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Hepatocellular carcinoma is a malignant tumor with high morbidity and mortality, a highly effective treatment with low side effects and tolerance is needed. Photothermal immunotherapy is a promising treatment combining photothermal therapy (PTT) and immunotherapy. PTT induces the release of tumor-associated antigens by ablating tumor and Ganoderma lucidum polysaccharides (GLP) enhance the antitumor immunity. Results showed that Indocyanine Green (ICG) was successfully encapsulated into SF-Gel. ICG could convert light to heat and SF-Gel accelerates the photothermal effect in vitro and in vivo. PTT based on ICG/ICG-SF-Gel inhibited the growth of primary and distal tumors, GLP enhanced the inhibitory efficacy. ICG/ICG-SF-Gel-based PTT and GLP immunotherapy improved the survival time. ICG/ICG-SF-Gel-based PTT induces tumor necrosis and GLP enhanced the photothermal efficacy. ICG/ICG-SF-Gel-based PTT inhibited cell proliferation and angiogenesis, induced cell apoptosis, enhanced cellular immunity, and GLP enhanced these effects. In conclusion, GLP could enhance the abscopal effect of PTT in Hepatoma-bearing mice. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus. The combination of insulin (Ins) with liraglutide (Lir) has a greater potential for preventing DN than monotherapy. However, the renal protective effect of the combined Ins/Lir therapy is largely compromised due to their short half-lives after subcutaneous injection. Herein, a glucose-responsive hydrogel was designed in situ forming the dynamic boronic esters bonds between phenylboronic acid-grafted γ-Polyglutamic acid (PBA-PGA) and konjac glucomannan (KGM). It was hypothesized that the KGM/PBA-PGA hydrogel as the delivery vehicle of Ins/Lir would enhance the combinational effect of the latter on preventing the DN progress. Scan electronic microscopy and rheological studies showed that KGM/PBA-PGA hydrogel displayed good glucose-responsive property. Besides, the glucose-sensitive release profile of either Ins or Lir from KGM/PBA-PGA hydrogel was uniformly displayed at hyperglycemic level. Furthermore, the preventive efficacy of KGM/PBA-PGA hydrogel incorporating insulin and liraglutide (Ins/Lir-H) on DN progress was evaluated on streptozotocin-induced rats with diabetic mellitus (DM). At 6 weeks after subcutaneous injection of Ins/Lir-H, not only the morphology of kidneys was obviously recovered as shown by ultrasonography, but also the renal hemodynamics was significantly improved. Meanwhile, the 24-h urinary protein and albumin/creatinine ratio were well modulated. Inflammation and fibrosis were also largely inhibited. Besides, the glomerular NPHS-2 was obviously elevated after treatment with Ins/Lir-H. The therapeutic mechanism of Ins/Lir-H was highly associated with the alleviation of oxidative stress and activation of autophagy. Conclusively, the better preventive effect of the combined Ins/Lir via KGM/PBA-PGA hydrogel on DN progress was demonstrated as compared with their mixed solution, suggesting KGM/PBA-PGA hydrogel might be a potential vehicle of Ins/Lir to combat the progression of DN. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Image, graphical abstract Macrophage polarization is one of the main factors contributing to the proinflammatory milieu of transplanted islets. It causes significant islet loss. Bilirubin exhibits protective effects during the islet transplantation process, but the mode of delivering drugs along with the islet graft has not yet been developed. In addition, it remains unclear whether bilirubin or its derivatives can modulate macrophage polarization during islet transplantation. Therefore, this study aimed to develop an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets for protection and to explore its macrophage modulation activities. In in vitro studies, the PLL-BR was shown to tightly adhere to the islet surface. It also exhibited enhanced cytoprotective effects against oxidative and inflammatory conditions by promoting M2-type macrophage polarization. In i n vivo studies, the PLL-BR-protected islets successfully prolonged the euglycemia period in diabetic mice and accelerated the blood glucose clearance rate by maintaining the insulin secretion function. Compared to the untreated islets, the PLL-BR-encapsulated islets induced anti-inflammatory responses that were characterized by elevated levels of M2 macrophage markers and local vascularization. In conclusion, PLL-BR can be used as a tool for reprograming macrophage polarization while providing a more efficient immune protection for transplanted islets. Macrophage polarization is one main factor that caused significant loss of transplanted islets. Bilirubin possesses protective effects toward pancreatic islet, but how to deliver the drug along with the islet graft has not yet been harnessed. More importantly, whether bilirubin or its derivatives could modulate macrophage polarization during the host rejections has also not been answered. In this study, we developed an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets and explore its role in macrophage modulation activities. PLL-BR could attach to the surface of islets and exerted high oxidation resistance and anti-inflammatory effect. For the first time, we demonstrate that bilirubin and its derivatives effectively promoted the M2-type macrophage polarization, and optimize the immune microenvironment for islets survival and function. [ABSTRACT FROM AUTHOR]

Bone repair and regeneration processes are markedly impaired in diabetes mellitus (DM). Intervening approaches similar to those developed for normal healing conditions have been adopted to combat DM-associated bone regeneration. However, limited outcomes were achieved for these approaches. Hence, together with osteoconductive hydroxyapatite (HA) nanocrystals, osteoinductive magnesium oxide (MgO) nanocrystals were uniformly mounted into the network matrix of an organic hydrogel composed of cysteine-modified γ-polyglutamic acid (PGA-Cys) to construct a hybrid and rough hydrogel scaffold. It was hypothesized that the HA/MgO nanocrystal hybrid hydrogel (HA/MgO-H) scaffold can significantly promote bone repair in DM rats via the controlled release of Mg2+. The HA/MgO-H scaffold exhibited a sponge-like morphology with porous 3D networks inside it and displayed higher mechanical strength than a PGA-Cys scaffold. Meanwhile, the HA/MgO-H scaffold gradually formed a tough hydrogel with G′ of more than 1000 Pa after hydration, and its high hydration swelling ratio was still retained. Moreover, after the chemical degradation of the dispersed MgO nanocrystals, slow release of Mg2+ from the hydrogel matrix was achieved for up to 8 weeks because of the chelation between Mg2+ and the carboxyl groups of PGA-Cys. In vitro cell studies showed that the HA/MgO-H scaffold could not only effectively promote the migration and proliferation of BMSCs but could also induce osteogenic differentiation. Moreover, in the 8th week after implanting the HA/MgO-H scaffold into femur bone defect zones of DM rats, more effective bone repair was presented by micro-CT imaging. The bone mineral density (397.22 ± 16.36 mg cm−3), trabecular thickness (0.48 ± 0.07 mm), and bone tissue volume/total tissue volume (79.37 ± 7.96%) in the HA/MgO-H group were significantly higher than those in the other groups. Moreover, higher expression of COL-I and OCN after treatment with HA/MgO-H was also displayed. The bone repair mechanism of the HA/MgO-H scaffold was highly associated with reduced infiltration of pro-inflammatory macrophages (CD80+) and higher angiogenesis (CD31+). Collectively, the HA/MgO-H scaffold without the usage of bioactive factors may be a promising biomaterial to accelerate bone defect healing under diabetes mellitus. [ABSTRACT FROM AUTHOR]

Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of –10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery. [ABSTRACT FROM AUTHOR]

Didymin is a dietary flavonoid that first found in citrus fruits, and possesses antioxidant properties. Our preliminary experiments first discovered that didymin was able to sensitize the resistant cancer cells against chemotherapeutics and combat multidrug resistance. However, its poor aqueous solubility and resultant low bioavailability limit its potentials as an adjuvant phytochemical drug for chemotherapy. Thus, this study prepared the inclusion complex of didymin with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin to improve its bioavailability and then evaluate their chemosensitization effects. The didymin inclusion complexes formulation was prepared and their host-guest structure was characterized by FT-IR, PXRD, DSC, and SEM techniques. In vitro/in vivo results demonstrated that didymin inclusion complex enhanced its water solubility and orally bioavailability. Furthermore, didymin inclusion complex exerted considerable chemosensitivity potency, and improve the anti-tumor effects of chemotherapeutics in vivo. Therefore, didymin inclusion complex could provide a safe, effective, economical, and adjuvant drug for future treatment of chemoresistant cancers. [ABSTRACT FROM AUTHOR]

Decellularized extracellular matrix (dECM) has been considered as a promising scaffold in xenotransplantation, yet natural tissue dECM is often mechanically weak and rapidly degraded, compromising the outcomes. How to restore the mechanical strength and optimise the in vivo degradation, but maintain the microstructure and maximumly suppress the immune rejection, remains challenging. For this aim, we prepared and characterised various crosslinked decellularized rabbit uterus matrix (dUECM) and evaluated in vivo performance after uterus xenotransplantation from rabbit to rat. Naturally derived genipin (GP) and procyanidins (PC) were chosen to crosslink the dUECM, producing significant mechanical enhanced crosslinked-dUECM along with prolonged enzymatic degradation rate. Xenogeneic subcutaneous graft studies revealed that PC- and GP-crosslinked dUECM experienced significant cell infiltration and caused low immune reactions, indicating the desired biocompatibility. In vivo transplantation of GP- and PC-crosslinked dUECM to a uterus circular excised rat yielded excellent recellularization ability and promoted uterus regeneration after 90 days. While the reconstruction efficacy of crosslinked dUECM is highly depended on the crosslinking degree, crosslinking condition must be carefully evaluated to balance the role of crosslinked dECM in mechanical and biological support for tissue regeneration promotion. [ABSTRACT FROM AUTHOR]

Instability of silk fibroin nanoparticles (SFNPs) in physiologic condition hinders its application as drug delivery vehicle. Herein, indocyanine green (ICG) loaded silk fibroin nanoparticles (ICG-SFNPs) was firstly prepared and then crosslinked by proanthocyanidins to obtain the stable ICG-CSFNPs for killing the residual tumour niche under near infra-red irradiation (NIR) after surgery. The particle size and zeta potentials of ICG-CSFNPs was 120.1 nm and -40.4 mV, respectively. Moreover, ICG-CSFNPs exhibited good stability of particle size in the physiological medium. Meanwhile, the stable photothermal properties of ICG-CSFNPs were not compromised even after several cycles of NIR. Few of the ICG-CSFNPs were phagocytized by RAW264.7 macrophage in vitro, while they were easily internalized by C6 glioma cells, resulting in their significant toxicity on tumour cells after NIR. The pharmacokinetic study showed that ICG-CSFNPs had a longer blood circulation time than ICG-SFNPs, making them more distribution in glioma after intravenous administration in vivo. Meanwhile, the pharmacological study showed the more effective inhibition of tumour growth was exhibited by ICG-CSFNPs in C6 glioma-bearing mice after NIR. Overall, the cross-linked nanoparticles of silk fibroin may be a promising vehicle of ICG for photothermal therapy of glioma after surgical resection. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The effective penetration of bFGF in formulation was highly dependent on the permeation enhancer, laurocapam. • The stability of the encapsulated bFGF in wound fluid was obviously enhanced. • The regenerative mechanism of hair follicle was highly associated with scar inhibition in wound zone. Abstract Excessive deposition of extracellular matrix (ECM) usually resulted in scar formation during wound healing, which caused skin dysfunction, such as hair loss. Basic fibroblast growth factor (bFGF) was very helpful for promoting hair follicle neogenesis and regulating the remodeling of ECM during wound healing. Because of its poor stability in wound fluids and low permeability against the dense wound scar, the repairing quality of bFGF on wound was hindered largely in clinical practice. To overcome these drawbacks, herein, a novel liposome with silk fibroin hydrogel core (bFGF-SF-LIP) was firstly prepared to stabilize bFGF, followed by insertion of laurocapam, a permeation enhancer, into the liposomal membrane to construct a skin-permeable liposome (SP-bFGF-SF-LIP). The encapsulated efficiency of bFGF was reaching to nearly 90% when ratio of drug/lipids above 1:300, and it activity was not compromised by laurocapam. SP-bFGF-SF-LIP exhibited a hydrodynamic diameter of 103.3 nm and Zeta potential of −2.31 mV. The stability of the encapsulated bFGF in wound fluid was obviously enhanced. After 24 h of incubation with wound fluid containing MMP-9, the remaining bFGF was as high as 65.4 ± 0.5% for SP-bFGF-SF-LIP, while only 2.1 ± 0.2% of free bFGF was remained. The skin-permeability of bFGF was significantly enhanced by SP-bFGF-SF-LIP and most of the encapsulated bFGF penetrated into the dermis. After treatment with SP-bFGF-SF-LIP, the morphology of hair follicle at wound zone was obviously improved and the hair regrew on the deep second scald mice model. The therapeutic mechanism was highly associated with inhibiting scar formation and promoting vascular growth in dermis. Conclusively, SP-bFGF-SF-LIP may a potential option to improve wound healing with high-quality. [ABSTRACT FROM AUTHOR]

Most breast tumours are heterogeneous and not only contain the bulk of differentiated tumour cells but also a small population of highly tumorigenic and intrinsically drug-resistant cancer stem cells (CSCs). Herein, a pH-sensitive nanoparticle with simultaneous encapsulation of curcumin and doxorubicin (CURDOX-NPs) was prepared by using monomethoxy (polyethylene glycol)-b-P (D,L-lactic-co-glycolic acid)-b-P (L-glutamic acid) polymer to simultaneously target the differentiated tumor cells and CSCs. CURDOX-NPs had a mean diameter of 107.5 nm and zeta potential of −13.7 mV, determined by DLS. Drug-loading efficiency for curcumin and doxorubicin was reaching to 80.30% and 96.2%, respectively. Moreover, a cascade sustained-release profiles with the faster release of CUR followed by a slower release of DOX was observed in normal pH7.4 condition. Moreover, a pH-sensitive release profile for each cargo was seen in pH5.0 condition. The anti-tumour effect of CURDOX-NPs on CSCs-enriching MCF-7/ADR mammospheres was confirmed by in vitro. Moreover, a significant regression of tumour growth after treatment with CURDOX-NPs was also observed in Xenograft mice model. The percentage of CSCs in tumour significantly decreased from 39.9% in control group to 6.82% after treatment with CURDOX-NPs. The combinational delivery of CUR and DOX may a potentially useful therapeutic strategy for refractory breast cancer. [ABSTRACT FROM AUTHOR]

Currently, combination drug therapy is one of the most effective approaches to glioma treatment. However, due to the inherent dissimilar pharmacokinetics of individual drugs and blood brain barriers, it was difficult for the concomitant drugs to simultaneously be delivered to glioma in an optimal dose ratio manner. Herein, a cationic micellar core (Cur-M) was first prepared from D-α-tocopherol-grafted-ε-polylysine polymer to encapsulate the hydrophobic curcumin, followed by dopamine-modified-poly-γ-glutamic acid polymer further deposited on its surface as a anion shell through pH-sensitive linkage to encapsulate the hydrophilic doxorubicin (DOX) hydrochloride. By controlling the combinational Cur/DOX molar ratio at 3:1, a pH-sensitive core-shell nanoparticle (PDCP-NP) was constructed to simultaneously target the cancer stem cells (CSCs) and the differentiated tumor cells. PDCP-NP exhibited a dynamic diameter of 160.8 nm and a zeta-potential of -30.5 mV, while its core-shell structure was further confirmed by XPS and TEM. The ratiometric delivery capability of PDCP-NP was confirmed by in vitro and in vivo studies, in comparison with the cocktail Cur/DOX solution. Meanwhile, the percentage of CSCs in tumors was significantly decreased from 4.16% to 0.95% after treatment with PDCP-NP. Overall, PDCP-NP may be a promising carrier for the combination therapy with drug candidates having dissimilar physicochemical properties. [ABSTRACT FROM AUTHOR]

Silk was easily dyed in traditional textile industry because of its strong affinity to many colorants. Herein, the biocompatible silk fibroin was firstly extracted from Bombyx mori silkworm cocoons. And SF nanoparticles (SFNPs) were prepared for dyeing indocyanine green (ICG) and construct a therapeutic nano-platform (ICG-SFNPs) for photo-thermal therapy of glioblastoma. ICG was easily encapsulated into SFNPs with a very high encapsulation efficiency reaching to 97.7 ± 1.1%. ICG-SFNPs exhibited a spherical morphology with a mean particle size of 209.4 ± 1.4 nm and a negative zeta potential of −31.9 mV, exhibiting a good stability in physiological medium. Moreover, ICG-SFNPs showed a slow release profile of ICG in vitro, and only 24.51 ± 2.27% of the encapsulated ICG was released even at 72 h. Meanwhile, ICG-SFNPs exhibited a more stable photo-thermal effect than free ICG after exposure to near-infrared irradiation. The temperature of ICG-SFNPs rapidly increased by 33.9 °C within 10 min and maintained for a longer time. ICG-SFNPs were also easily internalized with C6 tumor cells in vitro, and a strong red fluorescence of ICG was observed in cytoplasm for cellular imaging. In vivo imaging showed that ICG-SFNPs were effectively accumulated inside tumor site of C6 glioma-bearing Xenograft nude mice through vein injection. Moreover, the temperature of tumor site was rapidly rising up to kill tumor cells after local NIR irradiation. After treatment, its growth was completely suppressed with the relative tumor volume of 0.55 ± 033 while free ICG of 33.72 ± 1.90. Overall, ICG-SFNPs may be an effective therapeutic means for intraoperative phototherapy and imaging. [ABSTRACT FROM AUTHOR]

Basic fibroblast growth factor (bFGF) has shown great therapeutic effects for diabetic nephropathy (DN). However, its clinical applications are limited due to its short half-life, low stability and poor penetration. Herein, a bFGF-loaded liposome (bFGF-lip) was constructed and combined with ultrasound-targeted microbubble destruction (UTMD) to overcome these drawbacks. bFGF-lip exhibited spherical morphology with a diameter of 171.1 ± 14.2 nm and a negative zeta potential of -5.15 ± 2.08 mV, exhibiting a sustained-release profile of bFGF. DN rat models were successfully induced by streptozotocin. After treatment with bFGF-lip + UTMD, the concentration of bFGF in kidney of DN rats was significantly enhanced in comparison with free bFGF treatment. Additionally, the morphology and the function of the kidneys were obviously recovered after bFGF-lip + UTMD treatment as shown by ultrasonography and histological analyse. The molecular mechanism was associated with the inhibition of renal inflammation. After treatment with bFGF-lip + UTMD, the activation of NF-κB was obviously reduced in the renal tissues, and downstream inflammatory mediators including TGF-β1, MCP-1, IL-6 and IL-1β were also down regulated. In addition, inflammation-induced cellular apoptosis of renal tubular cells was also significantly inhibited by detecting Bax, caspase-3 and Bcl-2. Therefore, bFGF-lip in combination with UTMD might be a potential strategy to reverse the progression of early DN. [ABSTRACT FROM AUTHOR]

Traumatic spinal cord injury (SCI) results in paraplegia or quadriplegia, and currently, therapeutic interventions for axonal regeneration after SCI are not clinically available. Animal studies have revealed that glial cell-derived neurotrophic factor (GDNF) plays multiple beneficial roles in neuroprotection, glial scarring remodeling, axon regeneration and remyelination in SCI. However, the poor physicochemical stability of GDNF, as well as its limited ability to cross the blood-spinal cord barrier, hampers the development of GDNF as an effective therapeutic intervention in clinical practice. In this study, a novel temperature-sensitive heparin-poloxamer (HP) hydrogel with high GDNF-binding affinity was developed. HP hydrogels showed a supporting scaffold for GDNF when it was injected into the lesion epicenter after SCI. GDNF-HP by orthotopic injection on lesioned spinal cord promoted the beneficial effects of GDNF on neural stem cell proliferation, reactive astrogliosis inhibition, axonal regeneration or plasticity, neuroprotection against cell apoptosis, and body functional recovery. Most interestingly, GDNF demonstrated a bidirectional regulation of autophagy, which inhibited cell apoptosis at different stages of SCI. Furthermore, the HP hydrogel promoted the inhibition of autophagy-induced apoptosis by GDNF in SCI. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2816-2829, 2017. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of the most common and lethal microvascular complications of diabetes. This study aimed to explore whether coenzymeQ10 (CoQ10) as an antioxidant combined with ultrasound-targeted microbubble destruction (UTMD) could reverse the progress of early diabetic nephropathy (DN). CoQ10 has great potential to treat early DN. However, the clinical application of CoQ10 has been limited because of its low aqueous solubility and non-specific distribution. Therefore, CoQ10-loaded liposomes (CoQ10-lip) were prepared and combined with ultrasound microbubbles for the early theranostics of DN. CoQ10-lip exhibited a good round morphology with a diameter of 183 ± 1.7 nm and a negative zeta potential of −25.3 mV, which was capable of prolonging the release of the encapsulated CoQ10. The early DN rat models were induced by streptozotocin (STZ) and confirmed by contrast-enhanced ultrasound (CEUS) and 24-h urinary albumin. After the administration of CoQ10-lip combined with the UTMD technique to rats with early DN, the morphology and function of the kidney were evaluated by ultrasonography, histological and molecular analyses. The renal hemodynamics were significantly improved, moreover, 24-h urinary protein, and oxidative stress indexes were modulated after treatment with CoQ10-lip + UTMD indicating recovery of renal function. An elevated level of Nphs2 protein and reduced caspase 3 level indicated the preservation of podocytes and inhibition of cell apoptosis after CoQ10-lip + UTMD treatment. The molecular mechanism was associated with the upregulation of Bcl-2 and the downregulation of Bax. Moreover, the combination of CoQ10-lip and ultrasound microbubbles demonstrated a better protective effect on the damaged kidney than the other groups (free CoQ10 or CoQ10-lip+/− UTMD). Conclusively, CoQ10-lip in combination with ultrasound microbubbles might be a potential strategy to reverse the progress of early DN. [ABSTRACT FROM AUTHOR]

In this study, porous gelatin microspheres (GMSs) were constructed to improve the neuroprotective effect of basic fibroblast growth factor (bFGF) on spinal cord injury. GMSs were prepared by a W/O emulsion template, followed by cross-linking, washing and drying. The particle sizes and surface porosity of the blank GMSs were carefully characterized by scan electronic microscopy. The blank GMSs have a mean particle size of 35μm and theirs surface was coarse and porous. bFGF was easily encapsulated inside the bulk GMSs through diffusion along the porous channel. 200μg of bFGF was completely encapsulated in 100mg of GMSs. The bFGF-loaded GMSs displayed a continuous drug release pattern without an obvious burst release over two weeks in vitro. Moreover, the therapeutic effects of bFGF-loaded GMSs were also evaluated in spinal cord injury rat model. After implantation of bFGF-loaded GMSs, the recovery of the motor function of SCI rats were evaluated by behavioral score and foot print experiment. The motor function of SCI rats treated with bFGF-loaded GMSs was more obvious than that treated with free bFGF solution (P<0.05). At the 28th days after treatment, rats were sacrificed and the injured spinal were removed for histopathological and apoptosis examination. Compared with treatment with free bFGF solution, treatment with bFGF-loaded GMSs resulted in a less necrosis, less infiltration of leukocytes, and a reduced the cavity ratio and less apoptotic cells in injured spinal(P<0.01), indicating its better therapeutic effect. Implantable porous GMSs may be a potential carrier to deliver bFGF for therapy of spinal cord injury. [ABSTRACT FROM AUTHOR]

Endometrial injury usually results in intrauterine adhesion (IUA), which is an important cause of infertility and recurrent miscarriage in reproductive women. There is still lack of an effective therapeutic strategy to prevent occurrence of IUA. Keratinocyte growth factor (KGF) is a potent repair factor for epithelial tissues. Here, a temperature-sensitive heparin-modified poloxamer (HP) hydrogel with affinity to KGF (KGF-HP) was used as a support matrix to prevent IUA and deliver KGF. The rheology of KGF-HP hydrogel was carefully characterized. The cold KGF-HP solution was rapidly transited to hydrogel with suitable storage modulus (G′) and loss modulus (G″) for the applications of uterus cavity at temperature of 33 °C.In vitrorelease demonstrated that KGF was released from HP hydrogels in sustained release manner for a long time.In vivobioluminescence imaging showed that KGF-HP hydrogel was able to prolong the retention of the encapsulated KGF in injured uterus of rat model. Moreover, the morphology and function of the injured uterus were significantly recovered after administration of KGF-HP hydrogel, which were evaluated by two-dimensional ultrasound imaging and receptive fertility. Not only proliferation of endometrial glandular epithelial cells and luminal epithelial cells but also angiogenesis of injured uterus were observed by Ki67 and CD31 staining after 7 d of treatment with KGF-HP hydrogel. Finally, a close relatively relationship between autophagy and proliferation of endometrial epithelial cells (EEC) and angiogenesis was firstly confirmed by detecting expression of LC3-II and P62 after KGF treatment. Overall, KGF-HP may be used as a promising candidate for IUA treatment. [ABSTRACT FROM AUTHOR]

Didymin (isosakuranetin 7-O-rutinoside) is an orally bioactive dietary flavonoid glycoside first found in citrus fruits. Traditionally, this flavonoid has long been used in Asian countries as a dietary antioxidant. Recent studies have provided newer insights into this pleiotropic compound, which could regulate multiple biological activities of many important signaling molecules in health and disease. Emerging data also presented the potential therapeutic application of dietary flavonoid glycoside didymin against cancer, neurological diseases, liver diseases, cardiovascular diseases, and other diseases. In this review, we briefly introduce the source and extraction methods of didymin, and summarize its potential therapeutic application in the treatment of various diseases, with an emphasis on molecular targets and mechanism that contributes to the observed therapeutic effects. The dietary flavonoid didymin can be used to affect health and disease with multiple therapeutic targets, and it is anticipated that this review will stimulate the future development of this potential dietary medicine. [ABSTRACT FROM AUTHOR]

Because of the short half-life, either systemic or local administration of bFGF shows significant drawbacks to spinal injury. In this study, an acellular spinal cord scaffold (ASC) was encapsulated in a thermo-sensitive hydrogel to overcome these limitations. The ASC was firstly prepared from the spinal cord of healthy rats and characterized by scanning electronic microscopy and immunohistochemical staining. bFGF could specifically complex with the ASC scaffold via electrostatic or receptor-mediated interactions. The bFGF-ASC complex was further encapsulated into a heparin modified poloxamer (HP) solution to prepare atemperature-sensitive hydrogel (bFGF-ASC-HP). bFGF release from the ASC-HP hydrogel was more slower than that from the bFGF-ASC complex alone. An in vitro cell survival study showed that the bFGF-ASC-HP hydrogel could more effectively promote the proliferation of PC12 cells than a bFGF solution, with an approximate 50% increase in the cell survival rate within 24 h (P < 0.05). Compared with the bFGF solution, bFGF-ASC-HP hydrogel displayed enhanced inhibition of glial scars and obviously improved the functional recovery of the SCI model rat through regeneration of nerve axons and the differentiation of the neural stem cells. In summary, an ASC-HP hydrogel might be a promising carrier to deliver bFGF to an injured spinal cord. [ABSTRACT FROM AUTHOR]

Intrauterine adhesion (IUA) is characterized by endometrial stromal replaced with fibrous tissue during the trauma or operation induced injury. Current clinic IUA management mainly involves surgical removal of the connective tissues and physical separation and often results in reoccurrence. It is of clinic interest to directly address the issue via facilitating the endometrial repair and thereby inhibiting the formation of re-adhesion. To this end, we designed a nanocomposite aloe/poloxamer hydrogel for β-estradiol (E2) intrauterine delivery to exert multi-therapeutic effects and promote endometrial regeneration for IUA treatment. Nanoparticulate decellularized uterus (uECMNPs) was prepared to encapsulate E2 (E2@uECMNPs), which improved the solubility and prolonged cargo release. Then, E2@uECMNPs were further embedded into the thermosensitive aloe-poloxamer hydrogel (E2@uECMNPs/AP). Multiple components from E2@uECMNPs/AP system could collectively promote proliferation and inhibit apoptosis of endometrial stromal cells. E2@uECMNPs/AP significantly increased morphological recovery and decreased uterine fibrosis rate compared with IUA rats in other groups in vivo. Additionally, the levels of Ki67, cytokeratin, and estrogen receptor β were all up-regulated, along with the decreased expression of TGF-β1 and TNF-α in the uterus from rats receiving E2@uECMNPs/AP therapy. Taken together, in situ administration of E2@uECMNPs/AP hydrogel could effectively promote endometrial regeneration and prevent the re-adhesion. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Islet transplantation is the experimental strategy to treat type 1 diabetes by transplanting isolated islets from a donor pancreas into the recipient. While significant progress has been made in the islet transplantation field, islet loss before and after transplantation is still the major obstacle that currently precludes its widespread application. Islet must survive from possible cellular damages during the isolation procedure, storage time, islet injection process and post-transplantation immune rejection, only then the survived islets could produce insulin, actively regulating the blood glucose level. Therefore, islet protection needs to be addressed, especially regarding oxidative stress and immune response induced islet cell damages in diabetic patients. Many clinical data have shown that mildly elevated bilirubin levels in the body negatively correlate to the occurrence of an array of diseases that are related to increased oxidative stress, especially diabetes, and its complications. Recent studies confirmed that bilirubin helps receivers to suppress immune reaction and enable prolonged tolerance to islet transplantation. In this paper, we will review the pharmacological mechanism of bilirubin to modulate oxidative cellular damage and chronic inflammatory reaction in both diabetes and islet transplantation process. Also, we will present the clinical evidence of a strong correlation in bilirubin and diabetes. More importantly, we will summarize undergoing therapeutic applications of bilirubin in islet transplantation and discuss formulation approaches designed to overcome bilirubin delivery issues for future use. [ABSTRACT FROM AUTHOR]