 July 2018.

Synthesis of carbon dots from Hypocrella bambusae for bimodel fluorescence/photoacoustic imaging-guided synergistic photodynamic/photothermal therapy of cancer.

As phototheranostic agents, carbon dots (CDs), have recently drawn considerable attention due to their excellent physicochemical properties. However, the complex synthetic route and high-cost of CDs greatly limit their practical application. To address this issue, given their nearly infinite supply from nature, Hypocrella bambusae is used as the precursor for the preparation of CDs in this study. The obtained Hypocrella bambusae CDs (HBCDs) possess good water solubility, broad absorption (350-800 nm), red-light emission (maximum peak at 610 nm), and low biotoxicity. Moreover, HBCDs can highly generate 1O2 (0.38) and heat (27.6%) under 635 nm laser irradiation. These excellent properties of HBCDs capacitate them to be utilized for bimodal fluorescence/photoacoustic imaging-guided synergistic photodynamic therapy (PDT)/photothermal therapy (PTT). This work provides a new candidate for tumor treatment with the combination of PDT and PTT, and explores a novel approach for the preparation of CD-based phototheranostic agents with natural biomass as raw carbon sources.

Synchronous dynamic research on respiratory and intestinal microflora of chronic bronchitis rat model.

OBJECTIVES: To investigate the mechanism of the Chinese medicine theory that Fei (Lung) and Dachang (Large Intestine) are exteriorly and interiorly related via synchronous observation on the dynamic changes of the respiratory and intestinal microflora. METHODS: Forty specific pathogen free Sprague-Dawley rats were selected and randomly divided into blank (10 rats) and chronic bronchitis model groups (30 rats). The blank group rats were put into the smoke-free environment and the model group rats were put into the smoke environment in order to establish pulmonary disease (chronic bronchitis) model. Then the corresponding changes of the respiratory and intestinal microflflora of the model on 20th, 50th and 70th days were synchronously observed. RESULTS: The respiratory tract microflflora showed an increase in the total aerobic and Staphylococcus aureus and reduced anaerobic amount signifificantly on 20th day in the respiratory tract microflflora (P<0.05 or 0.01). On 50th day, total aerobic, total anaerobic amount and bififidobacterium signifificantly increased (P<0.05). On 70th day, Staphylococcus aureus reduced and lactobacillus increased signifificantly (P<0.01). The intestinal microflflora showed an increase in the total aerobic, Clostridium perfringens, enterobacter and enterococcus significantly increased on 20th day (P<0.05 or 0.01). Staphylococcus aureus on 50th day increased significantly (P<0.05). Total aerobic and enterococcus increased, total anaerobic and Clostridium perfringens reduced signifificantly on 70th day (P<0.05 or 0.01). CONCLUSION: The microecosystem of respiratory tract and intestine of rat model during the pathological process showed a dynamic disorder, indicating an interaction between the lung and large intestine which may be one of the connotations as they exteriorly and interiorly related.

[Changes of CCK-8, CGRP, SP, and VIP in the colon and the lung tissue of allergic asthma model rats: an experimental observation].

OBJECTIVE: To observe changes of cholecystokinin octapeptide (CCK-8), calcitonin gene related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP) in each tissue of the digestive system of allergic asthma (AA) model rats. METHODS: The pulmonary disease (AA) rat model was duplicated by 1% ovalbumin. Its effect on the pathological morphology of the six main parts of the digestive system (stomach, duodenum, jejunum, ileum, colon and rectum) and related regulating factors such as CCK8, CGRP, SP, and VIP were observed. RESULTS: The pathological morphology of the lung was synchronously changed as that of the colon of model rats. But there was no obvious change in the stomach, duodenum, jejunum, ileum, or rectum. Significant changes occurred in CCK8 (79 961.4 +/- 12 577.9, 48 519.5 +/- 12 240.7), CGRP (41 950.1 +/- 12 600.1, 38 059.8 +/- 11 942.4), and SP (88 243.9 +/- 32 177.2, 47 417.8 +/- 16 462.4), and VIP (20 711.4 +/- 7 334.6, 43 208.1 +/- 13 433.8) of the lung tissue and the colon tissue of model rats (P < 0. 05, P < 0.01). But there was no significant change in the aforesaid substances of the stomach, duodenum, jejunum, ileum and rectum (P > 0.05). CONCLUSIONS: Pulmonary disease might affect the colon, inducing pathological changes of the colon tissue and changes of related regulating factors such as CCK8, CGRP, SP, and VIP. It showed no significant effect on the stomach, duodenum, jejunum, ileum and rectum.

[Observation on therapeutic effect of multiple cupping at back-shu points on chronic fatigue syndrome].

OBJECTIVE: To observe therapeutic effect of multiple cupping at back-shu points of zang-and fu-organs on chronic fatigue syndrome. METHODS: One hundred and ninety-one cases were randomly divided into 2 groups. The multiple cupping group (n = 142) were treated with multiple cupping along both sides of the spinal cord, and the acupuncture group (n = 49) were treated with acupuncture at acupoints selected according to TCM syndrome differentiation. Their therapeutic effects were assessed by clinical symptoms and Fatigue Assessment Indexes (FAI). RESULTS: The total effective rate was 97.9% in the multiple cupping group and 79.6% in the acupuncture group with a very significant difference between the two groups (P < 0.01), and after treatment, there was a very significant difference between the two groups in FAI score (P < 0.01). CONCLUSION: Multiple cupping at back-shu points of zang-and fu-organs is an effective method for chronic fatigue syndrome.