A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy

Ovarian cancer(OC)is one of the most common and recurring malignancies in gynecology.Patients with relapsed OC always develop"cascade drug resistance"(CDR)under repeated chemotherapy,leading to subsequent failure of chemotherapy.To overcome this challenge,amphiphiles(P1)carrying a nitric oxide(NO)donor(Isosorbide 5-mononitrate,ISMN)and high-density disulfide are synthesized for encapsulatingmitochondria-targeted tetravalent platinum prodrug(TPt)to construct a nanocomposite(INP@TPt).Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum,depleting glutathione,and preventing apoptosis escape through generating highly toxic peroxynitrite anion(ONOO−).To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor,an OC patient-derived tumor xenograft(PDXOC)model in BALB/c nude mice was established.INP@TPt showed the best therapeutic effects in the PDXOC model.The corresponding tumor tissues contained high ONOO−levels,which were attributed to the simultaneous release of O_(2)^(·−)and NO in tumor tissues.Taken together,INP@TPtbased systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR,providing practical applications for ovarian therapy.

Cancer nanotechnology: Enhancing tumor cell response to chemotherapy for hepatocellular carcinoma therapy

Hepatocellular carcinoma(HCC)is one of the deadliest cancers due to its complexities,reoccurrence after surgical resection,metastasis and heterogeneity.In addition to sorafenib and lenvatinib for the treatment of HCC approved by FDA,various strategies including transarterial chemoembolization,radiotherapy,locoregional therapy and chemotherapy have been investigated in clinics.Recently,cancer nanotechnology has got great attention for the treatment of various cancers including HCC.Both passive and active targetings are progressing at a steady rate.Herein,we describe the lessons learned from pathogenesis of HCC and the understanding of targeted and non-targeted nanoparticles used for the delivery of small molecules,monoclonal antibodies,miRNAs and peptides.Exploring current efficacy is to enhance tumor cell response of chemotherapy.It highlights the opportunities and challenges faced by nanotechnologies in contemporary hepatocellular carcinoma therapy,where personalized medicine is increasingly becoming the mainstay.Overall objective of this review is to enhance our understanding in the design and development of nanotechnology for treatment of HCC.

Microbial Remediation of Heavy Metal(loid)Contaminated Soil: A Review

Because of the rapid development of industrial processes, increased urban pollution and agricultural chemicals applied in recent years, heavy metal(loid) pollution in soil has been very serious, and there is an urgent need for fast and efficient removal of heavy metal(loid) pollution. Currently, environmental microorganisms are always used to perform biological alteration or improvement of soils and sewage. Using functional microorganisms that are resistant to toxic heavy metal(loid) ions for alteration and transformation of heavy metal(loid)s in ionic form is an effective measure for microbial remediation of heavy metal(loid)contaminated soil. This paper reviewed the microbial remediation mechanism of heavy metal(loid) contaminated soils, and the approaches for breeding bacteria those can be used for highly efficient removal of heavy metal(loid)s, as well as the application examples of microbial remediation and transformation of heavy metal(loid) contaminated soil, and finally described the future trends and further research work of heavy metal(loid) contaminated soils by microbial remediation.

High-precision geochronology of the Early Cretaceous Yingcheng Formation and its stratigraphic implications for Songliao Basin,China

The Songliao Basin in Northeast Asia is the largest and longest-lived rift basin and preserves a nearcontinuous continental succession of the most of the Cretaceous period,providing great material to investigate the adaption of the terrestrial systems to the Cretaceous greenhouse climate and tectonic events.However,the paucity of precise and accurate radioisotopic ages from the Early Cretaceous strata of the Songliao Basin has greatly held back the temporal and causal correlation of the continental records to the global Early Cretaceous records.Three tuff layers intercalated in the Yingcheng Formation have been intercepted by the SK-2 borehole,which offer excellent materials for radioisotopic dating and calibration of the chronostratigraphy of the Lower Cretaceous sequence of Songliao Basin.Moreover,the Yingcheng Formation recorded the largest and the last of the two major volcanic events in Songliao Basin,which also represents a turning point in the basin evolution history of Songliao from syn-rift stage to post-rift stage.Here we report high-precision U–Pb zircon geochronology by the CA-ID-TIMS technique on three tuff samples from the Yingcheng Formation of the SK-2 borehole in the Songliao Basin to construct a greatly improved,absolute age framework for the Yingcheng Formation and provide crucial age constraints for the Songliao Lower Cretaceous Strata.The new CA-ID-TIMS geochronology constrained the Yingcheng Formation at 102.571+0.320/-2.346 Ma to ca.113 Ma,correlating to the Albian Stage.Combined with the previous published Songliao geochronology,the Quantou Formation is constrained to between 96.442+0.475/-0.086 Ma and 91.923+0.475/-0.086 Ma;the Denglouku Formation is constrained to between 102.571+0.320/-2.346 Ma and 96.442+0.475/-0.086 Ma;the age of the Shahezi Formation is estimated at ca.113 Ma to ca.118 Ma,which could extend to ca.125 Ma in some locations in Songliao Basin.The major unconformity between the Yingcheng Formation and the Denglouku Formation,which represents the transition of the basin from syn-rift to post-rift is thus confined to between 102.571+0.320/-2.346 Ma and 96.442+0.475/-0.086 Ma.This is roughly contemporaneous with the change in the direction of the paleo-Pacific plate motion from west-southwest to north or northwest in mid-Cretaceous,suggesting their possible connections.

0.35%THz pulse conversion efficiency achieved by Ti:sapphire femtosecond laser filamentation in argon at 1 kHz repetition rate

In this study,an optical setup for generating terahertz(THz)pulses through a two-color femtosecond laser filament was carefully designed to achieve a precise overlap of two-color laser pulses in space and time.β-barium borate(BBO),α-BBO,and a dual-wavelength plate were used to compensate the phase delay of the two-color lasers.Tilting ofα-BBO could further realize the precise spatial overlap of the two beams by counteracting the walk-off effect.The maximum out-put THz pulse energy reached 21μJ in argon gas when using a commercial Ti:sapphire laser with a pulse energy of 6 mJ at a 1 kHz repetition rate.The corresponding conversion efficiency exceeded 0.35%.

Locality preserving fusion of multi-source images for sea-ice classification

We present a novel sea-ice classification framework based on locality preserving fusion of multi-source images information.The locality preserving fusion arises from two-fold,i.e.,the local characterization in both spatial and feature domains.We commence by simultaneously learning a projection matrix,which preserves spatial localities,and a similarity matrix,which encodes feature similarities.We map the pixels of multi-source images by the projection matrix to a set fusion vectors that preserve spatial localities of the image.On the other hand,by applying the Laplacian eigen-decomposition to the similarity matrix,we obtain another set of fusion vectors that preserve the feature local similarities.We concatenate the fusion vectors for both spatial and feature locality preservation and obtain the fusion image.Finally,we classify the fusion image pixels by a novel sliding ensemble strategy,which enhances the locality preservation in classification.Our locality preserving fusion framework is effective in classifying multi-source sea-ice images(e.g.,multi-spectral and synthetic aperture radar(SAR)images)because it not only comprehensively captures the spatial neighboring relationships but also intrinsically characterizes the feature associations between different types of sea-ices.Experimental evaluations validate the effectiveness of our framework.

Effects of Exogenous Nutrient Additions on Azodye Wastewater Treatment

Since the azo dyes widely used in textile-dyeing industry are toxic,highly persistent,and ubiquitously distributed in the environment,their treatment efficiencies and fade in ecosystems have received worldwide attention.Due to the microbes play important roles in azo-dye degradation,exogenous nutrient addition is used as a promising biostimulation strategy to improve the treatment efficiencies of azo-dye wastewater.However,little is known about the effects of different kinds of exogenous nutrients on the azo-dye wastewater treatment directly.Here,three kinds of common nutrients,glucose,starch and yeast extract,were added to the sequencing batch reactors(SBR)for the treatment of wastewater containing acid red 73 to compare the biostimulation efficiencies by investigating the dye's removal efficiencies and the changes of related water qualities.Our results showed that the reactors added yeast extract had highest removal efficiencies and chemical oxygen demand(COD)as well,followed by glucose and starch.The removal rates of acid red 73 and COD were 90.63%and 87.3%in the reactors added yeast extract,respectively,while 86.49%and 78.4%in those with glucose and 85.38%and 75.2%in those with starch.This study provided some useful information for the biostimulation strategy of azo-dye wastewater treatment and preliminarily suggested that yeast extract would be the optimal choice.

规模化猪场非洲猪瘟采样检测关键点和常见误区

近年来,非洲猪瘟疫情对国内养猪业的冲击很大,严重影响了大中小型规模化猪场的发展和利润,也给养猪业造成了巨大的损失。然而,随着非洲猪瘟病毒自然和非自然变异株的大量出现,对ASFV传统采样和检测须得到一些新技术的支持,如“唾液/深咽拭子+血液”抗原抗体同步采样检测、多重PCR以及微滴数字PCR等。基于此,文章归纳总结了规模化猪场采样和检测的关键点和常见误区,以期为国内规模化猪场现场采样和检测方面提供理论借鉴。

Trace Element Mobility in Subducted Marble and Associated Eclogite:Constraints from UHP Rocks in the Shuanghe Area,Central-East China

In order to decipher element mobility in UHP meta-sedimentary rocks in the continental subduction zone,major and trace element compositions are investigated for a continuous profile from a representative UHP region in the Dabie Mountains.Among the lithologic contact zone,contents of K,Ca,LREE,and LILE exhibit varying degrees of downward trends in both marble and eclogite toward the contact zone,indicating that marble and their associated eclogite can release a large amount of K,Ca,and a small number of LILEs and LREEs.Titanite is the main Ti phase in both marble and eclogite.Titanite rims around rutile can occasionally be seen in eclogite.Contents of Ti and HFSE exhibit a well-coupled relation among marble and eclogite,indicating that substantial Ti and HFSEs were migrated from eclogite to marble,in accord with the capacity of a melt medium.Rutiles and titanites in marble exhibit a relatively limited variation in Nb/Ta ratios(12.9-16.2),similar to those of titanites in eclogite(14.2-16.7),which demonstrates that rutiles and titanites in marble were sourced from eclogite because of short-distance migrations of Ti and HFSEs.According to the P-T path and the temperature and pressure conditions of the peak metamorphism reported by previous studies,the eclogite associated with marble may not form supercritical fluids in the subduction zone because of the addition of carbonate minerals.

Bi-doped carbon quantum dots functionalized liposomes with fluorescence visualization imaging for tumor diagnosis and treatment

Liposomes are one of the significant classes of antitumor nanomaterials and the most successful nanomedicine drugs in clinical translation. However, it is difficult to accurately reveal liposome delivery modes and drug release rates at different p H values to assess the biodistribution and drug delivery pathways in vivo. Here, we established a strategy to integrate Bi-doped carbon quantum dots(CQDs)with liposomes to produce fluorescence visualization and therapeutic effects, namely lipo/Bi-doped CQDs.Lipo/Bi-doped CQDs show good water solubility and physicochemical properties, which can be used for in vitro labeling of colon cancer(CT26) cells and in vivo imaging localization tracking tumors for monitoring. Simultaneously, thanks to the excellent p H sensitivity and ion doping characteristic of Bi-doped CQDs, lipo/Bi-doped CQDs can be used to reveal the drug release rate of liposomes at different p H values and exhibit potential effects in vivo antitumor therapy.

β-Cyclodextrin derived full-spectrum fluorescent carbon dots: The formation process investigation and biological applications

Carbon dots(CDs), a new building unit, have been revolutionizing the fields of biomedicine, bioimaging, and optoelectronics with their excellent physical, chemical, and biological properties. However, the difficulty of preparing excitation-dependent full-spectrum fluorescent CDs has seriously hindered their further research in fluorescence emission mechanisms and biomedicine. Here, we report full-spectrum fluorescent CDs that exhibit controlled emission changes from purple(380 nm) to red(613 nm) at room temperature by changing the excitation wavelength, and the excitation dependence was closely related to the regulation of sp2 and sp3 hybrid carbon structures by β-cyclodextrin-related groups. In addition,by regulating the content of β-cyclodextrin, the optimal quantum yields of full-spectrum fluorescent CDs were 8.97%, 8.35%, 7.90%, 9.69% and 17.4% at the excitation wavelengths of 340, 350, 390, 410 and 540 nm,respectively. Due to their excellent biocompatibility and color tunability, full-spectrum fluorescent CDs emitted bright and steady purple, blue, green, yellow, and red fluorescence in MCF-7 cells. Moreover, we optimized the imaging conditions of CDs and mitochondrial-specific dyes;and realized the mitochondrialtargeted co-localization imaging of purple, blue and green fluorescence. After that, we also explored the effect of full-spectrum fluorescent CDs in vivo fluorescence imaging through the intratumorally, subcutaneously, and caudal vein, and found that full-spectrum fluorescent CDs had good fluorescence imaging ability in vivo.

Targeting self-enhanced ROS-responsive artesunatum prodrug nanoassembly potentiates gemcitabine activity by down-regulating CDA expression in cervical cancer

Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs(systemic distribution and side effects).It's noted the conversion of gemcitabine(GEM)to inactive ingredients under the action of cytidine deaminase(CDA)during metabolism in vivo limits its clinical effect.A high level of reactive oxygen species(ROS)results in a high level of oxidative stress in tumor cells,which changes the expression of CDA and optimizes the metabolism of GEM in vivo and overcome drug resistance.In this study,the ROS responsive and ROS self-supplied prodrug of artemisia(ART)-thioacetal bond(TK)-GEM was synthesized and self-vectors based on ART-TK-GEM(TK@FA NPs)was prepared by using nano precipitation.ROS responsive characteristics ensure specific release of prodrugs in tumor cells with high level of ROS thereby reducing side effects on normal cells and tissues.The endogenous ROS and newly generated ROS by ART can reduce the expression of CDA and optimizes the metabolism of GEM,and the accumulated ROS can also induce apoptosis of tumor cells,realizing synergistic anti-tumor effect of chemical drugs and traditional Chinese medicines.This paper proposes a simple method by using clinically approved drugs to improve the insufficient effect of existing chemotherapy and overcome resistance,which has potential to appropriately shorten the drug development cycle and accelerate the clinical investigation of drugs.

Self-oxygenated co-assembled biomimetic nanoplatform for enhanced photodynamic therapy in hypoxic tumor

Photodynamic therapy(PDT)has shown great application potential in cancer treatment and the important manifestation of PDT in the inhibition of tumors is the activation of immunogenic cell death(ICD)effects.However,the strategy is limited in the innate hypoxic tumor microenvironment.There are two key elements for the realization of enhanced PDT:specific cellular uptake and release of the photosensitizer in the tumor,and a sufficient amount of oxygen to ensure photodynamic efficiency.Herein,self-oxygenated biomimetic nanoparticles(CS@M NPs)co-assembled by photosensitizer prodrug(Ce6-S-S-LA)and squalene(SQ)were engineered.In the treatment of triple negative breast cancer(TNBC),the oxygen carried by SQ can be converted to reactive oxygen species(ROS).Meanwhile,glutathione(GSH)consumption during transformation from Ce6-S-S-LA to chlorin e6(Ce6)avoided the depletion of ROS.The co-assembled(CS NPs)were encapsulated by homologous tumor cell membrane to improve the tumor targeting.The results showed that the ICD effect of CS@M NPs was confirmed by the significant release of calreticulin(CRT)and high mobility group protein B1(HMGB1),and it significantly activated the immune system by inhibiting the hypoxia inducible factor-1alpha(HIF-1α)-CD39-CD73-adenosine a2a receptor(A2AR)pathway,which not only promoted the maturation of dendritic cells(DC)and the presentation of tumor specific antigens,but also induced effective immune infiltration of tumors.Overall,the integrated nanoplatform implements the concept of multiple advantages of tumor targeting,reactive drug release,and synergistic photodynamic therapy-immunotherapy,which can achieve nearly 90%tumor suppression rate in orthotopic TNBC models.

Exosomes-loaded electroconductive nerve dressing for nerve regeneration and pain relief against diabetic peripheral nerve injury

Over the years,electroconductive hydrogels(ECHs)have been extensively applied for stimulating nerve regeneration and restoring locomotor function after peripheral nerve injury(PNI)with diabetes,given their favorable mechanical and electrical properties identical to endogenous nerve tissue.Nevertheless,PNI causes the loss of locomotor function and inflammatory pain,especially in diabetic patients.It has been established that bone marrow stem cells-derived exosomes(BMSCs-Exos)have analgesic,anti-inflammatory and tissue regeneration properties.Herein,we designed an ECH loaded with BMSCs-Exos(ECH-Exos)electroconductive nerve dressing to treat diabetic PNI to achieve functional recovery and pain relief.Given its potent adhesive and self-healing properties,this laminar dressing is convenient for the treatment of damaged nerve fibers by automatically wrapping around them to form a size-matched tube-like structure,avoiding the cumbersome implantation process.Our in vitro studies showed that ECH-Exos could facilitate the attachment and migration of Schwann cells.Meanwhile,Exos in this system could modulate M2 macrophage polarization via the NF-κB pathway,thereby attenuating inflammatory pain in diabetic PNI.Additionally,ECH-Exos enhanced myelinated axonal regeneration via the MEK/ERK pathway in vitro and in vivo,consequently ameliorating muscle denervation atrophy and further promoting functional restoration.Our findings suggest that the ECH-Exos system has huge prospects for nerve regeneration,functional restoration and pain relief in patients with diabetic PNI.

Historical records of polycyclic aromatic hydrocarbon deposition in a shallow eutrophic lake:Impacts of sources and sedimentological conditions

Sediment core samples collected from Lake Chaohu were analyzed for 15 priority polycyclic aromatic hydrocarbons(PAHs)to assess the spatial and temporal distributions of the PAHs during lacustrine sedimentary processes and regional economic development.Assessing the PAH sedimentary records over an approximately 100-year time span,we identified two stages in the PAH inputs and sources(before the 1970 s and after the 1970s)in the eastern lake region near a village,whereas three stages(before the 1950 s,1950s–1990s and after the1990s)were identified in the western lake region near urban and industrial areas.Rapid increases in the PAH depositional fluxes occurred during the second stage due to increased human activities in the Lake Chaohu basin.The composition and isomeric ratios of the PAHs revealed that pyrolysis is the main source of PAHs in this lake.Strong positive relationships between PAH concentration and the total organic carbon concentration,sediment grain size(< 4 μm),as well as the local population and Gross Domestic Product indicated that the sedimentary conditions impact the depositional characteristics of the PAHs;simultaneously,socioeconomic activities,such as energy consumption and the levels of urban industrialization and civilization,affect both the composition and abundance of the PAHs.

Synergetic delivery of triptolide and Ce6 with light-activatable liposomes for efficient hepatocellular carcinoma therapy

Hepatocellular carcinoma(HCC)has been known as the second common leading cancer worldwide,as it responds poorly to both chemotherapy and medication.Triptolide(TP),a diterpenoid triepoxide,is a promising treatment agent for its effective anticancer effect on multiple cancers including HCC.However,its clinical application has been limited owing to its severe systemic toxicities,low solubility,and fast elimination in the body.Therefore,to overcome the above obstacles,photo-activatable liposomes(LP)integrated with both photosensitizer Ce6 and chemotherapeutic drug TP(TP/Ce6-LP)was designed in the pursuit of controlled drug release and synergetic photodynamic therapy in HCC therapy.The TP encapsulated in liposomes accumulated to the tumor site due to the enhanced permeability and retention(EPR)effect.Under laser irradiation,the photosensitizer Ce6 generated reactive oxygen species(ROS)and further oxidized the unsaturated phospholipids.In this way,the liposomes were destroyed to release TP.TP/Ce6-LP with NIR laser irradiation(TP/Ce6-LP+L)showed the best antitumor effect both in vitro and in vivo on a patient derived tumor xenograft of HCC(PDXHCC).TP/Ce6-LP significantly reduced the side effects of TP.Furthermore,TP/Ce6-LP+L induced apoptosis through a caspase-3/PARP signaling pathway.Overall,TP/Ce6-LP+L is a novel potential treatment option in halting HCC progression with attenuated toxicity.

Natural products as LSD1 inhibitors for cancer therapy

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase1(LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.

Synthesis,functionalization,and nanomedical applications of functional magnetic nanoparticles

Synthesis of magnetic nanoparticles(MNPs) is one of the most active research areas in advanced materials. MNPs that have magnetic properties and other functionalities have been demonstrated to show great promise in nanomedical applications. This review summarizes the current MNPs preparation,functionalization and stabilization methods. It also analyzes the detailed features of MNPs. And furthermore it highlights some actual case analyses of these MNPs for disease therapy, drug delivery,hyperthermia, bioseparation and bioimaging applications.

Highly luminescence manganese doped carbon dots

Heteroatom doped carbon dots(CDs)with distinct merits are of great attractions in various fields such as solar cells,catalysis,trace element detection and photothermal therapy.In this work,we successfully synthesized blue-fluorescence and photostability manganese-doped carbon dots(Mn-CDs)with a quantum yield up to 7.5%,which was prepared by a facile one-step hydrothermal method with sodium citrate and manganese chloride.The Mn-CDs is the high mono-dispersity,uniform spherical nanoparticles.The Mn element plays a critical role in achieving a high quantum yield in synthesis of carbon dots,which was confirmed by the structure analysis using XPS and FTIR.Spectroscopic investigations proved that the decent PLQY and luminescence properties of Mn-CDs are due to the heteroatom doped,oxidized carbon-based surface passivation.In addition,the Mn-CDs are demonstrated as promising fluorescent sensors for iron ions with a linear range of 0–500 μmol/L and a detection limit of2.1 nmol/L(turn-off),indicating their great potential as a fluorescent probe for chemical sensing.

Delivery of triptolide with reduction-sensitive polymer nanoparticles for liver cancer therapy on patient-derived xenografts models

Hepatocellular carcinoma(HCC)has become the fourth predominant cause of cancer-related deaths worldwide,and HCC is still one of the worst prognoses for survival as it is poorly responsive to both chemotherapy and surgical treatment due to drug resista nce and great toxic effects.Triptolide(TP),a key ingredient from the traditional Chinese medical herb,has been utilized to treat inflammation and antitumor for centuries.However,investigations of this potent agent have been met with only limited success due to the severe systemic toxicities in patients and low water solubility as well as its high toxicity over the past two decades.Herein,we reported the development of a reduction-responsive drug delive ry system loaded with TP fo r glutathione(GSH)-trigge red drug release for cancer therapy.With the GSH-sensitive TP loaded nanoparticles,the remarkable increases in tumor accumulation and amelioration of drug toxicity in animals are demonstrated,which is likely due to sustained stepwise release of active TP within cancer cells.Moreover,in a patient-derived tumor xenograft model of liver cancer,administration of tritolide nanoparticles enhances the antitumor efficacy relative to administration of free TP.These findings indicate that GSH-sensitive release of TP may be a promising strategy for cancer treatment.