• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Applications and challenges of low temperature plasma in pharmaceutical field

    2021-03-22 02:38:48LinggeGoXingminShiXiliWu
    Journal of Pharmaceutical Analysis 2021年1期

    Lingge Go , Xingmin Shi ,*, Xili Wu

    a School of Public Health, Medical Science Center, Xi'an Jiaotong University, Xi'an, 710061, China

    b Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China

    Keywords:Low temperature plasma Pharmacy Nanodrug Drug delivery system Plasma-activated liquids

    ABSTRACT Low temperature plasma (LTP) technology has shown an outstanding application value in the pharmaceutical filed in recent ten years.This paper reviews the research advances in LTP,including its effects on enhancing or inhibiting drug activity, its combined use with drugs to treat cancers, its effects on the improvement of drug delivery system, its use in preparation of new inactivated virus vaccines, its use with mass spectrometry for rapid detection of drug quality,and the anti-tumor and sterilization effects of plasma-activated liquids. The paper also analyzes the challenges of LTP in the pharmaceutical filed,hoping to promote related research.

    1. Introduction

    Lowtemperature plasma(LTP)isapartially ionizedgas containing a variety of ions, electrons, active molecules, electric fields and ultraviolet radiation(UV)[1,2].The non-thermal and non-equilibrium properties of LTP have attracted attention from the biomedical community.At present,LTP has been widely used in blood coagulation, wound disinfection and healing, surgical instruments and medical materials sterilization,and tumor therapy[3,4].

    As is known to all, drug therapy is one of the important approaches to treating and preventing diseases. Researchers have long been committed to developing new drugs [5-7] and other auxiliary means [8-10] to overcome the shortcomings of traditional drugs.

    As an emerging technology, LTP is gradually favored by the pharmaceutical community.LTP used in the field of pharmaceutical research is generated mainly by two devices: dielectric barrier discharge (DBD) and atmospheric-pressure plasma jet (APPJ). The basic structures of DBD and APPJ are shown in Fig.1.In general,LTP has two pharmaceutical applications: it is used as an auxiliary means to change the structure and function of drugs,improve drug delivery system, and play a synergistic role with drugs to treat diseases;on the other hand,it is used to treat solution and produce the plasma-activated liquid, which is a "new drug" with antiinfection and anti-cancer effects. In addition, LTP plays an active role in the research and development of inactivated vaccines, and qualitative and quantitative analyses of drugs.

    Peer review under responsibility of Xi'an Jiaotong University.

    * Corresponding author.

    ** Corresponding author.

    E-mail addresses: shixingmin142@163.com (X. Shi), wuxili1984@163.com(X. Wu).

    2. LTP's direct effects on drugs

    LTP contains rich active components and energy, which act on different compounds to cause a variety of chemical reactions. LTP has two major effects on drugs:producing byproducts with special physiological functions and destructing drug structure or reducing drug activity.

    2.1. LTP promotes drug activity

    LTP is a safe and environmentally friendly sterilization technology widely used in the food industry, and can extend the shelf life of food[11].It is found that LTP can improve the activity of the natural ingredients contained in food. Those natural ingredients have many biological effects, such as anti-cancer, anti-oxidation,anti-hypertension and other beneficial properties,and are regarded as important resources for new drug development [12]. Researchers have explored the efficacy and mechanism of LTP on these natural ingredients to develop applications of natural ingredients in the fields of health care, cosmetology and disease treatment.

    Fig.1. Experimental setup of LTP generation. (A) DBD. (B) APPJ. LTP: low temperature plasma; DBD: dielectric barrier discharge; APPJ: atmospheric-pressure plasma jet.

    Phloroglucinol compounds show a vast array of biological activities including anti-inflamation, anti-microbico and antioxidation. Choi et al. [13] synthesized phloroglucinol oligomers(dimer, trimer, tetramer and pentamer) by treating phloroglucinol with DBD. Compared with maternal phloroglucinol and other generated oligomers, the phloroglucinol pentamer can inhibit the activity of α-glucosidase more effectively.

    Trans-resveratrol (TR) is a stilbenoid found in grapes and low bush berries, and can reduce the risk of aging and heart diseases.Jeong et al.[14]treated TR with DBD and found that after 40 min of treatment, four known products were generated: (-)-ε-viniferin,(+)-ε-viniferin, 3,5-dihydroxybenzaldehyde, and p-hydroxybenzaldehyde, in addition to two unusual resveratrol dimers:methylenebisresveratrols A and methylenebisresveratrols B. The two unusual dimers can effectively inhibit the activities of αglucosidase and α-amylase,to delay the absorption of glucose and reduce the level of postprandial blood glucose. Moreover, LTP acts on quercetin and produces three degraded products, namely,(±)-alphitonin, protocatechuic acid methyl ester, and protocatechuic acid, among which (±)-alphitonin has excellent antidiabetic and anti-oxidant activities [15].

    Compared with classical drug synthesis methods which need harsh reaction conditions, lengthy response time and complex extraction procedures, LTP can promote the biological activities of natural ingredients or generate byproducts with beneficial properties more rapidly and easily. However, there are few researches on the enhancing effects of LTP on commercial drugs. The applications of LTP in increasing drug activity and developing new drugs are still in the initial stage.

    2.2. LTP decreases drug activity

    Due to abundant reactive oxygen species (ROS) and reactive nitrogen species (RNS), LTP has strong oxidation capacity. Therefore,there are various studies on degradation of drugs by LTP.Amini et al. [16] were the first to study the effects of LTP on saffron compounds. Crocin esters and safranal contents were important indexes to evaluate saffron quality. They found when the working gas was argon, and voltage was 8 kV, LTP could decrease the contents of crocin esters and safranal but increase the contents of isophorone and 4-ketoisophorone. Increasing voltage and adding 5% or 10% oxygen to working gas would cause more crocin esters and safranal to decrease while more isophorone and 4-ketoisophorone to increase.

    Lysozyme has been used as a clinical medicine due to its antibacterial, anti-inflammatory and antiviral effects [17,18]. Choi [19]compared the effects of lysozymes treated by different working gases(nitrogen and air)and devices(DBD and APPJ),and found that under the same conditions, compared with DBD, APPJ could significantly change the structure of lysozyme and decrease its activity. Compared with air-LTP, nitrogen-LTP could induce more structural changes of lysozyme. Also, the structure of α-chymotrypsin would be damaged after APPJ treatment for 5 min [20].

    LTP can degrade a variety of pharmaceutical components and destroy the activity of drugs,which seems to be detrimental to the development of LTP in the pharmaceutical field. However, from another perspective, this property can effectively destroy the structure and toxicity of drug wastes in sewage, reduce the concentrations of drug pollutants, and finally purify the sewage. Researchers have already used LTP to degrade sulfonamide antibiotics[21,22],β-lactam antibiotics[23]and pentoxifylline[24]in sewage.Therefore, LTP can be a promising technology to destroy nonbiodegradable pollutants.

    In addition, LTP is an efficient and safe sterilization equipment,which is widely used for sterilization of food and heat sensitive materials [25,26]. If LTP is applied to drug disinfection, it may degrade drug components and reduce drug efficacy. It is believed that researchers will find out the appropriate LTP conditions in the future, which can be used in drug sterilization without damaging drug activity.

    3. LTP's synergistic effects with drugs

    3.1. LTP's synergistic effects with chemotherapeutic drugs

    Chemotherapy has been a major treatment for cancers. However,in recent years,more and more tumor cells have shown drug resistance and the efficiency of chemotherapy is interfered[27].LTP has been proved to inhibit cell proliferation, induce cell apoptosis,inhibit metastasis and invasion of various cancer cells[28-32].LTP can be a new treatment for tumors. Many researchers have combined chemotherapeutic drugs with LTP in order to achieve the best efficacy and improve prognosis of tumor patients.

    Chang et al. [33] treated oral squamous cancer cells with 1 kV LTP and 10 μg/mL of cetuximab.Combined treatment with LTP and cetuximab could reduce the invasion and migration of oral squamous cancer cells.Sagwal et al.[34]discovered that combining LTP with chemotherapeutic drugs including doxorubicin, epirubicin and oxaliplatin could lead to the significant melanoma cell death.Studies on relevant mechanisms showed that the expression of organic cation importer SLC22A16 in SK-MEL 28 melanoma cells was significantly upregulated after LTP treatment, so melanoma cells could uptake doxorubicin better, and the concentration of doxorubicin in cells was increased.

    Chang et al.[35]found if APPJ with helium gas was used to treat BXPC-3 pancreatic cancer cells,followed by low dose(2.5 mg/mL or 5.0 mg/mL) of tegafur, the proliferation capacity of cells could be decreased in a synergistic manner. However, if tegafur was used first, followed by LTP treatment, the tumor inhibition effect was similar to that of using tegafur alone.Further experiments showed that tegafur could react with the short-lived radicals generated by LTP to form 5-fluorouracil (5-FU). 5-FU has a lower anti-tumor capacity than tegafur; thus, the synergistic anti-tumor effect was decreased when using tegafur before LTP to treat cells.Brulle et al.[36]successfully established an orthotopic mouse model of human pancreatic cancer and studied the effects of plasma gun and gemcitabine on pancreatic cancer. The results showed combined treatment with LTP and gemcitabine could synergistically inhibit the growth of pancreatic cancer.

    Joint application of radiotherapy and chemotherapy is one of the classical antineoplastic protocols. Damaging normal cells surrounding tumors and inducing radioresistance by repeated radiotherapy are the most important problems that radiotherapy must face. LTP is an interdisciplinary technology of physics, chemistry and biomedicine that has excellent effects in tumor treatment.LTP kills tumor cells selectively without damaging surrounding tissues,and this property overcomes the side effect of radiotherapy.LTP can also improve the sensitivity of tumor cells to drugs, overcome the cell resistance problem and reduce dosage of drugs, thus reducing the side effect of chemotherapy.In conclusion,although researches on the synergistic effects of LTP with drugs are still superficial,the combination of LTP and chemotherapy is a bold attempt in tumor treatment. Combination of LTP and drugs provides a new idea for cancer therapy and may become a new antineoplastic protocol in the future.

    3.2. LTP's synergistic effects with nanodrugs

    Nanomaterials are widely used as drug carriers due to their ability to adsorb and transport other components [37,38]. In the treatment of solid tumors, nanodrugs can significantly reduce the side effects of chemotherapy drugs,relieve suffering of patients and improve drug efficacy [39,40]. In the past decade, more and more studies have shown that the combination of LTP and nanodrugs can synergistically accelerate the tumor cells death without damaging normal cells[41-43].Zhu et al.[40]treated breast cancer cells with LTP and core-shell nanoparticles loaded with 5-FU and found they could synergistically inhibit the proliferation of cancer cells.Mechanism studies showed that LTP could promote the cellular uptake of nanoparticles.Yu et al.[44]discovered that combing LTP treatment with paclitaxel-loaded core-shell magnetic nanoparticles could inhibit A549 cells growth.

    Gold nanoparticles’ surface plasma resonance (SPR) characteristic can cause the scattering and absorption of light,which makes gold nanoparticles widely studied in the field of tumor diagnosis and treatment [45]. At present, in addition to serving as drug delivery carrier, gold nanoparticles can also be used as radiotherapy sensitizers and diagnostic agents in clinical research [46-48]. The SPR absorption of gold nanoparticles can rapidly transform light energy into local thermal energy, thus damaging tumor cells. In recent years, researches on gold nanoparticles as photothermal therapy have achieved preliminary results [49,50]. Many in vitro experiments showed that LTP and gold nanoparticles could synergistically inhibit tumor cells[42,43,51-54].For example,Irani et al.[52] investigated the synergy effect of LTP and nanoparticles on HCT-116 colorectal cancer cells. HCT-116 cells were cultured in the presence of gold nanoparticles and then treated with LTP. After combined treatment,the number of viable cells decreased sharply.He et al. [53] treated U373MG glioblastoma multiforme cells with LTP and gold nanoparticles,and drew a conclusion that combination of LTP and gold nanoparticles could induce more cells death.Further studies revealed LTP could enhance gold nanoparticles endocytosis and help intracellular gold nanoparticles transfer to lysosomes.

    ROS and RNS are the main active molecules of LTP to exert antitumor effects. In order to overcome the weak permeability of LTP,Kong et al. [55] proposed the chemical non-equilibrium characteristic of LTP could be combined with super penetration potential of nanoparticles to manufacture LTP-coded nano-capsules. The specific structure is shown in Fig. 2, in which the porous nanoparticles captured the reactive oxygen and nitrogen species(RONS)generated by LTP and formed the core of nano-capsules.The nanocapsules are then coated with polymer shells and have surface charges.Finally,the surface of nano-capsules could be connected to a variety of targeting ligands, transferred to sites of tumor growth or infection, and killed tumor cells and pathogens in a specific manner. Due to technical defects, the nano-capsules proposed cannot be successfully manufactured at this stage. This feasible theory may help LTP work deeper in the body.

    Nanodrugs have more advantages than traditional drugs.Firstly,nanomaterials can load a great many drugs,delay the degradation of drugs,and reduce the dosage of drugs,so as to decrease the side effects of chemotherapy. Secondly, nanoparticles loaded with a variety of specific ligands on surface will destroy tumors precisely.Thirdly, nanoparticles ranging 1-100 nm in size can reach deep regions which are inaccessible to macromolecules. Furthermore,nanodrugs can be used in the treatment of multidrug-resistant tumors [56]. For decades, LTP and nanodrugs applied separately on tumor treatment have achieved good results. At present, more researches focus on the combination of them in order to gain an optimal treatment efficacy. It is noteworthy that strong permeability of nanodrugs may cause unpredictable damage to the body,also known as nanotoxicity,and the way of LTP working deep in the body is not yet resolved.All these problems bring difficulties to the clinical application of the combination therapy of nanodrugs and LTP. However, it is undeniable that the combination of nanodrugs and LTP brings a promising future to tumor therapy.

    Fig. 2. Structure of LTP-coded nano-capsule. RONS: reactive oxygen and nitrogen species.

    4. LTP's use in drug control and release system

    Compared with the traditional material modification techniques, LTP surface modification technique is more rapid and convenient. What’s more, LTP only changes the characteristics of nanometer depth of the material surface,while retains most of the properties of the material.As shown in Fig.3,von Woedtke et al.[2]summarized five basic ways of LTP modification of material surface properties, namely, cleaning, thin film deposition, etching, modification/functionalization,and activation.Cleaning is helpful for the direct contact between LTP and material surface, and can be the first step of thin film deposition[57].Thin film deposition refers to LTP polymerizing certain monomers on the material surface to form a stable thin film. The functions and properties of film are related to the type of monomers. LTP etching material surface can be used in integrated circuit manufacturing [58]. LTP can promote the production of functional groups on the material surface so as to activate the material surface and improve the hydrophilicity and surface free energy of materials. Activated material surface may graft other components to form graft copolymer with special functions. For example, polyester fabrics after LTP treatment grafting with chitosan oligomers would have a good antibacterial ability and biocompatibility [59].

    Biomaterial surface modification is an important application of LTP material modification used in the medical field.LTP is a simple and green modification technology promoting the adhesion of cells on biomaterial surface by increasing biomaterials wettability and functionalization.Hyaluronan(HA)is essential for cell adhesion to extracellular matrix or material surface and is negatively charged by the carboxyl group. So Finke et al. [60] hoped to generate positively charged films by plasma polymerization on titanium surface to attract HA.They used allylamine as the monomer to form an adherent,ultra-thin and stable film.The film on titanium surface was rich in high-density amine groups. Compared with pure titanium, this titanium coated with plasma-polymerized film could promote the formation of osteoblastic focal adhesion and the development of actin cytoskeleton. Egghe et al. [61] used DBD to deposit N,N-dimethylacrylamide-based coatings on glass substrates, and found that coatings treated at a low power were unstable, while coatings treated at higher power were stable and showed a lower hydrophilicity.They found that good cell adhesion and survival were on the coatings obtained at high power.Because the production of plasma-polymerized film requires precise parameter control, Bullett et al. [62] studied different effects of several plasma deposition parameters on the functionality and stability of plasma-polymerized N-isopropyl acrylamide (NIPAAm)coatings. In addition to plasma power, temperature is one of the main factors determining the performance of coatings. The study showed that low substrate temperature and low power produced unstable plasma-polymerized NIPAAm films.On the contrary,high temperature and high power produced stable films. And the deposition rate of NIPAAm decreased with substrate temperature but increased with plasma power. Appropriate LTP parameters were required to produce plasma-polymerized films with good biocompatibility and stability on biomaterial surface.

    In the recent ten years,plasma material modification technique has also been widely applied in drug delivery system, which can regulate drug release rate in vivo and enhance therapeutic effects[63].LTP regulates drug release rate mainly by promoting thin film deposition,producing crosslinked layers,increasing wettability and free energy of material surface.

    Drug burst release refers to the phenomenon that a large dose of drugs is released from the drug delivery system within a short period of time, resulting in a sudden rise in blood drug concentration. Burst release is dangerous to human body and can cause waste of drugs. Slow and lasting drug release is very necessary in tumor therapy, hormone therapy and anti-infection therapy.Therefore, development of new drug release system to delay drug release rate has been a concern of many researchers[63,64].Canal et al. [65] treated β-tricalcium phosphate ceramics with helium-APPJ. The β-tricalcium phosphate ceramics were loaded with doxycycline hyclate. They found that APPJ did not change the morphological characteristics of the ceramics, but increased the ratio of oxygen atoms to carbon atoms(O/C ratio),and reduced the initial release percentages of doxycycline hyclate. Chen et al. [66]used LTP to treat a chitosan film loaded with ciprofloxacin hydrochloride for 30 s,and then deposited a zein coating on the chitosan/drug film. Results showed that after LTP treatment, encapsulation efficiency, chemical composition and crystal structure of ciprofloxacin hydrochloride remained unchanged,but the hydrophilicity and surface free energy of the chitosan/drug film had a remarkable increase,the sedimentary volume of zein on the surface of the film increased significantly, chitosan was more closely connected with zein, and the 24-h release rate of ciprofloxacin hydrochloride was effectively reduced. Saitaer et al. [67] used LTP to treat polypropylene (PP) meshes, and then LTP-treated PP meshes were coated with polydopamine (PDA). The PDA coated meshes were further loaded with levofloxacin.Compared with LTP untreated PP meshes, LTP-treated meshes could be more effectively in coating with PDA.Plasma treated and PDA coated meshes could load more levofloxacin, delay drug release, and display better antibacterial properties, which might be an effective way to prevent mesh infections in hernia surgery.

    In analgesia and sedation,the rapid release of drugs is needed to relieve the pain of patients in a short time. Some studies showed that LTP could act on drug delivery materials and increase drug release.Labay et al.[68]treated polyamide 6.6(PA 66)fabrics with LTP at different air flow rates (5,10,15 L/min). They observed that after LTP treatment, the surface polydimethylsiloxane (PDMS)softeners hydrophobic coatings on PA 66 fabrics were etched, and the release of caffeine from fabrics was increased significantly.The thickness of PDMS decreased and caffeine release increased with the flow rate. When the flow rate was 15 L/min, the 24-h release rate of caffeine could be increased to approximately 90%.

    Fig.3. Five ways of LTP to change material surface properties.Cleaning:LTP can clean the organic pollutants on materials surface.Thin film deposition:LTP can deposit monomers on the material surface to form a thin film. Etching: LTP can cause the loss of material surface particles. Modification/Functionalization: LTP can improve the hydrophilicity of material surface,and promote the generation of crosslinking and graft copolymer.Activation:LTP can promote the production of carbonyl,carboxyl,oxygen atoms and other groups on the material surface.

    The modification effect of LTP on drug delivery system is related to plasma’s parameters, including voltage, treatment time, and working gas. Working gases used in LTP are various, including oxygen, helium, argon, nitrogen, air and a mixture of several gases,and different gases may produce different modification effects on materials. Hagiwara et al. [69] studied LTP effects on curcumin release from poly (ethyl-co-vinyl acetate) (EVA) polymer and production of crosslinked layer in EVA using oxygen, argon and nitrogen as working gases. EVA surface became hydrophilic after treated by LTP.The drug release rate of EVA was constant up to 15 s of the oxygen plasma treatment time, and the amount of released drug decreased rapidly after 30 s of the treatment time. However,argon or nitrogen plasma treatment of only 5 s significantly suppressed the drug release.Argon plasma could be the most effective way to establish the crosslinking in EVA, followed by nitrogen plasma, while oxygen plasma would not induce the crosslinked layer in EVA.Ivanova et al.[70]modified poly(ε-caprolactone)(PCL)with LTP to improve the surface wettability and porosity, and promoted the deposition of porous CaCO3coating on PCL.Different working gases of LTP were used to treat PCL: argon, oxygen and ammonia.All the three LTP devices,especially oxygen plasma could produce strong functional groups on PCL surface and improve the hydrophilicity of PCL. The improvement of hydrophilicity was essential for the deposition of CaCO3. Vaterite CaCO3was porous,which was conducive to bone tissue adhesion and drug delivery and grew more preferentially on PCL after oxygen plasma treatment than ammonia/argon plasma-treated PCL. And the CaCO3coating formed on oxygen plasma-treated PCL was smoother and more homogenous than coatings on ammonia/argon plasmatreated PCL. To obtain the best performance of drug delivery materials, scientists need to evaluate LTP’s modification effects with different working gases and find the best treatment conditions.

    Aging is a common phenomenon in plasma-treated materials.The hydrophilicity of material surface will decrease and the surface will turn into hydrophobic gradually with the aging time. Aging is related to the surrounding environment of materials. The higher the temperature is,the more likely aging is to occur.The higher the humidity is,the more difficult aging is to occur.Murakami et al.[71]used dry nitrogen gas as the hydrophobic aging medium and used distilled water as the hydrophilic aging medium to test changes of the polystyrene (PS), PDMS and phenol-formaldehyde resin (PFR)respectively in two aging media after plasma treatment. The free energy and work of adhesion in all three plasma treated materials decreased when they were aged in nitrogen. It can be explained that polar groups moved from the surface to the depth of materials.When polymers were aged in water, the surface free energy of all materials would turn to be close to the free energy of water. The moving direction of polar groups depended on the level of material surface free energy and water free energy.The surface free energy of plasma-treated PS or PDMS was lower than water energy,so the polar groups moved from the deep to the material surface to improve the surface free energy.The surface free energy of oxygen plasma-treated PFR was higher than water energy, and the polar groups moved from the material surface to the deep layer to reduce the surface free energy of PFR. The results indicate that the movement of groups aims at reducing the free energy gap between the aging medium and material surface, and aging medium is important to aging. Aging impairs the surface properties of materials treated by LTP, and that is an urgent problem to be solved.

    Drug control and release systems require sophisticated technical support, so the appropriate LTP treatment condition is crucial for different drug delivery systems.Furthermore,whether the activity of drugs loaded on materials changes after LTP treatment also needs to be further studied. Although the development of LTP in drug delivery system is faced with many difficulties, LTP shows limitless applications in drug controlled release system and is expected to become a new device to control drug release.

    5. LTP's use in preparing inactivated vaccines

    Several experiments have proved that LTP has the ability to inactivate viruses significantly, such as feline calicivirus [72],adenovirus[73],and herpes simplex virus type 1[74].Terrier et al.[75]treated influenza virus type A,respiratory syncytial virus,and human parainfluenza virus type 3 suspensions with cold oxygen plasma generated by subjecting air to high-energy deep-UV light.They found a reduction of all three viruses after cold oxygen plasma treatment. The high efficient inhibition effect of LTP on multiple viruses shows that it has a great potential in the prevention and controlling of foodborne diseases and respiratory infectious diseases.

    As LTP has a strong potential to inactivate viruses, Wang et al.[76] further explored whether LTP could only eliminate the pathogenicity of virus while retaining antigenic activity. They treated Newcastle disease virus (NDV) and H9N2 avian influenza virus(AIV)with LTP to explore a new way to prepare inactivated poultry vaccines.In their experiments,the working parameters of LTP were 18 kV voltage,10 kHz frequency,a mixture of 88%argon,2%oxygen and 10%nitrogen working gas,and 5 L/min gas flow rate.Both NDV and AIV lost pathogenic activities after LTP treatment for 2 min.And NDV vaccines obtained by 2 min-LTP treatment induced SPF chickens to produce the higher antibody titers compared with traditional vaccines. 2 min-LTP-treated AIV vaccines induced the similar antibody titers compared with traditional AIV vaccines.With overdose LTP treatment, the titers of antibodies induced by the two inactivated viruses were significantly reduced. The inactivated NDV and AIV vaccines produced after LTP treatment for 2 min could effectively prevent chickens from being infected with NDV and AIV strains. Wang’s research provided a possibility for the application of LTP in vaccine manufacturing. More studies are needed to find out whether LTP can be used to produce vaccines and how safe and effective these vaccines are.

    6. LTP's use in drug quality control

    Ambient desorption/ionization mass spectrometry(ADI-MS)is a new type of analytical instrument, and does not require solvents and cumbersome drug pretreatment process.It is fast and accurate,and exhibits multiple advantages in qualitative and quantitative analyses of substances. There are multiple types of ADI-MS, and LTP-MS is one of them[77].Liu et al.[78]desorbed eleven drugs to be degraded into ions with an LTP probe,and input the ions into MS for analysis. LTP-MS could quickly and accurately show the components of each drug,and determined the authenticity and quality.Jackson et al. [79] analyzed the biological fluid samples (saliva,urine, hair extract) of 14 abused drugs, including opiates, euphoriants, stimulants and sedatives with LTP-MS.Results showed that LTP-MS could directly analyze liquid samples and show good sensitivity.Wiley et al.[80]first introduced a handheld LTP device for material analysis which could be used with a miniature or benchtop mass spectrometer.This LTP device consisted of a circuit system powered by a lithium polymer battery, a glass tube for generating plasma, a miniature helium gas reservoir and a plastic casing,with a total weight of only 910 g.Fig.4 is a brief schematic diagram of the device.Compared with traditional large LTP device,the handheld LTP source could still analyze experimental drugs accurately. Analogously, Ateacha et al. [81] combined a self-made small LTP probe with a benchtop high-resolution orbital MS, and successfully conducted qualitative analysis of the active ingredients in Coartem and Malarone tablets, which proved to be a new method for quick and accurate assessment of antimalarial drugs.LTP-MS has shown a broad application prospect in the field of realtime drug quality control.

    Fig. 4. Brief schematic diagram of LTP-MS.

    7. Use of plasma-activated liquids

    LTP was used in biomedical research in the following two ways to deal with samples: one is LTP acting directly on the biological samples;the second is LTP pretreating different solutions,and then the solutions are used in the tissues or microbial samples. The water or medium treated by LTP is known as plasma-activated water (PAW) or plasma-activated medium (PAM) [82,83]. Studies showed that plasma-activated liquids had a significant inhibitory effect on a variety of tumor cells and bacteria[82,84-89].

    Duan et al. [90] co-cultured hepatocellular carcinoma cells HepG2 with normal liver cells L02 to simulate the tumor growth environment in human body. HepG2-L02 cells co-culture system was treated with PAM.It was found that PAM generated by 10 min LTP treatment could induce the apoptosis of HepG2 cells to the greatest extent without obvious damage to normal liver cells.

    Kurake et al. [87] found that PAM induced apoptosis of glioblastoma cells by inhibiting glycolysis. In addition, PAM could kill cancer-initiating cells[91],human lung adenocarcinoma epithelial cells [92], human breast cancer cells [93] and other cancer cells.Chauvin et al. [82] successfully constructed colorectal tumor spheroids to simulate the real structure of tumor growth in human body. After cell culture medium was treated with helium LTP for 120 s,PAM was prepared.When the contact time with PAM reached more than 10 min,the spherules started to disintegrate,and PAM’s damage to the spherules became obvious. Further studies showed that PAM could significantly reduce the ATP content in colorectal cancer cells and destroy mitochondrial function. Some in vivo experiments in mice [86,94,95] showed that injecting plasmaactivated liquids into mice models could effectively inhibit the growth or metastasis of gastric, ovarian and pancreatic cancers.

    Zhang et al. [89] discovered that PAW could inactivate Staphylococcus aureus, and with the longer PAW generation time and treatment time, the sterilization effect was more obvious. PAW could effectively destroy bacterial membrane,membrane potential,intracellular pH homeostasis and DNA structure. It could be an efficient and environmental friendly sterilizer.Balan et al.[96]tried to explore whether PAW could be successfully used for duodenoscope disinfection and they found after 30 min PAW treatment,the activities of Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were all decreased significantly.PAW treated duodenoscopes continuously for 30 min daily for 45 days, and did not cause significant damage to the surface structure and material components of duodenoscopes. This indicated that PAW had a strong bactericidal ability and minimal damage to precision medical instruments; therefore, it can be applied in clinical diagnosis and treatment.

    Li et al. [97] treated Streptococcus mutans, Porphyromonas gingivalis and Actinomyces viscosus with PAW,and found that PAW could significantly reduce the number of all three bacteria in a short time. As a traditional mouthwash, chlorhexidine will cause side effects such as oral mucosal erosion, tooth staining, taste disturbance and parotid gland swelling. PAW is expected to become a new mouthwash due to its high antibacterial properties, but the issue of PAW biosafety needs further exploration.

    In addition, some studies showed that PAW could destroy various viruses.Guo et al.[98]treated bacteriophages T4,Φ174 and MS2 with PAW, and found PAW could effectively inactivate three phages and destroy their proteins and nucleic acids. Su et al. [99]revealed that 30 min PAW treatment could completely inactivate NDV,decrease the protein content and disintegrate RNA into small molecular fragments.

    Fig. 5 briefly describes the chemical reactions and RONS generated by liquids after LTP treatment. At present, it is believed that hydrogen peroxide (H2O2), nitrite (NO2-) and nitrate (NO3-)are the main active components of biological functions in plasmaactivated liquids [84,100-102]. Plasma-activated liquids can be stored for a long time under suitable conditions. Vlad et al. [103]found that conductivity, pH value, H2O2and NO3-concentration of PAW were almost unchanged after PAW was sealed from light for 21 days.Mohades et al.[84]also proposed that PAM produced by 4 min LTP treatment still had some ability to kill cancer cells after being stored at room temperature for 8 h. Shen et al. [104]compared the bactericidal effects of PAW at different storage temperatures(25°C,4°C,-20°C,-80°C),and found that PAW could still retain efficient bactericidal efficacy after 30 days of storage at-80°C,and its H2O2and NO2-contents were similar to the initial values without obvious attenuation.

    Due to the above characteristics, the plasma-activated liquid is considered as a special tumor treatment drug and a green and efficient disinfectant,which has attracted extensive attention from the medical community in recent years. Research on the specific mechanism of active ingredients acting on cancer cells and bacteria is not sufficient, and there is still a long way to go before plasmaactivated liquids are commercialized and applied in clinical diagnosis and treatment.

    8. Challenges

    It is undeniable that LTP has a great application prospect in the field of pharmacy, but it is still in the exploration stage faced with both opportunities and challenges.Due to the variety of drugs and chemical properties of drugs, as well as the multiple factors that can influence the effects of LTP, LTP still faces many challenges.

    Fig.5. Schematic diagram of plasma biological effects transmitted through liquid phase.LTP mainly contains hydroxyl(?OH),ozone(O3),nitric oxide(NO),nitrogen dioxide(NO2)and other RONS.After LTP contacts with liquids,RONS will dissolve in liquids and start various chemical reactions.In addition to containing dissolved RONS,plasma treated-liquids also produce many secondary RONS,including ?OH,H2O2,NO,NO3-,NO2-,peroxynitrite(ONOO-),etc.Those secondary RONS are considered to be the main factors of PAM/PAW to promote wound healing, kill cancer cells and inactivate microbes.

    1) The mechanism of LTP promoting and inhibiting drug activity is unclear.When plasma acts on drugs,the electric fields,charged particles,RONS and UV will react with the drug components and induce the promoting or inhibiting effects. At present, some studies suggest that the degradation of drug components in sewage by LTP is mainly dependent on hydroxylation,while the effect of nitrogen oxides is very small[22,105].However,it is not clear how deep RONS penetrates into the drugs,and which kind of RONS plays a major role.Therefore,new plasma devices need to be proposed so that they can control the identified types and levels of RONS to reach target drugs.

    2) In the process of LTP degrading medical wastes, the toxicity of intermediate products may be comparable to that of the parent drugs, or even higher, so the real-time detection of toxic substances in sewage treatment and selection of suitable plasma treatment conditions to thoroughly purify sewage are important issues [105]. In addition, the effects of LTP degrading active components of drugs limit its application in drug sterilization.How to reduce the inhibitory effects of LTP on drug activity and achieve good bacteriostasis and decontamination effects still need further research [16]. As there are various kinds of drugs but relatively few researches on LTP treatment of drugs, much remains to be done to explore appropriate ways for sewage disposal,drug sterilization and decontamination,and new drug development.

    3) The molecular mechanism of synergistic anticancer effect of LTP and drugs remains unclear.So far,there are few studies[33,34],and the molecular mechanism of the co-action of different types of drugs and LTP on tumor cells cannot be fully illustrated. The lack of theoretical basis limits the development of combined use of LTP and drugs in the treatment of tumors.

    4) Plasma-activated liquid has been proved to have antibacterial effects, and be able to promote wound healing and inactivate cancer cells [82,106,107]. How does the RONS enter the cancer cells? What is going on inside the cells? How do the transduction of intracellular tumor suppressor signaling pathways and cell to cell communication take place? All these questions remain unanswered.5) At present, most studies on LTP in the pharmaceutical field are based on in vitro experiments, such as cell experiments, 3D tumor modeling experiments and drug release experiments.There is lack of reliable in vivo experiments and clinical experiments.As a result,it needs strenuous efforts for LTP to become truly a "new drug."

    Declaration of competing interest

    The authors declare that there are no conflicts of interest.Acknowledgments

    This work was supported by the National Natural Science Foundation of China (Grant No.51677146), Project of Independent Innovative Experiment for Postgraduates in Medicine in Xi’an Jiaotong University (Grant No. JSCX-2018-014) and the Special Scientific Research Project Funds of Shaanxi Province (Grant No.18JK1102).

    午夜精品在线福利| 757午夜福利合集在线观看| 欧美成人免费av一区二区三区| 满18在线观看网站| 国产精品综合久久久久久久免费 | 免费在线观看日本一区| 正在播放国产对白刺激| 久久久精品国产亚洲av高清涩受| 国产又色又爽无遮挡免费看| 亚洲中文日韩欧美视频| 免费在线观看亚洲国产| 亚洲五月天丁香| 亚洲精品粉嫩美女一区| 在线视频色国产色| 每晚都被弄得嗷嗷叫到高潮| 亚洲男人的天堂狠狠| 国产97色在线日韩免费| 午夜老司机福利片| 在线永久观看黄色视频| 又紧又爽又黄一区二区| 久久青草综合色| 久久久久久亚洲精品国产蜜桃av| 啪啪无遮挡十八禁网站| 国产成年人精品一区二区| 神马国产精品三级电影在线观看 | 久久狼人影院| 亚洲 欧美 日韩 在线 免费| 可以在线观看毛片的网站| 久久草成人影院| 午夜免费激情av| 国产一区二区三区在线臀色熟女| 亚洲成人国产一区在线观看| 亚洲国产高清在线一区二区三 | 久久这里只有精品19| 老司机午夜十八禁免费视频| 人人妻人人爽人人添夜夜欢视频| 国产男靠女视频免费网站| 亚洲自偷自拍图片 自拍| 搞女人的毛片| 免费在线观看视频国产中文字幕亚洲| 欧美日韩瑟瑟在线播放| 两性午夜刺激爽爽歪歪视频在线观看 | 99热只有精品国产| 亚洲国产精品sss在线观看| 久久久国产欧美日韩av| 欧美av亚洲av综合av国产av| 曰老女人黄片| 99久久综合精品五月天人人| 中文字幕人妻熟女乱码| 亚洲av熟女| 亚洲一码二码三码区别大吗| 69av精品久久久久久| 高清黄色对白视频在线免费看| 欧美激情高清一区二区三区| 国产欧美日韩一区二区三| 国产xxxxx性猛交| 他把我摸到了高潮在线观看| 国产视频一区二区在线看| 亚洲色图av天堂| 欧美精品亚洲一区二区| 动漫黄色视频在线观看| 国产高清视频在线播放一区| 99国产极品粉嫩在线观看| 天天躁夜夜躁狠狠躁躁| 无限看片的www在线观看| 自拍欧美九色日韩亚洲蝌蚪91| 老司机午夜福利在线观看视频| 精品久久久久久成人av| 亚洲情色 制服丝袜| 欧美日本视频| 亚洲情色 制服丝袜| 国产97色在线日韩免费| 亚洲成av人片免费观看| 欧美激情高清一区二区三区| videosex国产| 亚洲熟妇熟女久久| 久久精品国产清高在天天线| 成人三级黄色视频| 亚洲中文字幕一区二区三区有码在线看 | 亚洲成av人片免费观看| 成在线人永久免费视频| 国产不卡一卡二| 人人妻,人人澡人人爽秒播| 国产极品粉嫩免费观看在线| 天堂动漫精品| av视频免费观看在线观看| 国产av在哪里看| 久久婷婷成人综合色麻豆| 亚洲午夜精品一区,二区,三区| 精品久久久久久久人妻蜜臀av | 久久精品亚洲精品国产色婷小说| 亚洲在线自拍视频| 一卡2卡三卡四卡精品乱码亚洲| 久久草成人影院| 国产麻豆69| 国产av又大| 很黄的视频免费| 国产成人啪精品午夜网站| 亚洲在线自拍视频| 咕卡用的链子| 亚洲国产中文字幕在线视频| 久9热在线精品视频| 青草久久国产| 十分钟在线观看高清视频www| 性欧美人与动物交配| 精品第一国产精品| 国产成人精品久久二区二区免费| 亚洲欧美日韩高清在线视频| 女人被狂操c到高潮| 大码成人一级视频| 国产aⅴ精品一区二区三区波| 精品久久久久久久久久免费视频| 亚洲 欧美一区二区三区| 日韩一卡2卡3卡4卡2021年| 搡老妇女老女人老熟妇| 99国产综合亚洲精品| 久久精品人人爽人人爽视色| 欧美色视频一区免费| 老司机午夜福利在线观看视频| 法律面前人人平等表现在哪些方面| 级片在线观看| 黑人操中国人逼视频| 精品国产乱子伦一区二区三区| 精品久久蜜臀av无| 国产精品一区二区免费欧美| 欧美激情久久久久久爽电影 | 亚洲av成人av| 美女高潮喷水抽搐中文字幕| 黄频高清免费视频| 亚洲人成电影免费在线| 久久伊人香网站| 韩国av一区二区三区四区| 国产一区二区三区视频了| 在线观看免费视频网站a站| 久久久久久大精品| 国产精品精品国产色婷婷| 亚洲熟妇熟女久久| or卡值多少钱| 1024香蕉在线观看| 久久中文看片网| 免费高清视频大片| 国产精品久久视频播放| 桃色一区二区三区在线观看| 一级毛片高清免费大全| 国产精品亚洲一级av第二区| 日韩精品青青久久久久久| 精品福利观看| 久久久久国产精品人妻aⅴ院| 色婷婷久久久亚洲欧美| 欧美性长视频在线观看| 国产亚洲精品一区二区www| 亚洲av成人一区二区三| √禁漫天堂资源中文www| 国产精品一区二区免费欧美| 国内久久婷婷六月综合欲色啪| 亚洲色图综合在线观看| 亚洲一区中文字幕在线| 97碰自拍视频| 亚洲成人久久性| 日韩中文字幕欧美一区二区| 在线观看免费视频日本深夜| 一二三四在线观看免费中文在| 女性被躁到高潮视频| 成年版毛片免费区| 九色亚洲精品在线播放| 9热在线视频观看99| www日本在线高清视频| 欧美日韩瑟瑟在线播放| 午夜激情av网站| 一边摸一边做爽爽视频免费| 女同久久另类99精品国产91| 亚洲 欧美 日韩 在线 免费| 老汉色∧v一级毛片| 少妇粗大呻吟视频| 午夜视频精品福利| 国产成人欧美| 午夜精品国产一区二区电影| 亚洲av成人不卡在线观看播放网| 此物有八面人人有两片| 男女午夜视频在线观看| 丁香欧美五月| 欧美+亚洲+日韩+国产| av在线播放免费不卡| 美女高潮到喷水免费观看| 亚洲人成伊人成综合网2020| √禁漫天堂资源中文www| 欧美成人免费av一区二区三区| 欧美另类亚洲清纯唯美| 高清在线国产一区| 91九色精品人成在线观看| 黑人巨大精品欧美一区二区mp4| 国产亚洲精品第一综合不卡| 午夜免费观看网址| 精品国产乱码久久久久久男人| 久久久久久国产a免费观看| av超薄肉色丝袜交足视频| 亚洲欧美激情综合另类| 精品国产乱子伦一区二区三区| 久久国产精品影院| 啦啦啦免费观看视频1| 国产精品九九99| 亚洲熟妇中文字幕五十中出| 国产蜜桃级精品一区二区三区| 国产av一区二区精品久久| 女性生殖器流出的白浆| 欧美在线一区亚洲| 欧美中文日本在线观看视频| 国产亚洲精品一区二区www| 午夜视频精品福利| 亚洲熟妇熟女久久| 精品熟女少妇八av免费久了| 亚洲欧美日韩高清在线视频| 久久久久久久久中文| 97人妻天天添夜夜摸| 欧美av亚洲av综合av国产av| 精品国产乱码久久久久久男人| 老司机午夜十八禁免费视频| 精品欧美一区二区三区在线| 久久午夜综合久久蜜桃| 国产精品乱码一区二三区的特点 | 欧美成人性av电影在线观看| 桃色一区二区三区在线观看| 亚洲中文日韩欧美视频| 嫩草影视91久久| 91成人精品电影| 美女免费视频网站| 国产一区在线观看成人免费| 国产一区二区三区综合在线观看| 这个男人来自地球电影免费观看| 精品久久蜜臀av无| 欧美日韩瑟瑟在线播放| 亚洲五月色婷婷综合| 色哟哟哟哟哟哟| 久久久国产欧美日韩av| 久久中文看片网| 嫩草影院精品99| 夜夜爽天天搞| 精品国产一区二区久久| 国产成人啪精品午夜网站| 国产精品野战在线观看| 九色亚洲精品在线播放| 免费看a级黄色片| 免费在线观看完整版高清| 给我免费播放毛片高清在线观看| 国产精品一区二区免费欧美| 欧美激情久久久久久爽电影 | 免费高清视频大片| 丝袜美腿诱惑在线| av网站免费在线观看视频| 欧美色视频一区免费| 久久久久国产一级毛片高清牌| 中文字幕最新亚洲高清| 亚洲av成人一区二区三| 精品少妇一区二区三区视频日本电影| 国产欧美日韩一区二区三区在线| 在线视频色国产色| 亚洲av日韩精品久久久久久密| av网站免费在线观看视频| 午夜福利成人在线免费观看| 91九色精品人成在线观看| 人人妻人人澡欧美一区二区 | av天堂久久9| 精品福利观看| 身体一侧抽搐| 国产精品香港三级国产av潘金莲| 日韩欧美免费精品| 国产麻豆成人av免费视频| 国产1区2区3区精品| 91字幕亚洲| 视频区欧美日本亚洲| 国内精品久久久久久久电影| 久久影院123| 少妇熟女aⅴ在线视频| 97碰自拍视频| 亚洲无线在线观看| 美女 人体艺术 gogo| 波多野结衣巨乳人妻| 久久香蕉精品热| 亚洲国产精品sss在线观看| 一区二区日韩欧美中文字幕| 啦啦啦 在线观看视频| 一区二区三区精品91| 国内久久婷婷六月综合欲色啪| 九色亚洲精品在线播放| 久久亚洲精品不卡| 久久精品成人免费网站| 欧美大码av| 亚洲成人免费电影在线观看| 男女午夜视频在线观看| 黄色视频,在线免费观看| 欧美色欧美亚洲另类二区 | www.自偷自拍.com| 深夜精品福利| 国产精品久久视频播放| 九色国产91popny在线| 99久久久亚洲精品蜜臀av| 露出奶头的视频| 国产精品亚洲av一区麻豆| 99久久99久久久精品蜜桃| 亚洲五月色婷婷综合| 好男人电影高清在线观看| 免费搜索国产男女视频| 可以免费在线观看a视频的电影网站| 成年版毛片免费区| 日韩欧美一区二区三区在线观看| 两性夫妻黄色片| 一区二区三区国产精品乱码| 成人国产一区最新在线观看| videosex国产| 电影成人av| 大码成人一级视频| 午夜日韩欧美国产| 老熟妇仑乱视频hdxx| 日本精品一区二区三区蜜桃| 日本 欧美在线| 老司机午夜福利在线观看视频| 亚洲中文日韩欧美视频| 老司机靠b影院| 国产高清激情床上av| 叶爱在线成人免费视频播放| tocl精华| 色综合婷婷激情| 巨乳人妻的诱惑在线观看| 狠狠狠狠99中文字幕| 精品无人区乱码1区二区| 免费久久久久久久精品成人欧美视频| 国产亚洲精品av在线| 少妇粗大呻吟视频| 在线免费观看的www视频| 中亚洲国语对白在线视频| 首页视频小说图片口味搜索| 精品午夜福利视频在线观看一区| 国产亚洲精品一区二区www| 日韩精品青青久久久久久| videosex国产| 国内精品久久久久久久电影| 97人妻天天添夜夜摸| 免费高清视频大片| 国产区一区二久久| 欧美性长视频在线观看| 国产精品久久久久久亚洲av鲁大| 在线观看免费视频网站a站| 国产精品av久久久久免费| tocl精华| 热re99久久国产66热| 亚洲自拍偷在线| 免费看十八禁软件| 日韩大尺度精品在线看网址 | 18禁裸乳无遮挡免费网站照片 | 满18在线观看网站| 正在播放国产对白刺激| 午夜视频精品福利| 久久精品国产亚洲av高清一级| 黄色丝袜av网址大全| 少妇粗大呻吟视频| 少妇裸体淫交视频免费看高清 | 很黄的视频免费| 欧美另类亚洲清纯唯美| 精品国产国语对白av| 国产免费av片在线观看野外av| 麻豆国产av国片精品| 少妇熟女aⅴ在线视频| 日韩欧美三级三区| 欧美色欧美亚洲另类二区 | 黄色视频不卡| 男女之事视频高清在线观看| 人成视频在线观看免费观看| 看黄色毛片网站| 色综合亚洲欧美另类图片| 日本撒尿小便嘘嘘汇集6| 亚洲专区国产一区二区| 久久精品人人爽人人爽视色| 黄色a级毛片大全视频| 少妇被粗大的猛进出69影院| 久久久久国内视频| 午夜精品久久久久久毛片777| 亚洲欧美激情综合另类| 国产视频一区二区在线看| АⅤ资源中文在线天堂| 18禁黄网站禁片午夜丰满| 丁香六月欧美| 国产精品影院久久| 俄罗斯特黄特色一大片| 亚洲在线自拍视频| 日韩中文字幕欧美一区二区| 亚洲熟妇中文字幕五十中出| 无人区码免费观看不卡| 欧美日本视频| 中文字幕人成人乱码亚洲影| 一级,二级,三级黄色视频| 最新美女视频免费是黄的| 日本免费一区二区三区高清不卡 | 色av中文字幕| 国产免费男女视频| 美女午夜性视频免费| 国产精华一区二区三区| 91精品国产国语对白视频| 亚洲 国产 在线| 黑丝袜美女国产一区| 成年女人毛片免费观看观看9| 欧美绝顶高潮抽搐喷水| 国产不卡一卡二| 高清毛片免费观看视频网站| 亚洲精品国产色婷婷电影| 日本黄色视频三级网站网址| 日本精品一区二区三区蜜桃| 免费不卡黄色视频| 一本大道久久a久久精品| 中文字幕人成人乱码亚洲影| 亚洲国产精品成人综合色| 熟女少妇亚洲综合色aaa.| 亚洲五月色婷婷综合| 亚洲精品粉嫩美女一区| 精品国产一区二区久久| 老司机深夜福利视频在线观看| 午夜福利欧美成人| 日韩av在线大香蕉| 久久午夜综合久久蜜桃| 12—13女人毛片做爰片一| 国产一区二区三区在线臀色熟女| 两人在一起打扑克的视频| 在线十欧美十亚洲十日本专区| av欧美777| 亚洲精品久久国产高清桃花| 91老司机精品| 男人舔女人的私密视频| 亚洲狠狠婷婷综合久久图片| 变态另类成人亚洲欧美熟女 | 97超级碰碰碰精品色视频在线观看| 国产成+人综合+亚洲专区| 亚洲片人在线观看| www.www免费av| 啦啦啦韩国在线观看视频| 此物有八面人人有两片| 日本a在线网址| 午夜成年电影在线免费观看| 国产午夜福利久久久久久| 女生性感内裤真人,穿戴方法视频| 热99re8久久精品国产| 欧美精品啪啪一区二区三区| 亚洲视频免费观看视频| 欧美色视频一区免费| 国产成人免费无遮挡视频| 国产精品久久久av美女十八| 中国美女看黄片| 99精品在免费线老司机午夜| 黑人巨大精品欧美一区二区蜜桃| 露出奶头的视频| 久久精品国产99精品国产亚洲性色 | 琪琪午夜伦伦电影理论片6080| a级毛片在线看网站| 国产成人精品久久二区二区免费| 国产不卡一卡二| 午夜精品在线福利| 色综合婷婷激情| 在线免费观看的www视频| 免费不卡黄色视频| 在线观看66精品国产| 大陆偷拍与自拍| 色av中文字幕| 色哟哟哟哟哟哟| 国产成人精品久久二区二区91| 怎么达到女性高潮| 一a级毛片在线观看| 日本一区二区免费在线视频| 午夜激情av网站| 久久久精品欧美日韩精品| 欧美日韩亚洲国产一区二区在线观看| 成人av一区二区三区在线看| 日本a在线网址| 91老司机精品| 搡老岳熟女国产| 欧美日韩一级在线毛片| 不卡av一区二区三区| 在线永久观看黄色视频| e午夜精品久久久久久久| 侵犯人妻中文字幕一二三四区| 国产精品自产拍在线观看55亚洲| √禁漫天堂资源中文www| 午夜免费成人在线视频| 久久九九热精品免费| 一边摸一边做爽爽视频免费| 一夜夜www| 国产精品亚洲美女久久久| 午夜福利免费观看在线| 久久午夜综合久久蜜桃| 国产男靠女视频免费网站| 青草久久国产| 岛国在线观看网站| 亚洲av电影在线进入| 成人18禁高潮啪啪吃奶动态图| 国产av在哪里看| 欧美成狂野欧美在线观看| 日韩精品中文字幕看吧| 亚洲av日韩精品久久久久久密| 国产人伦9x9x在线观看| 国产精品久久久av美女十八| 国产精品美女特级片免费视频播放器 | 亚洲国产精品久久男人天堂| av天堂在线播放| 国产熟女午夜一区二区三区| 在线观看66精品国产| 日本免费a在线| 可以在线观看毛片的网站| 久久精品aⅴ一区二区三区四区| 热99re8久久精品国产| 日韩中文字幕欧美一区二区| cao死你这个sao货| 9191精品国产免费久久| 99国产精品免费福利视频| 精品久久久久久成人av| 亚洲第一av免费看| 国产国语露脸激情在线看| 国产精品免费视频内射| 欧美激情高清一区二区三区| 国产精品电影一区二区三区| 国产av一区二区精品久久| 精品无人区乱码1区二区| 精品一区二区三区视频在线观看免费| 欧美成人性av电影在线观看| 欧美日本视频| 成人免费观看视频高清| 国产av一区在线观看免费| 国产又色又爽无遮挡免费看| 精品一区二区三区四区五区乱码| 国产一级毛片七仙女欲春2 | 精品久久久久久久毛片微露脸| 黄色a级毛片大全视频| 在线永久观看黄色视频| 亚洲avbb在线观看| 在线视频色国产色| 热99re8久久精品国产| 一区二区三区激情视频| 久久精品91无色码中文字幕| 亚洲午夜精品一区,二区,三区| 午夜亚洲福利在线播放| 精品卡一卡二卡四卡免费| 久久久水蜜桃国产精品网| 黑人欧美特级aaaaaa片| 国产私拍福利视频在线观看| 午夜成年电影在线免费观看| 巨乳人妻的诱惑在线观看| 久久久精品国产亚洲av高清涩受| 亚洲全国av大片| tocl精华| 亚洲av成人不卡在线观看播放网| 日本vs欧美在线观看视频| 欧美+亚洲+日韩+国产| 美女 人体艺术 gogo| 成人国产一区最新在线观看| av福利片在线| 成人国产一区最新在线观看| 麻豆国产av国片精品| 老司机靠b影院| 在线观看免费午夜福利视频| 亚洲全国av大片| x7x7x7水蜜桃| 日本五十路高清| 国产精品美女特级片免费视频播放器 | 国产精品自产拍在线观看55亚洲| 91在线观看av| 天天添夜夜摸| 久久久久国产精品人妻aⅴ院| 男女下面插进去视频免费观看| 欧美国产精品va在线观看不卡| 亚洲九九香蕉| 中文字幕精品免费在线观看视频| а√天堂www在线а√下载| 欧美日韩瑟瑟在线播放| 亚洲国产精品成人综合色| 老司机在亚洲福利影院| 久久精品91无色码中文字幕| 侵犯人妻中文字幕一二三四区| 中亚洲国语对白在线视频| 成人特级黄色片久久久久久久| 久久九九热精品免费| 每晚都被弄得嗷嗷叫到高潮| 久久久精品国产亚洲av高清涩受| 亚洲美女黄片视频| 少妇的丰满在线观看| av欧美777| 91大片在线观看| 啦啦啦 在线观看视频| 中文字幕高清在线视频| 色综合站精品国产| av电影中文网址| 男女下面插进去视频免费观看| 手机成人av网站| 午夜福利视频1000在线观看 | 夜夜爽天天搞| 国产成+人综合+亚洲专区| 男女下面插进去视频免费观看| 免费无遮挡裸体视频| 亚洲国产欧美一区二区综合| 国产亚洲av高清不卡| 青草久久国产| 亚洲 国产 在线| x7x7x7水蜜桃| 久久国产精品男人的天堂亚洲| 午夜成年电影在线免费观看| 欧美午夜高清在线| 精品国内亚洲2022精品成人| 90打野战视频偷拍视频| 香蕉久久夜色| 母亲3免费完整高清在线观看| 中文亚洲av片在线观看爽| 69精品国产乱码久久久| 精品电影一区二区在线| 国产97色在线日韩免费| 久久精品aⅴ一区二区三区四区| 精品第一国产精品| 啦啦啦 在线观看视频| 91九色精品人成在线观看| 免费搜索国产男女视频| 精品一区二区三区视频在线观看免费|