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Immunotherapy that stimulates the body's own immune system to kill cancer cells has emerged as a promising cancer therapeutic method. However, some types of cancer exhibited a low response rate to immunotherapy, and the high risk of immune-related side effects has been aroused during immunotherapy, which greatly restrict its broad applications in cancer therapy. Phototherapy that uses external light to trigger the therapeutic process holds advantages including high selectivity and efficiency, and low side effects. Recently, it has been proven to be able to stimulate immune response in the tumor region by inducing immunogenic cell death (ICD), the process of which was termed photo-immunotherapy, dramatically improving therapeutic specificity over conventional immunotherapy in several aspects. Among numerous optical materials for photo-immunotherapy, semiconducting polymer nanoparticles (SPNs) have gained more and more attention owing to their excellent optical properties and good biocompatibility. In this review, we summarize recent developments of SPNs for immunotherapy and imaging of immunoactivation. Different therapeutic modalities triggered by SPNs including photo-immunotherapy and photo-immunometabolic therapy are first introduced. Then, applications of SPNs for real-time monitoring immunoactivation are discussed. Finally, the conclusion and future perspectives of this research field are given.

Gastric cancer (GC) is an aggressive malignant tumor of the digestive system, with high morbidity rates. We previously demonstrated that miR-17-5p can modify tumorigenesis in GC. In addition, other studies have shown that circRNAs can regulate GC progression by sponging various miRNAs. However, the association between circRNAs and miR-17-5p in GC has not yet been explored. Hence, this study aimed to explore the possible interactions between various circRNAs and miR-17-5p using a dual-luciferase assay. CCK-8 was used to determine cell viability, and a Transwell assay was used to measure cell invasion and migration. Gene expression was assessed using quantitative reverse transcription PCR (RT-qPCR), and exosomes were identified using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Annexin V/PI staining was also used to detect cell apoptosis. These investigations collectively revealed that miR-17-5p is a target of the circRNA hsa_circ_0017252 and hsa_circ_0017252 is significantly downregulated in GC tissues. In addition, the overexpression of hsa_circ_0017252 inhibited GC cell migration by sponging of miR-17-5p, and GC cell-secreted exosomal hsa_circ_0017252 effectively inhibited macrophage M2-like polarization, which in turn suppressed GC cell invasion. Notably, exosomes containing hsa_circ_0017252 also suppressed GC tumor growth in vivo. Thus, our data suggest that the overexpression of hsa_circ_0017252 suppresses GC malignancy by sponging miR-17-5p. In addition, exosomal hsa_circ_0017252 excreted from GC cells attenuated GC progression by suppressing macrophage M2-like polarization. These findings improve our basic understanding of GC and open a novel avenue for developing more effective GC treatments.

Activatable phototheranostics holds promise for precision cancer treatment owing to the "turn-on" signals and therapeutic effects. However, most activatable phototheranostic probes only possess photodynamic therapy (PDT) or photothermal therapy (PTT), which suffer from poor therapeutic efficacy due to deficient cellular oxygen and complex tumor microenvironment. We herein report a dual-locked activatable phototheranostic probe that activates near-infrared fluorescence (NIRF) signals in tumor, triggers PDT in response to a tumor-periphery biomarker, and switches from PDT to PTT upon detecting a tumor-core-hypoxia biomarker. This PDT-PTT auto-regulated probe exhibits complete tumor ablation under the photoirradiation of a single laser source by producing cytotoxic singlet oxygen at the tumor periphery and generating hyperthermia at tumor-core where is too hypoxic for PDT. This dual-locked probe represents a promising molecular design approach toward precise cancer phototheranostics. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) K.P. thanks Singapore Ministry of Education, Academic Research Fund Tier 1 (2019-T1-002-045, RG125/19; RT05/ 20), Academic Research Fund Tier 2 (MOE2018-T2-2-042; MOE-T2EP30220-0010), and A*STAR SERC AME Programmatic Fund (SERC A18A8b0059) for the financial support.

Checkpoint immunotherapy holds great potential to treat malignancies via blocking the immunosuppressive signaling pathways, which however suffers from inefficiency and off-target adverse effects. Herein, checkpoint nano-proteolysis targeting chimeras (nano-PROTACs) in combination with photodynamic tumor regression and immunosuppressive protein degradation to block checkpoint signaling pathways for activatable cancer photo-immunotherapy are reported. These nano-PROTACs are composed of a photosensitizer (protoporphyrin IX, PpIX) and an Src homology 2 domain-containing phosphatase 2 (SHP2)-targeting PROTAC peptide (aPRO) via a caspase 3-cleavable segment. aPRO is activated by the increased expression of caspase 3 in tumor cells after phototherapeutic treatment and induces targeted degradation of SHP2 via the ubiquitin-proteasome system. The persistent depletion of SHP2 blocks the immunosuppressive checkpoint signaling pathways (CD47/SIRPα and PD-1/PD-L1), thus reinvigorating antitumor macrophages and T cells. Such a checkpoint PROTAC strategy synergizes immunogenic phototherapy to boost antitumor immune response. Thus, this study represents a generalized PROTAC platform to modulate immune-related signaling pathways for improved anticancer therapy. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Submitted/Accepted version K.P. thanks the Singapore Ministry of Education, the Academic Research Fund Tier 1 (2019-T1-002-045, RG125/19), the Academic Research Fund Tier 2 (MOE2018-T2-2-042), and the A*STAR SERC AME Programmatic Fund (SERC A18A8b0059) for the financial support.

Molecular imaging via afterglow luminescence minimizes tissue autofluorescence and increases the signal-to-noise ratio. However, the induction of afterglow requires the prior irradiation of light, which is attenuated by scattering and absorption in tissue. Here we report the development of organic nanoparticles producing ultrasound-induced afterglow, and their proof-of-concept application in cancer immunotheranostics. The 'sonoafterglow' nanoparticles comprise a sonosensitizer acting as an initiator to produce singlet oxygen and subsequently activate a substrate for the emission of afterglow luminescence, which is brighter and detectable at larger tissue depths (4 cm) than previously reported light-induced afterglow. We formulated sonoafterglow nanoparticles containing a singlet-oxygen-cleavable prodrug for the immune-response modifier imiquimod that specifically turn on in the presence of the inflammation biomarker peroxynitrite, which is overproduced by tumour-associated M1-like macrophages. Systemic delivery of the nanoparticles allowed for sonoafterglow-guided treatment of mice bearing subcutaneous breast cancer tumours. The high sensitivity and depth of molecular sonoafterglow imaging may offer advantages for the real-time in vivo monitoring of physiopathological processes. Ministry of Education (MOE) National Research Foundation (NRF) Submitted/Accepted version K.P. acknowledges financial support from the Singapore National Research Foundation (NRF) (NRF-NRFI07-2021-0005), and the Singapore Ministry of Education, Academic Research Fund Tier 1 (2019-T1-002-045, RG125/19, RT05/20) and Academic Research Fund Tier 2 (MOE-T2EP30220-0010).

Objective: Taraxasterol (TS) is the main active compound of Taraxacum, which plays a significant role in the treatment of diabetes in many classic prescriptions. However, the mechanisms of TS in the treatment of diabetes remain unclear. This study aimed to investigate the underlying mechanism of TS in hepatic gluconeogenesis and glycogen synthesis in HepG2 cells with insulin resistance (IR). Methods: Molecular docking was conducted by using Discovery Studio (DS) to predict the target of TS in the treatment of diabetes. Then we treated HepG2 cells with glucosamine for 18 h. After the cells were treated with TS, the glucose consumption was examined. Oil red O staining was used to detect the lipid accumulation of HepG2 cells, and cellular glucose uptake levels were assessed using fluorescent 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxy-D-glucose. The expression of the related proteins of the PI3K/Akt signaling pathway in the HepG2 cells was evaluated by western blot assay. Results: The molecular docking analysis revealed a good binding pose between the insulin receptor and TS. Furthermore, TS administration significantly enhanced glucose uptake and consumption, and reduced lipid accumulation in HepG2 cells with IR. The results of pharmacological mechanism study showed that TS up-regulated glycogenesis by PI3K/Akt/GSK3-motivated GS activation, and down-regulated gluconeogenesis by PI3K/Akt/FoxO1 expression of PEPCK and G6Pase in HepG2 cells with IR. Conclusions: Molecular docking and in vitro experimental results indicate that TS suppresses hepatic gluconeogenesis and augments glycogen synthesis by the PI3K/Akt signaling pathway, and it may have similar effects as insulin in regulating blood glucose.

Protease inhibitors can modulate intratumoral metabolic processes to reprogram the immunosuppressive tumor microenvironment (TME), which however suffer from the limited efficacy and off-targeted side effects. We report smart nano-proteolysis targeting chimeras (nano-PROTACs) with phototherapeutic ablation and cancer-specific protein degradation to reprogram the TME for photo-metabolic cancer immunotherapy. This nano-PROTAC has a semiconducting polymer backbone linked with a cyclooxygenase 1/2 (COX-1/2)-targeting PROTAC peptide (CPP) via a cathepsin B (CatB)-cleavable segment. CPP can be activated by the tumor-overexpressed CatB to induce the degradation of COX-1/2 via the ubiquitin-proteasome system. The persistent degradation of COX-1/2 depletes their metabolite prostaglandin E2 which is responsible for activation of immune suppressor cells. Such a smart PROTAC strategy synergized with phototherapy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) K.P. thanks Singapore Ministry of Education, Academic Research Fund Tier 1 (2019-T1-002-045, RG125/19, RT05/ 20), Academic Research Fund Tier 2 (MOE2018-T2-2-042; MOE-T2EP30220-0010), and A*STAR SERC AME Programmatic Fund (SERC A18 A8b0059) for the financial support .

Combination photoimmunotherapy holds promise for tumor suppression; however, smart phototherapeutic agents that only activate their immune pharmaceutical action in tumors have been rarely developed. Herein, we report a semiconducting polymer (SP) nano-regulator (SPNT ) with cascading activation for combinational photodynamic cancer immunotherapy. SPNT comprises an immunoregulator (M-Trp: 1-methyltryptophan) conjugating to the side chain of the SP backbone via an apoptotic biomarker-cleavable linker. Under near-infrared photoirradiation, SPNT produces singlet oxygen to induce immunogenic apoptosis. Concurrently, an apoptotic biomarker is upregulated, which triggers the specific cleavage of M-Trp for indoleamine 2,3-dioxygenase (IDO) activity inhibition, regulatory T cells reduction and cytotoxic T lymphocytes infiltration. SPNT -mediated combination photodynamic immunotherapy thus reprograms the tumor immune microenvironment, resulting in efficient suppression of tumors, and inhibition of lung metastasis. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) K.P. thanks Singapore Ministry of Education, Academic Research Fund Tier 1 (2019-T1-002-045, RG125/19, RT05/ 20), Academic Research Fund Tier 2 (MOE2018-T2-2-042; MOE-T2EP30220-0010), and A*STAR SERC AME Programmatic Fund (SERC A18 A8b0059) for the financial support.

Cancer nanomedicine combined with immunotherapy has become a promising strategy for treating cancer in terms of safety and potency; however, precise regulation of the activation of antitumor immunity remains challenging. Herein, a smart semiconducting polymer nano-immunomodulator (SPNI), which responds to the acidic tumor microenvironment (TME), for precision photodynamic immunotherapy of cancer, is reported. The SPNI is self-assembled by a near-infrared (NIR)-absorbing semiconducting polymer and an amphipathic polymer conjugated with a Toll-like receptor 7 (TLR7) agonist via an acid-labile linker. Upon arrival at tumor site, SPNI undergoes hydrolysis and triggers an efficient liberation of TLR7 agonist in response to the acidic TME for dendritic cell activation. Moreover, SPNI exerts photodynamic effects for direct tumor eradication and immunogenic cancer cell death under NIR photoirradiation. The synergistic action of released immunogenic factors and acidic-TME-activated TLR7 agonist can serve as an in situ generated cancer vaccine to evoke strong antitumor activities. Notably, such localized immune activation boosts systemic antitumor immune responses, resulting in enhanced cytotoxic CD8+ T infiltration to inhibit tumor growth and metastasis. Thereby, this work presents a general strategy to devise prodrug of immunotherapeutics for precise regulation of cancer immunotherapy. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) K.P. would like to acknowledge financial support from Singapore Ministry of Education, Academic Research Fund Tier 1 (2019-T1-002-045, RG125/19), Academic Research Fund Tier 2 (MOE2018-T2-2-042), and A*STAR SERC AME Programmatic Fund (SERC A18A8b0059). J.W. would like to acknowledge financial support from the National Key R & D Program of China (2017YFA0205600), the National Natural Science Foundation of China (51633008, 32071378, 31870996), the Science and Technology Program of Guangzhou (202103030004), Guangdong Provincial Pearl River Talents Program (2017GC010713, 2017GC010482), the China Postdoctoral Science Foundation (2021M701235), and the Natural Science Foundation of Guangdong Province, China (No. 2021A1515010592) for the financial support.

Cao Huang Gui Xiang (CHGX) formula, a Chinese herbal medicine, has been empirically used for the treatment of

Checkpoint immunotherapies have been combined with other therapeutic modalities to increase patient response rate and improve therapeutic outcome, which however exacerbates immune-related adverse events and requires to be carefully implemented in a narrowed therapeutic window. Strategies for precisely controlled combinational cancer immunotherapy can tackle this issue but remain lacking. We herein report a catalytical nano-immunocomplex for precise and persistent sono-metabolic checkpoint trimodal cancer therapy, whose full activities are only triggered by sono-irradiation in tumor microenvironment (TME). This nano-immunocomplex comprises three FDA-approved components, wherein checkpoint blockade inhibitor (anti-programmed death-ligand 1 antibody), immunometabolic reprogramming enzyme (adenosine deaminase, ADA), and sonosensitizer (hematoporphyrin) are covalently immobilized into one entity via acid-cleavable and singlet oxygen-activatable linkers. Thus, the activities of the nano-immunocomplex are initially silenced, and only under sono-irradiation in the acidic TME, the sonodynamic, checkpoint blockade, and immunometabolic reprogramming activities are remotely awakened. Due to the enzymatic conversion of adenosine to inosine by ADA, the nano-immunocomplex can reduce levels of intratumoral adenosine and inhibit A2A/A2B adenosine receptors-adenosinergic signaling, leading to efficient activation of immune effector cells and inhibition of immune suppressor cells in vivo. Thus, this study presents a generic and translatable nanoplatform towards precision combinational cancer immunotherapy. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Published version K.P. thanks Singapore Ministry of Education, Academic Research Fund Tier 1 (2019-T1- 002-045, RG125/19), Academic Research Fund Tier 2 (MOE2018-T2-2-042), and A*STAR SERC AME Programmatic Fund (SERC A18A8b0059) for the financial support.

The current research examined the influence of subjective loss on financial risk-taking tendency and negative emotional experience through inducing the experience of subjective loss in auction scenarios. In Study 1, we found that the subjective loss experience (compared to no-loss experience) in an auction scenario induced greater financial risk propensity, especially in gambling, greater negative emotion, and greater decision regret. In addition, we found that the subjective loss experience induced stronger negative emotion but less risk propensity in investment than the actual loss experience did, but these two types of loss did not yield a difference in risk propensity in gambling in Study 2. These results implicate that subjective loss is a distinct experience from no-loss and actual loss experiences, which is reflected by the degree of associated emotional experience and subsequent risk-taking propensity. The current research highlights the complex psychological processes of the experience of loss in decision-making contexts.

Cervical cancer is a highly prevalent female malignancy. Presently, cisplatin (DDP) is a first-line agent for cervical cancer chemotherapy. However, its curative effect is limited because of chemo-resistance. It has been previously reported that SOX9 targeted and activated oncogenic genes, enhancing cervical cancer cell resistance to DDP. The effects of the SOX9/lncRNA ANXA2P2/miR-361-3p/SOX9 regulatory loop on cervical cancer cell growth and resistance to DDP have been demonstrated. miR-361-3p expression was decreased in DDP-resistant cervical cancer cells and tissues. Moreover, miR-361-3p overexpression inhibited the growth of resistant cervical cancer cells and the resistance to DDP, whereas miR-361-3p inhibition exerted opposite effects. miR-361-3p inhibited SOX9 expression through binding; the effects of miR-361-3p inhibition were partially reversed by SOX9 knockdown. LncRNA ANXA2P2 expression was elevated in DDP-resistant cervical cancer cells and tissues. LncRNA ANXA2P2 inhibited miR-361-3p expression by binding, thereby upregulating SOX9. LncRNA ANXA2P2 knockdown inhibited DDP-resistant cervical cancer cell growth and resistance to DDP, whereas the effects of lncRNA ANXA2P2 knockdown were partially reversed by miR-361-3p inhibition. SOX9 expression was elevated in DDP-resistant cervical cancer cells and tissues, and SOX9 activated lncRNA ANXA2P2 transcription by binding. Collectively, SOX9, lncRNA ANXA2P2, and miR-361-3p form a regulatory loop, modulating DDP-resistant cervical cancer cell growth and response to DDP treatment.

Background: Gastric cancer (GC) is a source of global cancer death. MiR-17-5p is reported to regulate the tumorigenesis of GC. Meanwhile, hsa_circ_0017252 is known to be upregulated in GC. However, the relation between hsa_circ_0017252 and miR-17-5p in GC remains unclear. Methods: Cell viability, migration and invasion were tested by CCK-8 and transwell assay, respectively. Gene expressions were detected by RT-qPCR, and the protein levels in cells or exosomes were tested by western blot. The efficiency of exosomes isolation was investigated by transmission electron microscope (TEM) and nanoparticle tracking analysis (NTA). Meanwhile, cell apoptosis was tested by flow cytometry. In vivo model was constructed to assess the function of MKN45 cells-derived exosomal hsa_circ_0017252 in GC. Results: Hsa_circ_0017252 was verified to be significantly downregulated in GC tissues. Hsa_circ_0017252 upregulation significantly decreased the viability and migration of GC cells, and hsa_circ_0017252 could bind with miR-17-5p. Additionally, exosomal hsa_circ_0017252 reversed the polarization of M2 macrophages, and the polarized macrophages decreased the GC cell invasion. Furthermore, exosomes with upregulated hsa_circ_0017252 suppressed the tumor growth of GC. Conclusion: Delivery of hsa_circ_0017252 by GC cells-derived exosomes inhibits the tumorigenesis of GC through reversing M2 polarization of macrophages. Thus, our finding might provide a new method for GC treatment.

Cultivated strawberry, one of the major fruit crops worldwide, is an evergreen plant with shallow root system, and thus sensitive to environmental changes, including drought stress. To investigate the effect of 5-aminolevulinic acid (ALA), a new environment-friendly plant growth regulator, on strawberry drought tolerance and its possible mechanisms, we treated strawberry (Fragaria × annanasa Duch. cv. 'Benihoppe') with 15% polyethylene glycol 6000 to simulate osmotic stress with or without 10 mg l-1 ALA. We found that ALA significantly alleviated PEG-inhibited plant growth and improved water absorption and xylem sap flux, indicating ALA mitigates the adverse effect of osmotic stress on strawberry plants. Gas exchange and chlorophyll fluorescence analysis showed that ALA mitigated PEG-induced decreases of Pn , Gs , Tr , Pn /Ci , photosystem I and II reaction center activities, electron transport activity, and photosynthetic performance indexes. Equally important, ALA promoted PEG-increased antioxidant enzyme activities and repressed PEG-increased malondialdehyde and superoxide anion in both leaves and roots. Specially, ALA repressed H2 O2 increase in leaves, but stimulated it in roots. Furthermore, ALA repressed abscisic acid (ABA) biosynthesis and signaling gene expressions in leaves, but promoted those in roots. In addition, ALA blocked PEG-downregulated expressions of plasmalemma and tonoplast aquaporin genes PIP and TIP in both leaves and roots. Taken together, ALA effectively enhances strawberry drought tolerance and the mechanism is related to the improvement of water absorption and conductivity. The tissue-specific responses of ABA biosynthesis, ABA signaling, and H2 O2 accumulation to ALA in leaves and roots play key roles in ALA-improved strawberry tolerance to osmotic stress.

Noninvasive regulation of CRISPR/Cas9 gene editing is conducive to understanding of gene function and development of gene therapy; however, it remains challenging. Herein, a photolabile semiconducting polymer nanotransducer (pSPN) is synthesized to act as the gene vector to deliver CRISPR/Cas9 plasmids into cells and also as the photoregulator to remotely activate gene editing. pSPN comprises a 1 O2 -generating backbone grafted with polyethylenimine brushes through 1 O2 -cleavable linkers. NIR photoirradiation spontaneously triggers the cleavage of gene vectors from pSPN, resulting in the release of CRISPR/Cas9 plasmids and subsequently initiating gene editing. This system affords 15- and 1.8-fold enhancement in repaired gene expression relative to the nonirradiated controls in living cells and mice, respectively. As this approach does not require any specific modifications on biomolecular components, pSPN represents the first generic nanotransducer for in vivo regulation of CRISPR/Cas9 gene editing.

Metal-based drugs have drawn significant attention over the past few decades due to their advanced properties and benefits in biomedical therapeutic and diagnostic systems. Among those, phototherapy using photosensitive metal-based drugs is of particular interest to researchers since the combination of light with metallo drugs allows controlled, light-activated release of anti-disease compounds with tremendous clinical significance. Due to its promising prospectives, especially in cancer treatment, numerous drug delivery carriers, including polymer nanoparticles, solid lipid, and inorganic nanoparticles, were developed for delivering photosensitive metal-based drugs. This review presents a comprehensive overview on recent advances of the controlled delivery of photosensitive metal-based drugs. Every aspect of novel polymer-based photosensitive metal-based drug delivery systems, including their fabrication methods, mechanism of action, applications in cancer therapy, as well as the prospect of future development is discussed in detail. It can be promisingly envisioned that the future direction of drug delivery systems with photosensitive metal-based drugs will result in a new generation of clinical and translational medicines combined with the rapid progression of targeted therapy, gene therapy, and immunotherapy.

Topographical relief is a key factor that limits population distribution and economic development in mountainous areas. The limitation is especially apparent in the mountain- plain transition zone. Taking the transition zone between the Qinling Mountains and the North China Plain (i.e. the mountainous area in western Henan Province) as an example and based on the 200-m resolution DEM data, we used the mean change-point analysis to determine the optimal statistical unit for topographical relief, and thereafter extracted the relief degree. Taking the 1:100,000 land use data, township population and county-level industrial data, population and economic spatial models were constructed, and 200-m resolution grid population and economic density maps were generated. Afterwards, statistical analysis was carried out to quantitatively reveal the impact of topographical relief on population and economy. In addition, the impacts of other topographical factors were discussed. The results showed the following. (1) The relief degree in western Henan is generally low, where 58.6% of the regional topography does not exceed half the height of a reference mountain (relative elevation ⩽250 m). Spatially, the relief degree is high in the west while low in the east, and high in the middle while low in the north and south. There is a positive correlation between relief degree and elevation, and a much stronger correlation between relief degree and slope. (2) The linear fitting degree between the population and economic validation data and the corresponding simulation data are 0.943 and 0.909, respectively, indicating that the spatialized results can reflect the actual population and economic distribution. (3) The impact of topographical relief on population and economy was stronger than that of other topographical factors. The relief degree showed a good logarithmic fit relationship with population density (0.911) and economic density (0.874). Specifically, 88.65% of the population lives in areas where the topographical relief is ⩽0.5 and 88.03% of the gross regional product was from areas where the relief is ⩽0.3. Compared with the population distribution, the economic development showed an obvious agglomeration trend towards low relief areas.

In the present work, high performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry (HPLC-ESI-QTOF-MS/MS) has been used for the identification of the major chemical constituents from the fruits of Sapindus mukorossi. A total of 31 peaks were identified based on their accurate masses and fragmentation characteristics. Among these 9 acyclic sesquiterpene oligoglycosides and 8 triterpenoid saponins were reported from the fruits of Sapindus mukorossi for the first time. This study demonstrates the potential of HPLC-ESI-QTOF-MS/MS for analysis and identification of acyclic sesquiterpene oligoglycosides and triterpenoid saponins.

Objective: To investigate the effects of hydrogen-rich water (HGRW) on the structure and composition of intestinal microflora in mice fed high-fat diets (HFDs). Materials and Methods : C57BL/6 mice were divided into four groups: (1) normal diet (CD)-normal water (W); (2) CD-HGRW; (3) HFD-W; and (4) HFD-HGRW. After 12 weeks, we sampled fasting blood glucose, lipids, transaminases, and tissue oxidative stress levels and measured body weight. High-throughput sequencing technology was used to sequence the intestinal microflora and differences in intestinal microflora were compared by group, using bioinformatics analysis. Results: Body weight, oral glucose tolerance, and blood glucose increased significantly in the HFD group compared with the CD group (P < 0.001), and malondialdehyde levels were significantly increased in the livers of mice fed a HFD (P < 0.05). Steatosis was seen in the liver parenchyma of the HFD group, and to a lesser degree in the HGRW group. The richness and diversity of intestinal flora only decreased significantly in the HFD group (P < 0.05). However, 24 genera and 26 species were significantly different between the HFD and CD subgroups of mice fed HGRW. Nine genera and five species were significantly different between the HGRW and W subgroups of mice fed a HFD. Correlations were confirmed for 10 physiological parameters; and were positively correlated with 17 genera in the HFD group; six genera were negatively correlated in the HGRW group. Importantly, Lactobacillus was closely related to tissue malondialdehyde levels. Conclusion: Oral HGRW has beneficial effects against antioxidant stress and liver damage. It may improve the diversity and structure of the intestinal flora, enhancing the relative abundance of beneficial flora.

Widespread intra-peritoneal metastases is a main feature of high grade serous ovarian carcinoma (HGSOC). Recently, the extent of tumour heterogeneity was used to evaluate the cancer genomes among multi-regions in HGSOC. However, there is no consensus on the effect of tumour heterogeneity on the evolution of the tumour metastasis process in HGSOC.We performed whole-exome sequencing in multiple regions of matched primary and metastatic HGSOC specimens to reveal the genetic mechanisms of ovarian tumourigenesis and malignant progression.63 samples (including ovarian carcinoma, omentum metastasis, and normal tissues) were used. We analyzed the genomic heterogeneity, traced the subclone dissemination and establishment history and compared the different genetic characters of cancer evolutionary models in HGSOC.We found that HGSOC had substantial intra-tumour heterogeneity (median 54.2, range 0 ∼ 106.7), high inter-patient heterogeneity (P 0.001), but relatively limited intra-patient heterogeneity (P = 0.949). Two COSMIC mutational signatures were identified in HGSOCs: signature 3 was related to homologous recombination, and signature 1 was associated with aging. Two scenarios were identified by phylogenetic reconstruction in our study: 3 cases (33.3 %) showed star topology, and the other 6 cases (66.7 %) displayed tree topology. Compared with star topology group, more driver events were identified in tree topology group (P 0.001), and occurred more frequently in early stage than in late stage of clonal evolution (P 0.001). Moreover, compared with the star topology group, the tree topology group showed higher rate of intra-tumour heterogeneity (P = 0.045).A dualistic classification model was proposed for the classification of HGSOC based on spatial heterogeneity, which may contribute to better managing patients and providing individual treatment for HGSOC patients.

In situ reaction-synthesized TiB-reinforced titanium-matrix composite coatings were fabricated using the rapid, non-equilibrium synthesis technique of laser cladding. The Ti and B mixture was the original powders, while the Ti-matrix composite coatings enhanced with TiB were treated on a Ti-6Al-4V surface with different laser scan powers of 2.5 kW, 3.0 kW and 3.5 kW. The phase composition, microstructure evaluation, and microhardness of the cladding coatings were investigated by X-ray diffractometry (XRD), scanning electron microscopy (SEM) and microhardness. The composite coatings mainly consist of black fishbone-shaped -Ti dendrites and white needle-like TiB phases. The microstructure evolution from the top to the bottom of the coatings was investigated. The TiB reinforcement dispersed homogeneously in the composite coatings and a fine microstructure was obtained in a sample fabricated with a laser power of 3.0 kW. The microhardness of the cladding coatings fabricated by different powders was over 2-fold greater than that of the Ti-6Al-4V titanium alloy substrate and achieved a maximum average of 792.2 HV with the laser power of 3.0 kW. The microstructures and properties of the coatings were changed by adjusting of the laser cladding power. The effects of the laser scan power on the microstructure, hardness and friction and wear properties of the laser cladding coatings were investigated and discussed.

Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test. Ministry of Education (MOE) K.P. thanks the Ministry of Education Singapore, Academic Research Fund Tier 1 (2019-T1-002-045 RG125/19 and RT05/20) and Academic Research Fund Tier 2 (MOE2018-T2-2-042 and MOE-T2EP30220-0010) for financial support. H.W. thanks the Zhejiang Provincial Natural Science Foundation of China (LR19H160002) and the National Natural Science Foundation of China (82073296 and 81773193) for financial support.

Bronchopulmonary dysplasia is a relatively common and severe complication of prematurity, and its pathogenesis remains ambiguous. Revolutionary advances in microbiological analysis techniques, together with the growing sophistication of the gut-lung axis hypothesis, have resulted in more studies linking gut microbiota dysbiosis to the occurrence and development of bronchopulmonary dysplasia. The present article builds on current findings to examine the intrinsic associations between gut microbiota and bronchopulmonary dysplasia. The gut microbiota affects bronchopulmonary dysplasia via several potential mechanisms including alteration of the gut-lung axis, promotion of inflammation and the ensuing growth effects, therefore these are also investigated. By evaluating the potential mechanisms, new therapeutic targets and potential therapeutic modalities for BPD can be identified from a microecological perspective.

Additional file 2. Neurodevelopment score and physical growth from T0 to T2.

This chapter examines whether the 15 psychological constructs developed from the PATHS Project could fit into the Five Cs model (competence, confidence, character, connection, and caring) of Positive Youth Development (PYD) in the Chinese context. We used Confirmatory Factor Analysis (CFA) to test the fit of the Five Cs model based on 15 Chinese PYD constructs developed in the PATHS Project in China. Participants were 1116 middle school students aged 11 to 17 years old (M = 14.43, 49% males) from Shanghai, Suzhou, Yangzhou and Changzhou who participated in the PATHS project. The results confirmed a five-factor model consistent with the conceptualization of the Five Cs model of PYD. We conclude that the 15 Chinese PYD constructs and the Five Cs model might conceptually overlap although some cultural differences should be considered.

Immunotherapy has offered new treatment options for cancer; however, the therapeutic benefits are often modest and desired to be improved. A semiconducting polymer nanoadjuvant (SPNII R) with a photothermally triggered cargo release for second near-infrared (NIR-II) photothermal immunotherapy is reported here. SPNII R consists of a semiconducting polymer nanoparticle core as an NIR-II photothermal converter, which is doped with a toll-like receptor (TLR) agonist as an immunotherapy adjuvant and coated with a thermally responsive lipid shell. Upon NIR-II photoirradiation, SPNII R effectively generates heat not only to ablate tumors and induce immunogenic cell death (ICD), but also to melt the lipid layers for on-demand release of the TLR agonist. The combination of ICD and activation of TLR7/TLR8 enhances the maturation of dendritic cells, which amplifies anti-tumor immune responses. Thus, a single treatment of SPNII R-mediated NIR-II photothermal immunotherapy effectively inhibits growth of both primary and distant tumors and eliminates lung metastasis in a murine mouse model. This study thus provides a remote-controlled smart delivery system to synergize photomedicine with immunotherapy for enhanced cancer treatment. Ministry of Education (MOE) Nanyang Technological University J.L. and X.Y. contributed equally to this work. K.P. thanks Nanyang Technological University (Start-up Grant No. NTU-SUG: M4081627.120), Singapore Ministry of Education, Academic Research Fund Tier 1 (2017T1-002-134; 2019-T1-002-045), and Academic Research Fund Tier 2 (MOE2018-T2-2-042) for the financial support.

Additional file 1. information about how to implement EI program in the early preterm infants.

Despite the great promises of sonodynamic therapy (SDT) in combination cancer therapy, its clinical applications are hindered by the "always-on" pharmacological activities of therapeutic agents and the lack of efficient sonosensitizers. Herein, the development of semiconducting polymers as efficient sonosensitizers and further development of sono-immunotherapeutic nanobodies (SPNAb ) for activatable cancer sono-immunotherapy are reported. Conjugation of anti-CTLA-4 antibodies onto the polymer nanoparticles through a 1 O2 -cleavable linker affords SPNAb with relatively low CTLA-4 binding affinity. Upon sono-irradiation, SPNAb generates 1 O2 not only to elicit a sonodynamic effect to induce immunogenic cell death, but also to release anti-CTLA-4 antibodies and trigger in situ checkpoint blockade. Such a synergistic therapeutic action mediated by SPNAb modulates the tumoricidal function of T-cell immunity by promoting the proliferation of cytotoxic T lymphocytes and depleting immunosuppressive regulatory T cells, resulting in effective tumor regression, metastasis inhibition, durable immunological memory, and prevention of relapse. Therefore, this study represents a proof-of-concept sonodynamic strategy using semiconducting polymers for precise spatiotemporal control over immunotherapy. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) K.P. thanks Singapore Ministry of Education, Academic Research Fund Tier 1 (2019-T1-002-045, RG125/19, RT05/20), Academic Research Fund Tier 2 (MOE2018-T2-2-042; MOE-T2EP30220-0010), and A*STAR SERC AME Programmatic Fund (SERC A18A8b0059) for the financial support.

Disability and even death from acute thrombosis remain a grave menace to public health. At present, the traditional drugs represented by urokinase (UK) in clinical thrombolysis can cause side effects of bleeding when the dosage is excess. Therefore, a more effective and safer method of thrombolysis is urgently needed. In this paper, a multifunctional dual-drug sequential release thrombolysis platform (UK-UH@PDA@HMSNs) consisting of polydopamine (PDA)-modified hollow mesoporous silicon (HMSNs) loading with UK and unfractionated heparin (UH) was constructed with a double physical assistance (NIR-II and bubbles). With the aid of near infrared-II (NIR-II, 1064 nm, 1.0 W cm-2) laser, the photothermal effect of PDA could be motivated to facilitate the UH release, thereby accelerating the dissolution of thrombus. Afterward, the local hyperthermia effect could expedite the phase transition of l-menthol in HMSNs to generate bubbles to promote the release of UK, thereby realizing the sequential release of two thrombolytic drugs. Importantly, this method deftly conquered the inherent obstacle that UK and UH cannot be combined directly. In vivo and in vitro experiments proved that the thrombolytic efficiency of UK-UH@PDA@HMSNs stimulated by NIR-II was nearly 3 times than that of UK alone. Collectively, the proposed dual physical assistance and sequential dual-drug delivery system significantly improved the efficiency of thrombolysis under the premise of limiting drug doses; the risk of death from intracranial hemorrhage thus could be decreased radically.

Background: 5-Aminolevunic acid (ALA), as a natural non-protein amino acid and the first essential precursor of tetrapyrrole biosynthesis in all living bodies, has been suggested to improve salt tolerance of plants. In the previous work, we reported that ALA induces H2O2 accumulation in roots of strawberry, which is involved in up-regulating Na+ transporter gene expressions to intercept Na+ in roots with less upward transport. However, the signal route is not clear.Results: In this study, we propose that nitric oxide (NO) is involved in ALA signaling cascade. Therefore, we applied sodium nitrosylpentacy (SNP, NO donor), Na2WO4 (NO biosynthetic inhibitor), and 2, 4-carboxyphenyl-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO, NO scavenger) to the culture solution when strawberry (Fragaria × ananassa Duch. cv. ‘Benihoppe’) was stressed by 100 mmol L-1 NaCl with or without exogenous ALA. The results reveal that salinity greatly impaired plant growth while 10 mg L-1 ALA or 10 µM SNP ameliorated the inhibition. When 5 µM Na2WO4 or cPTIO was co-treated, the ALA-improved salt tolerance was almost completely eliminated. This suggests that ALA-improved salt tolerance is dependent on NO presence. We found that salinity caused NO, H2O2, Na+ and Cl- increases in the whole plants, while ALA induced additional increases in roots but significant depressions in leaves. These tissue-specific responses to ALA are important for plant salt tolerance. Conclusion: We propose that the regulation of ALA in roots is critical, which is mediated through NO and then H2O2 signal to up-express genes related with Na+ and Cl- transport, selectively retaining Na+ and Cl- in roots with less upward transport. The hypothesis can reasonably explain how ALA-treated plants cope with toxic ions under salinity.

Endometrial cancer is one of the three major malignant tumors of the female reproductive system. Although cyclin-dependent kinase 9 (CDK9) has a definitive pathogenic role in various types of cancer, little is known concerning its function in endometrial cancer. Our study was conducted to evaluate the expression and therapeutic potential of CDK9 in endometrial cancer. CDK9 expression was determined by immunohistochemistry in endometrial cancer tissues constructed with paired primary, metastatic, and recurrent tumor tissues from 32 endometrial cancer patients. Small interfering RNA (siRNA) and inhibitors of CDK9 were used to evaluate the effect of CDK9 inhibition on the anti-apoptotic activity and proliferation in endometrial cancer cells. Colony formation assay and wound-healing assays were adopted to assess clonal formation and migratory capacity. The results of the immunohistochemistry demonstrated that CDK9 was highly expressed in the human endometrial cancer cell lines; moreover, it was elevated in metastatic and recurrent endometrial tumor tissue compared when compared with that in patient-matched primary endometrial tumor tissue. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with the inhibitor suppressed cell proliferation and promoted apoptosis in endometrial cancer. In conclusion, our results provide evidence that CDK9 may be a potential prognostic biomarker and a promising therapeutic target for the treatment of endometrial cancer in the future.

OBJECTIVE This study aimed to evaluate the effects of intermittent energy restriction (IER; only for 2-3 d/wk) versus continuous energy restriction (CER) on weight loss and metabolic outcomes in adults with overweight or obesity. METHODS Methods included searching databases from the last decade to December 18, 2019, for randomized controlled trials (RCTs) that assessed weight loss and metabolic outcomes in IER and CER. RevMan version 5.3 software was used for statistical analysis of the data. The effect sizes were expressed as weight mean differences and 95% CI. RESULTS This review included 11 RCTs (n = 850). Meta-analysis showed that IER had greater effects on absolute weight loss, the percentage of weight loss, and improving insulin sensitivity than CER. In the subgroup analysis, short-term (2-3 months) intervention (P

Stimuli-responsive and targetable nanomedicine systems have been widely applied as effective modalities for drug delivery and tumor therapeutics. Particle shape is also important for the biodistribution and cellular uptake in drug delivery applications. Here, morphology tunable and acid-responsive dextran-doxorubicin conjugate assemblies of DD-M and DDF-V for targeted doxorubicin (DOX) delivery were constructed, which contain the following favorable advantages: (1) one-pot synthesis of the drug loaded system with a Schiff base reaction is a green chemistry method which is better than the conventional drug conjugation/encapsulation methods. (2) The morphology of the nanoparticles could be regulated from a micelle (DD-M) to vesicle (DDF-V) structure by either introducing folic acid (FA) or not. (3) The abundant hydroxyl groups and electronegativity give DD-M and DDF-V superior stability in the physiological environment. (4) Besides, the multifunctional DDF-V with its important merits including tumor-targeting ability and acid-responsiveness is specific for DOX delivery in cancer therapy. (5) Compared to free DOX and DD-M, DDF-V displayed enhanced anti-tumor efficacy both in vitro and in vivo without obvious systematic toxicity. The morphology tunable, acid-sensitive and targetable nanosystem could be a promising strategy for site-specific drug delivery and potential cancer therapy in the future.

Combination therapy based on polymer–drug conjugates is one of the exciting developments in polymeric drug delivery systems. A single polymer carrier with two or more drugs attached is advantageous because it provides a platform for synergistic agent action. To expand the concept of combination therapy using a single polymer–drug conjugate, we report a polymer–(multifunctional single-drug) conjugate strategy, in which three different drugs (platinum, azidyl radical and DMC) and two different types of therapies are rationally integrated and then conjugated to an amphiphilic block copolymer. When this polymer–(multifunctional single-drug) conjugate is internalized by cancer cells via endocytosis, the three integrated drugs are expected to be activated and execute therapeutic functions in a sequential fashion under extracellular (UVA irradiation) and intracellular (endosomes/lysosomes) environments to amplify the signals of cancer treatment, especially in cisplatin-resistant cancer cells.

Lithium tantalite (LiTaO3) is a common piezoelectric and ferroelectric crystal, but the LiTaO3 polycrystalline ceramics have rarely been reported, and their refractory character presents difficulties in their fabrication. In this study, LiTaO3-based ceramics with different amounts of CoO were prepared by pressureless sintering at 1250 &deg, C, and the effects of the amount of sintering aid on the sinterability, microstructure, and dielectric properties of the ceramics were investigated. The relative densities of the LiTaO3-based ceramics were significantly improved by the addition of CoO powder. The LiTaO3-based ceramics achieved the highest relative density (89.4%) and obtained a well-grained microstructure when the added amount of CoO was 5 wt.%. Only the LiTaO3 phase in the ceramics was observed, indicating that the ions Co diffused into the LiTaO3 lattices and mainly existed in two forms: Co2+ and Co3+. The effects of the added amount of CoO on the dielectric properties of the LiTaO3-based ceramics were studied thoroughly. Consequently, the dielectric constant was enhanced, and the dielectric loss decreased in the LiTaO3-based ceramics with the addition of CoO. The optimal value was obtained at 5 wt.% of CoO-added LiTaO3-based ceramics.

Osteosarcoma is the most common bone tumor affecting both adolescents and children. Early detection is critical for the effective treatment of the disease. Derived from cancer cells, miR‑21 contained within exosomes in the tumor microenvironment may act on both cancer cells and the surrounding tumor microenvironment (TME), including immune cells, endothelial cells and fibroblasts. In human serum and plasm, the level of exosomal miR‑21 between osteosarcoma patients and healthy controls differs, supporting the role of miR‑21 as a biomarker for osteosarcoma. The involvement of a number of miR‑21 target genes in tumor progression suggests that miR‑21 may significantly affect the plasticity of cancer cells, leading to tumor progression, metastasis, angiogenesis and immune escape in osteosarcoma. Understanding the biogenesis and functions of exosomal miR‑21 is of great value for the diagnosis and therapy of cancer, including osteosarcoma. The present review discusses the role of miR‑21 in the tumor microenvironment, and in the development and progression of osteosarcoma, with an aim to summarize the functions of this miRNA in cancer.

In order to better describe the complexity of images, this paper proposes a method to describe the complexity of images, namely to measure the complexity of images by the approximate entropy value of time series. In order to verify the effectiveness of the method, first, design the image complexity of subjective evaluation experiment, through the subjective ratings experiment get different complexity of images, and then on the basis of general experimental images into one dimensional time series, the complexity of calculating the approximate entropy measures image, and the existing test method is used to describe the complexity of the image. Experimental results show that this method can reflect the overall complexity of images, and can be used for qualitative and quantitative comparison of different image complexity.

Hierarchical PPy@MoS2 microtubes were obtained using easy operation steps of a hydrothermal process, in-situ polymerization method and sulfidation course. These were regarded as a good adsorption material to adsorb methylene blue (MB) and congo red (CR) dyes in aqueous solution. The synthetic composite displayed huge specific surface areas and excellent adsorption performance for MB (127.0 mg·g−1) and CR (598.7 mg·g−1) because of the 1D hierarchical hollow structure and the synergistic effect between the MoS2 nanoflakes and PPy coating. Adsorption performance of PPy@MoS2 fits well with the pseudo-second-order kinetic pattern for both MB and CR and conforms to Langmuir model for MB and Freundlich model for CR. Moreover, their excellent adsorption performance makes the PPy@MoS2 composites ideal for the adsorption of organic dyes.

Drug, targeting ligand, and imaging agent are the three essential components in a nanoparticle-based drug delivery system. However, tremendous batch-to-batch variation of composition and drug content typically accompany the current approaches of building these components together. Herein, we report the design of photoactivatable platinum(IV) (Pt(IV)) amphiphiles containing one or two hydrophilic lactose targeting ligands per hydrophobic Pt(IV) prodrug for an all-in-one precise nanomedicine. Self-assembly of these Pt(IV) amphiphiles results in either micelle or vesicle formation with a fixed Pt/targeting moiety ratio and a constantly high content of Pt. The micelles and vesicles are capable of hepatoma cell-targeting, fluorescence/Pt-based CT imaging and have shown effective anticancer efficacy under laser irradiation in vitro and in vivo. This photoactivatable, active self-targeting, and multimodal theranostic amphiphile strategy shows great potential in constructing precise nanomedicine.

Compared to traditional clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system, CRISPR/dead Cas9 (dCas9) system can precisely regulate endogenous gene expression without damaging the host gene, representing a greater potential for cancer therapy. Cancer/testis antigen 45 (CT45) is proved to enhance platinum-based chemosensitivity for individualized ovarian cancer therapy. However, the development of a single nanocarrier codelivering CRISPR/dCas9 system and chemotherapeutics for synergistic cancer therapy still faces challenges. Herein, a reduction-sensitive fluorinated-Pt(IV) universal transfection nanoplatform (PtUTP-F) is developed for the CT45-targeted CRISPR/dCas9 activation to achieve synergistic and individualized treatment of ovarian cancer. Overcoming multiple physiological barriers, PtUTP-F condensed gene can efficiently transfect into different cells including 293T cells, A2780, SKOV3, A549, and A2780/cisplatin (DDP) cancer cells, which is superior to Lipofectamine 6000. With the responsive release of gene and Pt(II) in the intracellular reducing microenvironment, PtUTP-F/dCas9-CT45 can generate CRISPR/dCas9 activation of CT45 expression for protein phosphatase 4C (PP4C) activity inhibition to hinder the DNA repair pathway and thus enhances the sensitivity to Pt(II) drugs for individualized A2780 tumor therapy. The PtUTP-F not only represents a powerful nanoplatform for CRISPR/dCas9 system delivery but also initiates a novel strategy for synergistic and individualized treatment of CRISPR/dCas9-based gene therapy with chemotherapy.

Stimuli-responsive nanosystems have been widely applied as effective modalities for drug/gene co-delivery in cancer treatment. However, precise spatiotemporal manipulations of drug/gene co-delivery, as well as multi-modality imaging-guided cancer therapy, still remain a daunting challenge. Here, multifunctional polyprodrug/siRNA loaded upconversion nanoparticles (UCNPs) are reported that combine computed tomography (CT), magnetic resonance (MR), and upconversion luminescence (UCL) tri-modality imaging and near-infrared (NIR) light-activated drug/gene on-demand delivery. The photoactivatable platinum(IV) (Pt(IV))-backbone polymers (PPt) and the siRNA targeting polo-like kinase 1 (Plk1) are loaded on the surface of polyethyleneimine (PEI)-coated UCNPs (PUCNP) to obtain the multifunctional polyprodrug/siRNA loaded UCNPs (PUCNP@Pt@siPlk1). The PUCNP@Pt@siPlk1 can be served as a "nanotransducer" to convert NIR light (980 nm) into local ultraviolet (UV) to visible light for the cleavage of photosensitive PPt, resulting in the simultaneous on-demand release of high toxic platinum(II) (Pt(II)) and siPlk1. Meanwhile, the PUCNP@Pt@siPlk1 has CT, T1 -weighted MR, and UCL tri-modality imaging abilities. Based on these merits, PUCNP@Pt@siPlk1 displayed excellent synergistic therapeutic efficacy via image-guided and NIR light-activated platinum-based chemotherapy and RNA interfering in vitro and in vivo. Thus, this developed nanosystem with NIR light-controlled drug/gene delivery and multi-modality imaging abilities, will display great potential in combining chemotherapy and gene therapy.

Citrus fruits are rich in flavonoids and well-recognized for their health values. In order to describe the flavonoid characters of a citrus fruit type accurately, the flavonoid in fruits (peels and pulps) of four most commonly cultivated Citrus species represented by sweet orange ( Citrus sinensis Osbeck cv. Newhall), lemon ( C. limon Burm.f. cv. Eureka), pummelo ( C. grandis Osbeck cv. Liangpingyou) and tangerine ( C. tangerina Tanaka cv. Dahongpao), respectively, were studied using a new UPLC-PDA method. In this study, the results showed that different cultivated species were characterized by different dominant flavonoid compounds, such as naringin, erocitrin and hesperidin were the most predominant components of pummelo, lemon, mandarin and sweet orange, respectively. Nine polymethoxylated flavones (PMFs) were identified in the peels of sweet orange and mandarin using this new method, and nobiletin was proved to be the most dominant one. The flavonoid contents varied obviously among different fruit samples even collected from the same production area and the same cultivars. However, it is important to note that all the samples of the same cultivated species grouped in the same cluster in three dimensional scatter plots of principal components analysis (PCA). This study emphasized that the UPLC-PDA method is a simple, rapid and accurate method for citrus flavonoids analysis.

Current data have shown that punicalagin (PUN), an ellagitannin isolated from pomegranate, possesses anti-inflammatory and anti-oxidant properties; however, its direct targets have not yet been reported. This is the first report that PTP1B serves as a direct target of PUN, with IC50 value of 1.04μM. Results from NPOI further showed that the Kon and Koff of PUN-PTP1B complex were 3.38e2M-1s-1 and 4.13e-3s-1, respectively. The active site Arg24 of PTP1B was identified as a key binding site of PUN by computation simulation and point mutation. Moreover, inhibition of PTP1B by PUN promoted an M2c-like macrophage polarization and enhanced anti-inflammatory cytokines expression, including IL-10 and M-CSF. Based on gene expression profile, we elucidated that PUN treatment significantly up-regulated 275 genes and down-regulated 1059 genes. M1-like macrophage marker genes, such as Tlr4, Irf1/2, Hmgb1, and Stat1 were down-regulated, while M2 marker genes, including Tmem171, Gpr35, Csf1, Il1rn, Cebpb, Fos, Vegfα, Slc11a1, and Bhlhe40 were up-regulated in PUN-treated macrophages. Hmox-1, a gene encoding HO-1 protein, was preferentially expressed with 16-fold change. Inhibition of HO-1 obviously restored PUN-induced M2 polarization and IL-10 secretion. In addition, phosphorylation of both Akt and STAT3 contributed to PUN-induced HO-1 expression. This study provided new insights into the mechanisms of PUN-mediated anti-inflammatory and anti-oxidant activities and provided new therapeutic strategies for inflammatory diseases.

// Sisi Wang 1 , Chunhong Hu 1 , Fang Wu 1 and Shasha He 1 1 Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China Correspondence to: Shasha He, email: laishiweisha611@126.com Keywords: Rab25, small GTPase, vesicle trafficking, ovarian cancer, renal cancer Received: March 21, 2017 Accepted: July 19, 2017 Published: July 26, 2017 ABSTRACT Rab25, a small GTPase belongs to the Rab protein family, has a pivotal role in cancer pathophysiology. Rab25 governs cell-surface receptors recycling and cellular signaling pathways activation, allowing it to control a diverse range of cellular functions, including cell proliferation, cell motility and cell death. Aberrant expression of Rab25 was linked to cancer development. Majority of research findings revealed that Rab25 is an oncogene. Elevated expression of Rab25 was correlated with poor prognosis and aggressiveness of renal, lung, breast, ovarian and other cancers. However, tumor suppressor function of Rab25 was reported in several cancers, such as colorectal cancer, indicating the tumor type-specific function of Rab25. In this review, we recapitulate the current knowledge of Rab25 in cancer development and therapy.

Nanogels with several special advantages have been widely applied in protein delivery. However, biocompatible and biodegradable nanogels used for hemoglobin (Hb) delivery are far less explored. Herein, we developed a facile method to prepare functionalized dextran nanogels for conjugation of Hb. In situ cross-linked and aldehyde group functionalized nanogels (FNGs) were prepared from dextran-g-succinic anhydride-g-dopamine conjugate (Dex-SA-DA) assembly by simple pH adjustion and oxidization in water. Hb was further conjugated into the swelling FNGs by Schiff base reaction under mild condition. The obtained hemoglobin-loaded nanogels (HbNGs) exhibited high stability, oxygen affinity and good hemo-compatibility, suggesting the potential for oxygen carriers. We expected that the designed functionalized nanogels with high stability and loading capacity could bring a new opportunity for protein delivery.

The limitation for the biomedical application of porous organic polymers (POPs) is the big size and poor dispersibility in aqueous media. Herein, a nanoscale metal–organic framework (MOF)@POP composite, named UNM, has been synthesized by epitaxial growth of the photoactive porphyrin-POPs (H2P-POP) on the outer surface of amine containing UiO-66 (UiO-AM). After the growth of POPs, the crystallization, pore structure, and size distribution of UNM are retained well. The formed UNM possesses a small size of less than 200 nm and could be internalized by cancer cells. Such light-activated UNM exhibits efficient ability to generate 1O2 under various experimental conditions, which can be further applied for PDT efficacy. The present work demonstrates the great potential of nanoscale porous polymers in biomedical fields and cancer treatment.