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Chronic refractory wounds have been a challenge for clinical treatment because of their diverse causative factors and complex pathological processes, long healing times, and high treatment costs. The microenvironment of the wound surface includes the external microenvironment of the periwound surface, the internal microenvironment of the wound surface, and subsurface physiological structures. Research on clinical treatment strategies based on the microenvironment of chronic refractory wounds continues to innovate and make progress. Hydrogels have the advantages of high-water content, adjustable performance, good biocompatibility, and similarity to extracellular matrix. The ability of hydrogels to load drugs and their modification to confer excellent tissue adhesion, antibacterial, antioxidant, and modulation of inflammatory factor expression can be used to achieve a multi-factor response and modulation of the physical, chemical, and biological aspects of the trauma microenvironment. Therefore, hydrogels have outstanding advantages and clinical application prospects in the repair of chronic, difficult-to-heal wounds. In this review paper, the characteristics and etiology of chronic refractory wounds were introduced, and the classification of microenvironment-responsive hydrogels for chronic refractory wounds and their application in the repair of refractory wounds were reviewed. Besides, the shortcomings of current hydrogels were discussed, and an outlook was proposed.
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The biomimetic strategy of using the cell membrane-coated nanoparticles can retain the physical and chemical properties of the nanoparticles and show the biological characteristics of the source cell membrane, which can further enhance the role of the nanodrug in tumor treatment. A hybrid cell membrane is the fusion of two or more different types of cell membranes. A hybrid cell membrane can endow nanoparticles with multiple biofunctions derived from the source cells compared with a single cell membrane. Hybrid cell membranes provide a foundation to stimulate extensive research into multifunctional biomimetic nano-drug delivery system (NDDS), which is expected to broaden the application of biomimetic nanotechnology in drug delivery systems. In this review paper, the types of hybrid cell membrane used to construct nano-drug delivery systems, the preparation and characterization methods, and cancer treatment research progress in recent years were reviewed.
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Objective:To construct an aggregation induced emission (AIE) self-assembled probe based on glutathione (GSH) response covalent cyclization and evaluate it in vitro.Methods:The peptide sequence containing the 2-cyano-6-aminobenzothiazole-cysteine (CBT-Cys) condensation sequence was synthesized by the solid-phase peptide synthesis method. After coupling with an AIE molecule by click chemical reaction, an AIE self-assembled probe 1 based on GSH response covalent cyclization was constructed, and probe 2 lacking Cys structure was used as the control. The absorption and emission spectra of probes were tested and the specificity of probes to GSH was analyzed. The hydrodynamic diameter and structure of the probes after response were compared. The effects of different pH values, temperatures, probe concentrations, and GSH concentrations on fluorescence intensity were investigated. The toxicity of probes to tumor cells such as HeLa, HepG2 and MDA-MB-231 was evaluated.Results:After GSH response, the fluorescence of probe 1 was enhanced by about 6 times and that of probe 2 was enhanced by about 2 times; probe 1 was converted into a dimer with a hydrodynamic diameter of about 896.1 nm. Probe 2 lacked a cyclization motif and was converted into a monomer with a hydrodynamic diameter of about 427.4 nm. The fluorescence intensity of probe 1 was significantly higher than that of probe 2 at pH=7.0 and 37 ℃, and the toxicity of probes to tumor cells (HeLa, HepG2 and MDA-MB-231) was low.Conclusions:After the disulfide bond of probe 1 was reduced by GSH, the probe molecule lost the hydrophilic sequence, resulting in fluorescence turn-on (the first aggregation), and probe 1 immediately generates an AIE dimer (the second aggregation) because it contains a CBT-Cys cyclization sequence, which realizes the dual AIE effect compared with the single aggregation of probe 2, and significantly enhances the fluorescence emission. Probe 1 has better applicability in physiological environments, which provides an idea for in-situ generation of covalent cycling probes in vivo and is expected to be used in tumor imaging and treatment in the later stages.
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Objective:To explore the effect of photobiomodulation (PBM) combined with umbilical cord mesenchymal stem cell transplantation on motor function recovery in rats with spinal cord injury.Methods:The mesenchymal stem cells were irradiated with a laser energy density of 1.5, 3, 6 and 12 J/cm 2. The optimal energy density was screened by the MTT method on the 3rd day. Before cell transplantation, 32 male SD rats were randomly divided into the spinal cord injury group, which was injected with normal saline without cells; the stem cell transplantation group, which was injected with stem cells in the injury model; the laser irradiation group, which was injected with cell-free saline and laser irradiation; and the combined treatment group, which was treated with cell transplantation and laser irradiation. BBB score and inclined plate test were performed on the 1st, 3rd, 7th, 14th and 21st day, and hematoxylin-eosin staining and Nissl staining were performed on the 21st day. Results:The laser irradiation with an energy density of 12 J/cm 2 can accelerate cell proliferation ( P<0.05). After the modeling, the BBB score of the combined treatment group was higher than that of the other groups (all P<0.05), and the motor function recovered significantly. In the inclined plate experiment, the performance of the combined treatment group and the laser irradiation group was also better than that of other groups. The results of hematoxylin-eosin staining showed that the cavity area in the combined treatment group was significantly reduced, and the inflammatory reaction was the lightest. The staining of Nissl bodies became deeper, and the spinal cord injury was significantly reduced. Conclusions:PBM can promote the recovery of motor function in rats with spinal cord injury after the transplantation of umbilical cord mesenchymal stem cells, and has an obvious therapeutic effect on spinal cord injury in rats. This study provides a basis for the treatment of spinal cord injury.
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Oral squamous cell carcinoma (OSCC) has a high incidence of metastasis. Tumour immunotherapy targeting PD-L1 or PD-1 has been revolutionary; however, only a few patients with OSCC respond to this treatment. Therefore, it is essential to gain insights into the molecular mechanisms underlying the growth and metastasis of OSCC. In this study, we analysed the expression levels of protein kinase D3 (PKD3) and PD-L1 and their correlation with the expression of mesenchymal and epithelial markers. We found that the expression of PKD3 and PD-L1 in OSCC cells and tissues was significantly increased, which correlated positively with that of mesenchymal markers but negatively with that of epithelial markers. Silencing PKD3 significantly inhibited the growth, metastasis and invasion of OSCC cells, while its overexpression promoted these processes. Our further analyses revealed that there was positive feedback regulation between PKD3 and PD-L1, which could drive EMT of OSCC cells via the ERK/STAT1/3 pathway, thereby promoting tumour growth and metastasis. Furthermore, silencing PKD3 significantly inhibited the expression of PD-L1, and lymph node metastasis of OSCC was investigated with a mouse footpad xenograft model. Thus, our findings provide a theoretical basis for targeting PKD3 as an alternative method to block EMT for regulating PD-L1 expression and inhibiting OSCC growth and metastasis.
Subject(s)
Animals , Humans , Mice , B7-H1 Antigen/metabolism , Carcinoma, Squamous Cell , Cell Line, Tumor , Feedback , Head and Neck Neoplasms , Mouth Neoplasms , Protein Kinase C , STAT1 Transcription Factor , Squamous Cell Carcinoma of Head and NeckABSTRACT
Although the combination of surgery, radiotherapy and chemotherapy is the main methods of cancer treatment, it still fails to solve certain tumors, especially metastatic tumors. With the in-depth study of tumorigenesis and development mechanism, and the exploration and clinical application of tumor immunotherapy, the survival period of patients with malignant tumors has been significantly prolonged. Tumor immunotherapy has become an effective anti-tumor method by activating the body′s own immune system to achieve tumor suppression. The combination of chemotherapy and immunotherapy has a significant effect and has become a feasible solution for cancer treatment. The rationally designed nanomedicines can effectively combine chemical drugs and immunological preparations, and have become an effective delivery carrier basis and treatment means for clinically targeting tumor tissues, synergistic immune mechanisms to kill tumor cells, and treating tumors. In this paper, the types of multifunctional nanomedicines used in chemotherapy and various immunotherapies in recent years and their advantages in cancer therapy were reviewed.
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Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5-10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.
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Although the combination of surgery, radiotherapy and chemotherapy is the main methods of cancer treatment, it still fails to solve certain tumors, especially metastatic tumors. With the in-depth study of tumorigenesis and development mechanism, and the exploration and clinical application of tumor immunotherapy, the survival period of patients with malignant tumors has been significantly prolonged. Tumor immunotherapy has become an effective anti-tumor method by activating the body's own immune system to achieve tumor suppression. The combination of chemotherapy and immunotherapy has a significant effect and has become a feasible solution for cancer treatment. The rationally designed nanomedicines can effectively combine chemical drugs and immunological preparations, and have become an effective delivery carrier basis and treatment means for clinically targeting tumor tissues, synergistic immune mechanisms to kill tumor cells, and treating tumors. In this paper, the types of multifunctional nanomedicines used in chemotherapy and various immunotherapies in recent years and their advantages in cancer therapy were reviewed.
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As the outermost part,cornea plays a critical role in protecting the eyeball and functions as main component of the dioptric media. Trauma,inflammation,malnutrition,inherited diseases,tumors,contact lens problems and complications of refractive surgeries may cause corneal injury. However,there are still no perfect treatments for severe corneal damage. Progresses have been made in the research field of corneal stem cells in recent years. Epithelial stem cells play an important role in corneal wound healing, whereas the contribution of stromal and endothelial stem cells is less studied. Moreover, corneal cells differentiated from alternative cell sources have a brilliant prospect in transplantation. This article reviewed the recent research progress of stem cells in the corneal epithelial,stromal and endothelial wound healing.
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Bromodomain and extra-terminal domain(BET)Bromodomain has become a new target for the treatment of cancers and other human disorders. Nowadays,several classes of its potent and selective small-molecule inhibitors have been identified,many of which are in clinical trials. Preclinical and clinical data have shown that BET Bromodomain inhibitors have good prospects. Howev-er,there are potential therapeutic deficiencies,such as drug resistance. At present,attempts are being made to develop BET Bromodo-main inhibitors and degraders based on polypharmacology,combining BET Bromodomain with other targets of different mechanisms. In this paper,small-molecule kinase/BET inhibitors,small-molecule histone deacetylases(HDAC)/BET inhibitors and BET protein degraders are reviewed,which may provide guidance for further research on BET protein.
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Objective To study the biocompatibility of bone marrow mesenchymal stem cells (BMSCs) on acellular collagen matrix double-layer material.Methods BMSCs with acellular collagen matrix double-layer material were trained as experimental group,while separately cultured BMSCs as control group.The growth and proliferation of BMSCs on acellular collagen matrix double-layer material were investigated.Scanning electron microscope was used to observe the adherence of cells,and cell vitality was detected by CCK-8 method.Results The acellular collagen matrix double-layer material did not influence the growth and proliferation of BMSCs.The difference between the growth curves of experimental group and control group was not significant (P＞0.05).Conclusions The acellular collagen matrix double-layer material has acceptable biocompatibility.This research provides a scientific basis for the application of this composite material.
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Objective To study the radioresistance increased by low level laser irradiation (LLLI) in stem cells.Methods Umbilical cord mesenchymal stem cells (UC-MSCs) were divided into control group and experimental groups (LLLI only,γ-ray irradiation only and LLLI combined with γ-ray irradiation groups).635 nm (10 mW/cm2,12 J/cm2) laser irradiation was applied using for 3 days (twice a day),and cells were exposed in 2 Gy dose γ-ray irradiation on the third day.DNA injury was detected by alkaline single cell gel electrophoresis,reactive oxygen species (ROS),superoxide dismutase (SOD) and catalase (CAT) activity were valued using detection kits.Results DNA injury in LLLI combined with γ-ray irradiation group was lower than that in γ-ray irradiation exposed group,activity of oxidation stress kinases was enhanced,and level of ROS was inhibited.Conclusions Ironizing radioresistance of UC-MSCs can be increased after treatment of 635 nm LLLI,which will induce the radiation sensitivity of transplanting cells.
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@#Recognizing acetyl-lysine of histone is a key process of epigenetic regulation that is mediated by a protein module called bromodomain(BRD). The bromodomain inhibitors of the bromodomains and extra-terminal(BET)family have shown great potential in anti-inflammatory and antiproliferative effects. Through a review of diseases and structures about BET bromodomain, different kinds of inhibitors were analyzed and their structure-activity relationships were summarized. Herenin, the recent advances reported are reviewed for discovering more excellent small molecule inhibitors.
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Objective Folate receptors ( FRs) , overexpressed on the surface of a variety of tumor cells , are potential targets for tumor targeting therapy .This study aimed to prepare an FR-mediated drug nanocarrier with folate conjugated pullulan acetate ( FPA) to target chemotherapeutic agents to FR-overexpressed tumor cells and investigate its tumor-suppressing effect in vitro. Methods The cytotoxicity of epirubicin-loaded FPA nanoparticles ( FPA/EPI NP) against HepG2 and Hela cells was evaluated by MTS assay.The HepG2 and Hela cells were divided into five groups to be treated with NPs (NP control), chlorpromazine, chloro-quine, amiloride, and folate, respectively, followed by detection of the fluorescence intensity by flow cytometry . Results FPA/EPI NP was successfully formulated into NPs , with the mean particle size of (268.5 ±12.0) nm, by dialysis with an almost spherical shape . The drug-loading rate and entrapment rate of FPA/EPI NP were (6.45 ±1.04) and (72.45 ±11.50) %, respectively.The survival rates of the HepG2 and Hela cells were both >95%after 24 hours of incubation with FPA NP at 5, 40, 200, 400 and 1000μg/mL and 90.0%after 72 hours.The survival rates of the HepG2 cells treated with 5, 40, 200, 400 and 1000μg/mL FPA/EPI NP for 24 hours were (92.3 ±5.2), (70.4 ±4.6), (50.0 ±4.0), (41.1 ±4.1) and (27.0 ±3.6) %, respectively.Compared with the NP control group, the Hela cells of the chlorpromazine , amiloride and folate groups showed a significantly lower rate of NP uptake (P<0.05), and so did the HepG2 cells pretreated with chlorpromazine or amilo-ride (P<0.05).At 72 hours, the half maximal inhibitory concentrations (IC50) of FPA/EPI NP against HepG2 and Hela cells were 168 and 105μg/mL, respectively . Conclusion Clathrin-mediated endocytosis and macropinocytosis are involved in the internaliza-tion of FPA/EPI NP in HepG2 cells, while clathrin-and FR-mediated endocytosis in that of Hela cells .FPA NP may serve as a new drug carrier for tumor-targeted therapy .
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Objective To investigate the clinical effect and security of spraying Zhikang Capsules guided by gastroscopy in treatment elderly upper gastrointestinal bleeding.Methods Eighty-four elderly gastric duodenal ulcer bleeding patients were randomly assigned to group A,B and C (n =28 for each group).Patients in group A were used noradrenalin to spray with gastroscopy,in group B were used thrombin and in group C were used Zhikang Capsules.The total effective,the immediate homeostasis rate,the incidence of rebleeding,the emergency operation rate and the incidence of adverse reaction were recorded and analyzed.Results Total effective rate of group C was 96.4％ (27/28),significantly higher than that in group A (71.4％,20/28),B (75.0％,21/28) and the difference was significant(P＜0.05).The incidence of rebleeding in group A,B,C were 28.6％ (8/28),17.9％ (6/28),3.6％ (1/28) respectively,and the difference was significant (P ＜0.05).The same trend was seen regarding of the incidence of adverse reaction among three groups (25.0％,7/28;10.7％,3/28;0,0/28;P＜0.05).Conclusion Spraying Zhikang Capsules guided by gastroscopy is showed with good therapeutic effect in treating elderly upper gastrointestinal bleeding and high safety,and with less adverse reaction.
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Objective The dose and type of light and photosensitizer could seriously affect the curative effect of photodynamic therapy (PDT).The purpose of this study was to observe whether or not PDT with hematoporphyrin monomethyl ether (HMME) can cure laryngocarcinoma in the solid tumor model,and to define the proper laser amount for killing the cancer cells.Methods Forty eight BALB/c mouse models with subcutaneous Hep-2 laryngeal carcinomas were prepared.Mice were divided into six groups depending on the amount of laser received from 30 J/cm2 to 480 J/cm2 including a control group,tumor size in each group was between 8 mm and 10 mm.Tail vein injection were given with HMME prior to applying the laser light,and then illumination was carried out on the tumor at 3 h after HMME administration.Tumor volume,animal weight and histopathologic changes were observed after PDT.Results All mice apparently showed positive results via PDT,and the cancer had been cured in 120 J/cm2 and 480 J/cm2 groups.The laryngeal cancer lesions began to form scab 1 d after PDT and the scab became hard and black after 5 d.The tumor regression began simultaneously and completed around 30 d after PDT.Conclusions PDT may treat laryngeal cancers which sized less than 10 mm in mouse models.The optimum energy to destruct the laryngeal cancer cells may be 120 J/cm2.
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Objective To study the structure and function changes of erythrocyte in hypercholesterolemia rabbits that treated with irradiation in auricle root by low level 650 nm laser.Methods Sixteen male rabbits were selected to establish the model animal of hypercholesterolemia,successful model rabbits were divided into 2 groups (model and treatment groups),6 rabbits per group,and 6 normal rabbits were selected as control group.650 nm laser of 100 mW were given in auricle root in rabbits of treatment group for 16 weeks (6 d one week,twice a day,30 min one time).Blood from ear vein was collected every 4 weeks to perform routine and biochemical blood examination,and one-drop blood test under microscope was used for blood accumulation observation.Results Total number of red blood cells of treatment group decreased,while model group showed an increasing trend than normal group (P＜0.05).Hemoglobin in three groups were lower than other two groups (P＞0.05).Hematocrit (HCT) in treatment group were lower than that in normal group,while HCT in model group were higher than that in other two groups and showed a higher aggregation degree also.Less than model group,treatment group showed less aggregation degree but with higher total bilirubin.Conclusions Low level laser of 650 nm showed an effect on total number of erythrocytes,HCT and red blood cells aggregation,high dose of laser might be injury for erythrocytes and lead to total bilirubin increasement.
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Objective To investigate the effect of Zhikang capsules on treatment of gastric duodenal ulcer bleeding.Methods Eighty patients with gastric duodenal ulcer bleeding were randomly divided to therapy group(patients received Pantoprazole(20 mg) + Zhikang capsules(1.2 g),2 time/d,n =46) and control group (patients received Pantoprazole,20 mg,2 time/d,n =34).All treatment period was a week.The clinical efficacy were evaluated.Results The rate of total effective of therapy group was 95.7％ (44/46),and control group was 79.4％ (27/34).The difference was statistically significant (x2 =5.164,P ＜ 0.05).Conclusion Zhikang capsules is proved to be an efficacy drug to treatment of gastric duodenal ulcer bleeding,and with less adverse reaction.
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Objective To investigate the pharmacokinetic characteristics of PSD-007 in BN rats.Methods Blood of the BN rats was collected from the inner canthus after iv administration of PSD-007,and the plasma drug concentrations at different times were determined by fluorescent spectrometry.The best compartment model and the pharmacolinetic were calculated by the software of DNS 2.0.Results The elimination process of PSD-007 fitted three-compartment open model after iv administration.The principal pharmacokinetic parameters were t1/2α=0.096 h,t1/2β=1.299 h,t12γ=19.387 h,V1=0.259 L/kg,A UC=15.263 mg/(L ·h).Conclusions The sensitivity of fluorescent spectrometry was high and the operation is sinple and the progress is short.PSD-007 has fast absorption,quick effect and elimination without accumulation phenomenon.
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The steroidal enzyme cytochrome P45017alpha catalyzes the conversion of progesterone and pregnenolone into androgens, androstenedione and dehydroepiandrosterone, respectively, the direct precursors of estrogens and testosterone. Dihydrotestosterone is the principal active androgen in the prostate, testosterone is also an active stimulant of the growth of prostatic cancer tissue. Inhibition of this enzyme as a mechanism for inhibiting androgen biosynthesis could be a worthwhile therapeutic strategy for the treatment of PCA. In this paper, four categories of steroidal inhibitors of cytochrome P45017alpha will be reviewed, a diverse range of steroidal inhibitors had been synthesized and shown to be potent inhibitors of P45017alpha.