Lymphotoxins Promote the Progression of Human Lymphatic Malformation by Enhancing Lymphatic Endothelial Cell Proliferation.

Formation of inflammation-related tertiary lymphoid organs promotes human lymphatic malformation (LM) development. However, the role of lymphotoxins (LTs) and LT-related inducible ligand, the crucial mediators for tertiary lymphoid organ formation, is undetermined in LMs. Herein, we show that LTs and LT-related inducible ligand promote LM development by enhancing lymphatic endothelial cell (LEC) proliferation via activating NF-κB pathways. The expression of LTs and their receptors was increased in LMs, especially the infected ones, when compared with normal skins. Nuclear translocation of p65, p52, and RelB in the LECs of LMs indicated the activation of classic and alternative NF-κB pathways. Pearson's correlation and cluster analysis suggested the close relationship between LEC proliferation and NF-κB activation. Moreover, in vitro data demonstrated LTs accelerated the proliferation of human dermal LECs (HdLECs) through activation of NF-κB. In addition, lipopolysaccharide (LPS) up-regulated LT receptor expression in HdLECs, leading to increased sensitivity to LTs. Suppression of LT receptors hampered LPS-enhanced HdLEC proliferation, indicating the crucial role of LT pathways in inflammatory lymphangiogenesis. Besides, evidence from the LM rat models demonstrated LTα and LPS enhanced LEC proliferation, therefore promoting LM development. Blocking LT pathways by neutralizing antibodies against LTα and lymphotoxin ß receptor may decelerate the growth of the disease. In summary, our present study demonstrated activation of LT signaling pathways in LECs contributed to the progression of LMs.

A Double-Lobe Flap Design Combined Nasolabial Advancement and Infraorbital Rotation for Reconstruction of Infraorbital Defect.

Various adjacent flaps have been designed to close infraorbital defect, and each of them is trying to get an aesthetic outcome and meanwhile circumvent eyelid retraction, ectropion, and functional disability. Here, the authors report an adjacent double-lobe flap, which took advantage of nasolabial advancement and infraorbital rotation of the 2 lobes, combinatorially closed a pentagon infraorbital defect by removal of 2 small skin paddles as donor sites, and finally yielded an acceptable aesthetic and functional outcome. This flap may be a new option for closure of polygon infraorbital defects.

Spatiotemporal characteristics of tissue derived small extracellular vesicles is associated with tumor relapse and anti-PD-1 response.

Small extracellular vesicles (sEVs) residing at tumor tissues are valuable specimens for biopsy. Tumor heterogeneity is common across all cancer types, but the heterogeneity of tumor tissue-derived sEVs (Ti-sEVs) is undefined. This study aims to discover the spatial distributions of Ti-sEVs in oral squamous cell carcinoma (OSCC) tissues and explore how these vesicle distributions affect the patients' prognosis. Multi-regional sampling enabled us to uncover that Ti-sEVs' accumulation at peritumoral sites correlates with a higher disease-free survival rate, and conversely, sparse peritumoral Ti-sEVs tend to forecast a higher risk of relapse. Of those relapsed patients, Ti-sEVs strongly bind to extracellular matrix and subsequently degrade it for allowing themselves enter the bloodstream rather than staying in situ. In advanced OSCC patients, the quantity and spatial distribution of Ti-sEVs prior to anti-PD-1 treatment, as well as the temporal variance of Ti-sEVs before and after immunotherapy, strongly map the clinical response and can help to distinguish the patients with shrinking tumors from those with growing tumors. Our work elucidates the correlation of spatiotemporal features of Ti-sEVs with patients' therapeutic outcomes and exhibit the potential for using Ti-sEVs as a predictor to forecast prognosis and screen the responders to anti-PD-1 therapy.

A retrospective study of the malignant change of odontogenic keratocyst.

The odontogenic keratocyst (OKC) is a common cystic lesion of the maxilla and mandible. Squamous cell carcinoma (SCC) arising from OKC or dysplasia occurring in OKC is rare. This study aimed to explore the incidence and clinical features of the dysplasia and malignant transformation of OKC. In this study, 544 patients diagnosed with OKC were collected. Among them, 3 patients were diagnosed as SCC arising from OKC, and 12 patients were diagnosed as OKC with dysplasia. The incidence was calculated. Clinical features were analyzed by chi-square test. In addition, a representative case reconstructing mandible with vascularized fibula flap under general anesthesia was reported. And cases reported before were reviewed. The incidence of the dysplasia and malignant transformation of OKC, which are highly associated with the clinical features of swelling and chronic inflammation, is about 2.76%. But the relevance between the dysplasia and malignant transformation and age, gender together with pain is not statistically high. All in all, the clinical features of swelling and chronic inflammation can be considered as characteristics of the dysplasia and malignant transformation of OKC. Although the pain isn't statistically relevant, it may be a dangerous clew. Also, combined with earlier literatures, the dysplasia and malignant transformation of OKC shows unique features of radiographs and histopathology.

Myofascial iliac crest flap for reconstruction of combined oral mucosa-mandibular defects: A single-centre experience.

BACKGROUND: Deep circumflex iliac artery (DCIA) myofascial iliac crest flap has been used for combined oral mucosa-mandibular defects reconstruction. The bone component of this composite flap can reconstruct the mandible with superior contour match, and the muscle fascia which used for repairing the oral mucosa defect will transform into an oral mucosa-like appearance. To explore its scope of clinical application and how the fascia transformed into oral mucosa will give surgeons flexibility to reconstruct the combined oral mucosa-mandibular defects. METHODS: A retrospective review of 18 patients who received combined oral mucosa-mandibular defects reconstruction with DCIA myofascial iliac crest flaps from Dec 2016 to Dec 2020 was performed. The characteristics of the mandibular defects and the flaps were recorded. The postoperative dynamic changes of one graft's fascia were observed from serial photographs. RESULTS: All myofascial iliac crest flaps survived successfully. The bone grafts were from 4.0 to 9.5 cm (mean 7.6 ± 1.5 cm) in length and from 2.0 to 3.5 cm (mean 2.7 ± 0.4 cm) in height. The sizes of fascia were from 13.5 to 48.0 cm2 (mean 27.2 ± 9.4 cm2). The grafted fascia firstly changed into a yellow pseudomembrane-like appearance, and then experienced muscle oedema before finally transformed into an oral mucosa-like appearance at about 60 days after operation. CONCLUSION: Myofascial iliac crest flap is a good option for reconstruction of combined oral mucosa-mandibular defects because of its excellent bone and oral mucosa matches.

Effect of Strain Rates on Failure of Mechanical Properties of Lumbar Intervertebral Disc Under Flexion.

OBJECTIVE: To evaluate the strain-rate-dependent viscoelastic properties of the intervertebral disc by in vitro experiments. METHOD: The biomechanical experiments were conducted from September 2019 to December 2019. The lumbar spines of sheep were purchased within 4-6 hours from the local slaughterhouse, and the intervertebral disc samples were divided into three groups. In rupture group, the samples were used to test the mechanical behavior of the intervertebral disc rupture at different strain rates. In fatigue injury group, the samples were used to test the mechanical behavior of fatigue injury on the intervertebral disc under different strain rates. In internal displacement group, the samples were used to test the internal displacement distribution of the intervertebral disc at different strain rates by applying an optimized digital image correlation (DIC) technique. RESULTS: Both the yielding and cracking phenomenon occurs at fast and medium loading rates, while only the yielding phenomenon occurs at a slow loading rate. The yield stress, compressive strength, and elastic modulus all increase with the increase of the strain rate, while the yield strain decreases with the increase of the strain rate. The logarithm of the elastic modulus in the intervertebral disc is approximately linear with the logarithm of the strain rate under different strain rates. Both before and after fatigue loading, the stiffness in the loading and unloading curves of the intervertebral disc is inconsistent, forming a hysteresis loop, which is caused by the viscoelastic effect. The strain rate has no significant effect on the internal displacement distribution of the intervertebral disc. Based on the experimental data, the constitutive relationship of the intervertebral disc at different strain rates is obtained. The fitting curves are well coupled with the experimental data, while the fitting parameters are approximately linear with the logarithm of the strain rate. CONCLUSIONS: These experiments indicate that the strain rate has a significant effect on the mechanical behavior of the intervertebral disc rupture and fatigue injury, while the constitutive equation can predict the rate-dependent mechanical behavior of lumbar intervertebral disc under flexion very well. These results have important theoretical guiding significance for preventing lumbar disc herniation in daily life.

Comprehensive evaluation of wild Cordyceps cicadae from different geographical origins by TOPSIS method based on the macroscopic infrared spectroscopy (IR) fingerprint.

Cordyceps cicadae is an entomogenous fungus that has been used as a valuable traditional Chinese herbal tonic, however, it can be difficult to discern the false from the genuine. In this study, the macroscopic IR fingerprint methods containing Fourier transform infrared spectroscopy (FT-IR) and second derivative infrared spectroscopy (SD-IR) were used to elucidate wild C. cicadae. The TOPSIS (Technique for Order Preference by Similarity to Ideal Solution) method was used to comprehensively evaluate C. cicadae from different geographical origins based on the macroscopic infrared spectroscopy (IR) fingerprint. The FT-IR spectra of C. cicadae exhibited the major characteristics of the absorptive peaks of carbohydrates, lipids and nucleosides at the position of 3291, 2925, 2845, 1651, 1547, 1455, 1080 and 950 cm-1. The high resolution of SD-IR further amplified the difference and revealed the potentially characteristic IR absorption spectrum. TOPSIS evaluation showed that C. cicadae from Anhui possess the strongest intensity of absorption bands among all the samples. Notably, FT-IR combined with SD-IR can effectively reveal the overall chemical components without damaging medicinal materials, and TOPSIS methods can provide a novel scientific evidence for comprehensively assessing different origins of wild C. cicadae.

Jatrorrhizine inhibits colorectal carcinoma proliferation and metastasis through Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition.

PURPOSE: Jatrorrhizine (JAT) is a natural protoberberine alkaloid, possesses detoxification, bactericidal and hypoglycemic activities. However, its anti-cancer mechanism is not clear. This study aimed to investigate the mechanism of JAT through which inhibits colorectal cancer in HCT-116 and HT-29 cells. METHODS: MTT assay and colony formation assay were used to check the cell proliferation ability. Cell apoptosis and cell cycle were measured by Hoechst 33342 staining and flow cytometry, respectively. Cell migration and invasion were detected by scratch wound healing assay and trans-well assay, respectively. Further, expression of related proteins was examined via Western blotting and the in vivo anti-cancer effect of JAT was confirmed by nude mice xenograft model. RESULTS: The research showed that JAT inhibited the proliferation of HCT-116 and HT-29 cells with IC50 values of 6.75±0.29 µM and 5.29±0.13 µM, respectively, for 72 hrs. It has also showed a time dependently, cell cycle arrested in S phase, promoted cell apoptosis and suppressed cell migration and invasion. In addition, JAT inhibited Wnt signaling pathway by reducing ß-catenin and increasing GSK-3ß expressions. Increased expression of E-cadherin, while decreased N-cadherin, indicating that JAT treatment suppressed the process of cell epithelial-mesenchymal transition (EMT). In HCT-116 nude mice xenograft model, JAT inhibited tumor growth and metastasis, and induced apoptosis of tumor cells. CONCLUSION: This study demonstrated that JAT efficiently inhibited colorectal cancer cells growth and metastasis, which provides a new point for clinical treatment of colorectal cancer.

[Start-up of Combined Floc-granule CANON Process and the Effects of SRT on Reactor Performance].

To shorten the start-up time of CANON process and guide the sludge dischargement in the practical project, the start-up of CANNON process and influence of different flocs SRT were studied by inoculation ANAMMOX granules of different proportions in two same specifications of SBR reactor. During the experiment, the temperature was controlled at 30℃±1℃ and pH was 7-8. The results showed that it was not good for CANON process rapid start-up when the two reactors were inoculated with 5% and 10% ANAMMOX granules respectively and the initial FA concentration exceeded 44 mg·L-1. When the two reactors were inoculated with 5% and 10% ANAMMOX granular sludge, the reactors were started-up successfully on Day 46 and Day 35, respectively. When the flocs SRT was maintained at 30 d, 90 d and un-initiative discharge respectively, the average total nitrogen removal rate could reach 0.35 kg·(m3·d)-1 stably. The quantitative PCR results of the three different flocs SRT showed that with increasing flocs SRT, the abundance of AOB was relatively stable, the abundance of ANAMMOX increased slightly, while the abundance of NOB significant increased. Therefore, it is necessary to elutriate flocs from reactor for decreasing the quantity of NOB and long-term stable operation of the CANON process.

[Start-up of Granule CANON Process and the Strategy for Enhancing Total Nitrogen Removal Rate].

To shorten the start-up time of the CANON granular sludge process and improve the total nitrogen removal rate in the engineering, the start-up method of CANON granular sludge process and the strategy for enhancing the total nitrogen removal rate were studied in an SBR reactor. During the experiment, the temperature was controlled at 30℃±1℃ and the pH was 7-8, the aeration rate and settling time were operated according to the sludge properties and effect of nitrogen removal. The results showed that the transition of the sludge properties from combined floc-granule to granule was realized after 55 d. The total nitrogen removal rate reached 0.32 kg·(m3·d)-1 and remained stable after 117 d, thus the reactor was started up successfully. With constant improvement of the aeration rate, the average NRR was maintained at 1.35 kg·(m3·d)-1 after 77 d and improvement of the process load was achieved. The results showed that there was good correlation between the NRR and DO, therefore, the NRR can be determined by observing the DO and the process can be maintained stably.

[Stability of the CANON Process Based on Real-Time Control Technologies].

In order to achieve the optimization of the CANON process, ensuring the stability of water quality and increasing the removal rate of ammonia nitrogen, the stability of CANON process water quality under real-time control was studied in the SBR reactor. During the experiment, the temperature was controlled at 30℃±1℃ and the pH was 7-8, based on the corresponding relationship between indirect parameters and nitrogen pollutants, the real-time control strategy was formulated. The results showed that when the influent ammonia nitrogen concentration was 917-1540 mg·L-1, the residual ammonia nitrogen concentration of 6 mg·L-1 can be used as the control parameter to meet the requirements of process stability but the ammonia nitrogen sensor had many problems such as high costs and large errors. The characteristic points and platforms of pH, DO, and ORP value can be the automatic control parameters, which can maintain the long-term stable operation of the CANON process and ensure that the average ammonia nitrogen removal rate is above 99% and the effluent quality is stable.

Down-regulation of polycystin in lymphatic malformations: possible role in the proliferation of lymphatic endothelial cells.

Lymphatic malformations (LMs) are composed of aberrant lymphatic vessels and regarded as benign growths of the lymphatic system. Recent studies have demonstrated that the mutant embryos of PKD1 and PKD2, encoding polycystin-1 (PC-1) and polycystin-2 (PC-2), respectively, result in aberrant lymphatic vessels similar to those observed in LMs. In this study, for the first time, we investigated PC-1 and PC-2 expression and assessed their roles in the development of LMs. Our results demonstrated that PC-1 and PC-2 gene and protein expressions were obviously decreased in LMs compared with normal skin tissues. In addition, the expression of phosphorylated ERK but not total ERK was up-regulated in LMs and negatively correlated with the expression of PC-1 and PC-2. Moreover, up-regulation of Ki67 was detected in LMs and positively correlated with ERK phosphorylation levels. Furthermore, cluster analysis better reflected close correlation between these signals. All of the above results provided strong evidence suggesting that the hyperactivation of the ERK pathway may be caused by down-regulation of PC-1 and PC-2 in LMs, contributing to increased proliferation of lymphatic endothelial cells in LMs. Our present study sheds light on novel potential mechanisms involved in LMs and may help to explore novel treatments for LMs.

Downregulation of miR-145 in venous malformations: Its association with disorganized vessels and sclerotherapy.

Venous malformations (VMs) are characterized by ectatic and tortuous venous channels with decreased perivascular cell coverage. Recent studies have discovered that miR-145 plays a critical role in amounts of vascular diseases through regulating the differentiation and phenotype of vascular smooth muscle cells (VSMCs). However, the potential roles of miR-145 in VMs remain unknown. In this study, 21 samples of VMs without treatment history, and 10 samples of healthy donor skin, were collected to evaluate the expression level of TGF-ß, miR-145, and α-SMA by immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction (PCR). Subsequently, their correlations were analyzed using the Spearman rank correlation test. In vitro studies were performed using human umbilical vein endothelial cells (HUVECs). The results showed that miR-145 was significantly downregulated in VMs compared with normal skin tissues, accompanied by a synchronously decreased TGF-ß expression level and perivascular α-SMA+ cell coverage. Correlation analysis revealed that miR-145 expression was positively correlated with TGF-ß expression and perivascular α-SMA+ cell coverage in VMs. In addition, TGF-ß, miR-145, and α-SMA were concurrently increased in the tissues of VMs treated with bleomycin A5. More importantly, in vitro studies revealed that both recombinant human TGF-ß and bleomycin A5 could significantly upregulate TGF-ß and miR-145 expression in HUVECs with the similar increasing tendency. In summary, our present study unmasked the downregulation of miR-145 in VMs, possibly induced by TGF-ß depression and closely correlated with disorganized vessels. Moreover, miR-145 may be involved in the sclerotherapy of VMs and possess the target potential.

Isaria cicadae conidia possess antiproliferative and inducing apoptosis properties in gynaecological carcinoma cells.

Isaria cicadae is an entomogenous fungus that has been used as a traditional Chinese medicinal materials to treat different diseases, including cancer. However, Isaria cicadae conidia for inhibitory activity against breast cancer cells growth are still not systematically studied. The present aim was to elucidate the phytochemical composition of Isaria cicadae conidia and to explore relevant anti-cancer potential in gynaecological carcinoma MCF-7 and Hela cells. Isaria cicadae conidia were identified by UPLC-ESI-Q-TOF-MS: high performance liquid chromatography-electrospray/quadrupole time of flight tandem mass spectrometry technology. Eight main compounds were identified which are nucleosides, cordycepic acid, cordycepin, beauvericin and myriocin by MS fragmentation ions. The nuclear morphology indicated the typical characteristics of apoptosis by Hoechst staining. Annexin V/PI staining revealed that the number of apoptotic cells was increased by Isaria cicadae conidia treatment. Furthermore, Isaria cicadae conidia also induced the caspase-mediated mitochondrial apoptosis pathway. The findings suggest that the full-scale active ingredients highlight the significance of Isaria cicadae conidia as potential anti-cancer agent in China.

Targeting adeno-associated virus and adenoviral gene therapy for hepatocellular carcinoma.

Human hepatocellular carcinoma (HCC) heavily endangers human heath worldwide. HCC is one of most frequent cancers in China because patients with liver disease, such as chronic hepatitis, have the highest cancer susceptibility. Traditional therapeutic approaches have limited efficacy in advanced liver cancer, and novel strategies are urgently needed to improve the limited treatment options for HCC. This review summarizes the basic knowledge, current advances, and future challenges and prospects of adeno-associated virus (AAV) and adenoviruses as vectors for gene therapy of HCC. This paper also reviews the clinical trials of gene therapy using adenovirus vectors, immunotherapy, toxicity and immunological barriers for AAV and adenoviruses, and proposes several alternative strategies to overcome the therapeutic barriers to using AAV and adenoviruses as vectors.

Mesenchymal status of lymphatic endothelial cell: enlightening treatment of lymphatic malformation.

In contrast to blood capillaries, lymphatic capillaries in peripheral tissues are composed of a single-cell layer of lymphatic endothelial cells (LECs) without a covering of mural cells. However, in lymphatic malformations, the enlarged lymphatic vessels were covered with mural cells. This study aimed to understand the molecular mechanism of differences between human dermal lymphatic endothelial cells (HDLECs) and human umbilical vein endothelial cells (HUVECs) and to determine the changes of LECs in the pathological condition of lymphatic malformation. Results showed that HDLECs exhibited lower expression of endothelial proteins, including VE-cadherin and CD31, than HUVECs; HDLECs also showed higher expression of mesenchymal proteins, including α-SMA, SM22α, calponin, and epithelial mesenchymal transition-related transcription factor Slug, than HUVECs. Likewise, HDLECs displayed higher permeability and weaker recruitment of SMCs than HUVECs; HDLECs also exhibited low PDGF-BB expression. TGF-ß2 treatment and FGF2 depletion enhanced mesenchymal marker expression with increased permeability and reduced SMC recruitment. By contrast, Slug depletion in HDLECs enhanced VE-cadherin expression, inhibited α-SMA expression, decreased permeability, and enhanced PDGF-BB expression. These results suggested that HDLECs were in a mesenchymal status, which contributed to their functions and might determine their identities. Our data also revealed that miR143/145 was implicated in the mesenchymal status of HDLECs. In lymphatic malformations (LMs) treated with OK-432 sclerotherapy, immunohistochemistry results showed that Prox1 expression was reduced and mural cell investment was increased; these results indicated that LECs lost their mesenchymal status after OK-432 treatment was administered. The decreased mesenchymal status of LECs in LMs may induce dilated vessel constriction, which could be the mechanism of OK-432 sclerotherapy.

Effect of fatigue load on internal mechanical properties of the intervertebral disc / Efecto de la carga de fatiga en las propiedades mecánicas internas del disco intervertebral

SUMMARY: Lumbar disc herniation is considered to be the main pathological factor for the common clinical disease of low back pain. Biomechanical factor is an important cause of lumbar disc herniation, so it is urgent to analyze the stress/strain behavior of intervertebral disc under different loading condition. Slow repetitive loading is considered to be an important factor of spine and disc injuries, and the effect of fatigue load on internal displacement in the intervertebral disc was investigated by applying the optimized digital image correlation technique in this study. The first finding was that fatigue load had a significant effect on the displacement distribution in the intervertebral disc under compression. Superficial AF exhibited the largest axial displacements before fatigue load, while it exhibited the smallest axial displacements after fatigue load. Inner AF exhibited slightly smaller radial displacements than outer AF before fatigue load, while it exhibited significantly greater radial displacements than outer AF displacements after fatigue load. The second finding was that fatigue load had a certain effect on the internal displacement distribution in the flexed intervertebral disc under compression. Middle AF exhibited the smallest axial displacements before fatigue load, while deep AF exhibited the smallest axial displacements after fatigue load. The radial displacement distribution did not change before and after fatigue load, as the radial displacement in outer AF was the smallest, while the radial displacement in inner AF was the largest. The third finding was that with the increase in fatigue time and amplitude, the Young's modulus of the intervertebral disc increased significantly. This study can provide the basis for clinical intervertebral disc disease prevention and treatment? and is important for mechanical function evaluation of artificial intervertebral disc as well.

RESUMEN: La hernia de disco lumbar se considera el principal factor patológico para la enfermedad clínica común del dolor lumbar. El factor biomecánico es una causa importante de hernia de disco lumbar, por lo que es urgente analizar el comportamiento de esfuerzo / tensión del disco intervertebral bajo diferentes condiciones de carga. La carga repetitiva lenta se considera un factor importante de lesiones de columna y disco, y en este estudio el efecto de la carga de fatiga sobre el desplazamiento interno en el disco intervertebral se investigó mediante la aplicación de la técnica de correlación de imagen digital optimizada. El primer hallazgo fue que la carga de fatiga tuvo un efecto significativo en la distribución del desplazamiento en el disco intervertebral bajo compresión. El AF superficial exhibió los desplazamientos axiales más grandes antes de la carga de fatiga, mientras que exhibió los desplazamientos axiales más pequeños después de la carga de fatiga. El AF interno exhibió desplazamientos radiales ligeramente más pequeños que el AF externo antes de la carga de fatiga, mientras que exhibió desplazamientos radiales significativamente mayores que los desplazamientos AF externos después de la carga de fatiga. El segundo hallazgo fue que la carga de fatiga tenía un cierto efecto sobre la distribución del desplazamiento interno en el disco intervertebral flexionado bajo compresión. El AF medio exhibió los desplazamientos axiales más pequeños antes de la carga de fatiga, mientras que el AF profundo exhibió los desplazamientos axiales más pequeños después de la carga de fatiga. La distribución del desplazamiento radial no cambió antes ni después de la carga de fatiga, ya que el desplazamiento radial en la FA externa fue el más pequeño, mientras que el desplazamiento radial en la FA interna fue el más grande. El tercer hallazgo fue que con el aumento del tiempo de fatiga y la amplitud, el módulo de Young del disco intervertebral aumentó significativamente. Este estudio puede proporcionar la base para la prevención y el tratamiento clínico de la enfermedad del disco intervertebral, y también es importante para la evaluación de la función mecánica del disco intervertebral artificial.

Tetrandrine and fangchinoline, bisbenzylisoquinoline alkaloids from Stephania tetrandra can reverse multidrug resistance by inhibiting P-glycoprotein activity in multidrug resistant human cancer cells.

The overexpression of ABC transporters is a common reason for multidrug resistance (MDR) in cancer cells. In this study, we found that the isoquinoline alkaloids tetrandrine and fangchinoline from Stephania tetrandra showed a significant synergistic cytotoxic effect in MDR Caco-2 and CEM/ADR5000 cancer cells in combination with doxorubicin, a common cancer chemotherapeutic agent. Furthermore, tetrandrine and fangchinoline increased the intracellular accumulation of the fluorescent P-glycoprotein (P-gp) substrate rhodamine 123 (Rho123) and inhibited its efflux in Caco-2 and CEM/ADR5000 cells. In addition, tetrandrine and fangchinoline significantly reduced P-gp expression in a concentration-dependent manner. These results suggest that tetrandrine and fangchinoline can reverse MDR by increasing the intracellular concentration of anticancer drugs, and thus they could serve as a lead for developing new drugs to overcome P-gp mediated drug resistance in clinic cancer therapy.

pH-responsive mesoporous silica nanocarriers based on layer-by-layer self-assembly.

Significant progress has been achieved in the field of pH-sensitive drug delivery system in recent years. For layer-by-layer self-assembly nanocarriers, various pH values can induce the change of permeability and structural stability of the outer polyelectrolyte multi-layers, resulting in the release of the loaded drug. In the present study, carboxyl-modified mesoporous silica nanoparticles (MSNs-COOH) were prepared as reservoirs to hold model cargo, i.e. Rhodamine B (RhB). Polycations, including 1, 4-butanediamine (BDA)-modified linear poly (glycerol methacrylate) (L-B) or BDA-modified star-shaped poly (glycerol methacrylate) (S5-B) and 1,2-ethanediamine (EDA)-modified star-shaped poly (glycerol methacrylate) (S5-E), and polyanion, i.e. poly (acrylic acid) (PAA), are self-assembled by electrostatic interactions as coating. The loading process of RhB was characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, thermo-gravimetric analysis, and dynamic light scattering, and the release of RhB was controlled by changing the pH of phosphate buffer saline. The results showed that the loading capacity and entrapment efficiency of RhB were the highest for S5-B/PAA, which were 10.1% and 44.4%, respectively. In addition, the release of RhB was about 90% at pH 2.0 and 35% at pH 7.4, which was indicative of obvious pH-responsivity. The MSNs-COOH coated by S5-B/PAA proposed in the present study show potential applications in targeted drug delivery.