Integration of molecular docking, molecular dynamics and network pharmacology to explore the multi-target pharmacology of fenugreek against diabetes.

Fenugreek is an ancient herb that has been used for centuries to treat diabetes. However, how the fenugreek-derived chemical compounds work in treating diabetes remains unclarified. Herein, we integrate molecular docking and network pharmacology to elucidate the active constituents and potential mechanisms of fenugreek against diabetes. First, 19 active compounds from fenugreek and 71 key diabetes-related targets were identified through network pharmacology analysis. Then, molecular docking and simulations results suggest diosgenin, luteolin and quercetin against diabetes via regulation of the genes ESR1, CAV1, VEGFA, TP53, CAT, AKT1, IL6 and IL1. These compounds and genes may be key factors of fenugreek in treating diabetes. Cells results demonstrate that fenugreek has good biological safety and can effectively improve the glucose consumption of IR-HepG2 cells. Pathway enrichment analysis revealed that the anti-diabetic effect of fenugreek was regulated by the AGE-RAGE and NF-κB signalling pathways. It is mainly associated with anti-oxidative stress, anti-inflammatory response and ß-cell protection. Our study identified the active constituents and potential signalling pathways involved in the anti-diabetic effect of fenugreek. These findings provide a theoretical basis for understanding the mechanism of the anti-diabetic effect of fenugreek. Finally, this study may help for developing anti-diabetic dietary supplements or drugs based on fenugreek.

Combined Phycocyanin and Hematoporphyrin Monomethyl Ether for Breast Cancer Treatment via Photosensitizers Modified Fe3O4 Nanoparticles Inhibiting the Proliferation and Migration of MCF-7 Cells.

Photodynamic therapy (PDT), combining the laser and photosensitizers to kill tumor cells, has the potential to address many current medical requirements. In this study, magnetic Fe3O4 nanoparticles were first employed as cores and modified with oleic acid (OA) and 3-triethoxysilyl-1-propanamine. Then, the photosensitizers phycocyanin (PC) and hematoporphyrin monomethyl ether (HMME), which might be able to stimulate the cell release of reactive oxygen species after the irradiation of a near-infrared (NIR) laser, were grafted on the surface of such nanoparticles. Our results revealed the high-efficiency inhibition of breast cancer MCF-7 cells growing upon near-infrared irradiation both in vitro and in vivo. Furthermore, it was the synergy between the natural photosensitizers PC and the synthetic photosensitizers HMME that deeply influenced such inhibition compared to the groups that used either of these medicines alone. To utilize the combination of different photosensitive agents, our study thus provides a new strategy for breast cancer treatment.

Preparation and characterization of hydroxyapatite nanoparticles carrying insulin and gallic acid for insulin oral delivery.

Although nanoparticles carriers for oral delivery of insulin have been researched for many years, this method still fails to solve issues with toxicity, biocompatibility, and degradability in the organism. We therefore developed an innovative conjugation system to solve this problem. Nano hydroxyapatite (HAP) particles were used as the core, then polyethylene glycol (PEG) was wrapped onto the surface of hydroxyapatite, and, finally, insulin (INS) and gallic acid (GA) were conjugated with PEG. PEG functionalized HAP was increased the hydrophilicity of the nanoparticles, also protected them from degradation in the gastrointestinal (GI) tract. Most importantly, the in vivo absorption of nanoparticles in rat small intestines revealed that HAP-PEG-GA-INS was absorbed by the small intestine epithelium. The blood glucose of the type 1 diabetes (T1D) rats that were given intragastrically HAP-PEG-GA-INS showed an obvious downward trend. Overall, we synthesized a safe, non-toxic, and effective oral insulin delivery system.

Neuroprotective effect of gold nanoparticles composites in Parkinson's disease model.

Parkinson's disease (PD) is second most common neurodegenerative disorder worldwide. Although drugs and surgery can relieve the symptoms of PD, these therapies are incapable of fundamentally treating the disease. For PD patients, over-expression of α-synuclein (SNCA) leads to the death of dopaminergic neurons. This process can be prevented by suppressing SNCA over-expression through RNA interference. Here, we successfully synthesized gold nanoparticles (GNP) composites (CTS@GNP-pDNA-NGF) via the combination of electrostatic adsorption and photochemical immobilization, which could load plasmid DNA (pDNA) and target specific cell types. GNP was transfected into cells via endocytosis to inhibiting the apoptosis of PC12 cells and dopaminergic neurons. Simultaneously, GNP composites are also used in PD models in vivo, and it can successfully cross the blood-brain barrier by contents of GNP in the mice brain. In general, all the works demonstrated that GNP composites have good therapeutic effects for PD models in vitro and in vivo.

Preparation and Characterization of Hypoglycemic Nanoparticles for Oral Insulin Delivery.

Polymeric nanoparticles have been widely investigated as insulin delivery systems for oral administration. However, the toxic nature of many artificial polymers hampers their effective application, creating a demand for the further exploration of alternative natural polymers. In addition, ethnobotanical research has reported that over 800 plant species have a hypoglycemic function, some of which are polymers. For the advantages of both areas to be combined, the aim of this work was to choose an organic hypoglycemic polymer and prepare it into an insulin carrier to build a dual-functional oral insulin delivery system. We found that the insulin loading rate, release mode, thermostability, and both in vitro and in vivo absorption and efficacy varied with the different modifications of polygalacturonic acid (PGLA) nanoparticulate backbones. By in vivo pharmaceutical testing and constantly monitoring the symptoms of type 1 diabetic (T1D) rats, we ascertained the hypoglycemic function of the nanoparticles and showed that overall diabetic symptoms were ameliorated after the long-term daily administration of nanoparticles with no significant damage to organ structure or cell viability.

Induction, purification, and characterization of a thermo and pH stable laccase from Abortiporus biennis J2 and its application on the clarification of litchi juice.

A fungus J2 producing laccase with high yield was screened in soils and identified as Abortiporus biennis. The production of laccase was induced by 0.1 mM Cu2+, 0.1 mM tannic acid, and 0.5 M ethanol. The laccase from Abortiporus biennis J2 was purified to electrophoretic homogeneity by a couple of steps. The N-terminal amino acid sequence of the enzyme was AIGPTADLNISNADI. The properties of the purified laccase were investigated. The result showed the laccase from Abortiporus biennis J2 is a thermo and pH stable enzyme. The laccase activity was inhibited by Hg2+, Cd2+, Fe2+, Ag+, Cu2+, and Zn2+, while promoted by Mg2+, Mn2+ at 10 mM level. Purified laccase was used to the clarification of litchi juice. After treatment with this laccase, the phenolic content of litchi juice had been found to be greatly reduced along with an increase in the clarity of the juice. The result indicated the potential of this laccase for application in juice procession.

Highly stable nanofluid based on polyhedral oligomeric silsesquioxane-decorated graphene oxide nanosheets and its enhanced electro-responsive behavior.

Graphene oxide (GO) shows potential as an anisotropic nanofiller or a dispersed phase of electro-responsive electrorheological (ER) nanofluid due to its small size and high aspect ratio. But it is difficult to disperse GO in non-polar oil due to the hydrophilic nature of GO and thus the resulting fluid is often subject to dispersion instability and low ER effect. These disadvantages largely limit the real application of GO-based ER nanofluid. In this paper, we develop the polyhedral oligomeric silsesquioxane (POSS)-decorated GO (POSS-GO) nanosheets and demonstrate that decorating with POSS overcomes the dispersion instability of GO in silicone oil and enhances the ER effect. The morphology and structure of samples are characterized by atomic force microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and x-ray photoelectronic spectroscopy. The results show that the POSS-GO nanosheets are ultrathin with ∼3 nm thickness and have good compatibility with silicone oil and, as a result, the nanofluid of POSS-GO nanosheets in silicone oil shows high dispersion stability. After standing for one year at room temperature, no sedimentation occurs. Under an external electric field, the ER efficiency of the POSS-GO nanofluid is ten times as high as that of the pure GO fluid. This enhanced electro-responsive behavior is related to the fact that decorating with POSS partly reduces the GO and compresses the dielectrophoretic effect of the negatively charged pure GO fluid.

Electrically tunable negative refraction in core/shell-structured nanorod fluids.

We theoretically investigate optical refraction behavior in a fluid system which contains silica-coated gold nanorods dispersed in silicone oil under an external electric field. Because of the formation of a chain-like or lattice-like structure of dispersed nanorods along the electric field, the fluid shows a hyperbolic equifrequency contour characteristic and, as a result, all-angle broadband optical negative refraction for transverse magnetic wave propagation can be realized. We calculate the effective permittivity tensor of the fluid and verify the analysis using finite element simulations. We also find that the negative refractive index can vary with the electric field strength and external field distribution. Under a non-uniform external field, the gradient refraction behavior can be realized.

Focused ultrasound-mediated cerium-based nanoreactor against Parkinson's disease via ROS regulation and microglia polarization.

Neuronal damage caused by oxidative stress and inflammatory microenvironment dominated by microglia are the main obstacles in the treatment of Parkinson's disease (PD). In this study, we developed an integrated nanoreactor Q@CeBG by encapsulating CeO2 nanozyme and quercetin (Que) into glutathione-modified bovine serum albumin, and then selected focused ultrasound (FUS) to temporarily open the blood-brain barrier (BBB) to enhance the accumulation level of Q@CeBG in the brain. Q@CeBG exhibited superior multi-ROS scavenging activity. Under the assistance of FUS, Q@CeBG nanoreactor can penetrate the BBB and act on neurons as well as microglia, reducing the neuron's oxidative stress level and polarizing microglia's phenotype from proinflammatory M1 to anti-inflammatory M2. In vitro and In vivo experiments demonstrated that Q@CeBG nanoreactor with good biocompatibility exhibit outstanding neuroprotection and immunomodulatory effects. In short, this dual synergetic nanoreactor will become a reliable platform against PD.

Hippocampal-derived extracellular vesicle synergistically deliver active adenosine hippocampus targeting to promote cognitive recovery after stroke.

Ischemic stroke is a neurological disease that leads to brain damage and severe cognitive impairment. In this study, extracellular vesicles(Ev) derived from mouse hippocampal cells (HT22) were used as carriers, and adenosine (Ad) was encapsulated to construct Ev-Ad to target the damaged hippocampus. The results showed that, Ev-Ad had significant antioxidant effect and inhibited apoptosis. In vivo, Ev-Ad reduced cell death and reversed inflammation in hippocampus of ischemic mice, and improved long-term memory and learning impairment by regulating the expression of the A1 receptor and the A2A receptor in the CA1 region. Thus, the developmental approach based on natural carriers that encapsulating Ad not only successfully restored nerves after ischemic stroke, but also improved cognitive impairment in the later stage of ischemic stroke convalescence. The development and design of therapeutic drugs provides a new concept and method for the treatment of cognitive impairment in the convalescent phase after ischemic stroke.

Reactive oxygen species produced by photodynamic therapy enhance docosahexaenoic acid lipid peroxidation and induce the death of breast cancer cells.

Breast cancer remains a serious threat to women's physical and emotional health. The combination therapies can overcome the deficiency of single therapy, enhance the therapeutic effects and reduce the side effects at the same time. In this study, we synthesize a novel nanomedicine that enhanced the therapeutic effects of breast cancer treatment by combining photodynamic therapy and chemotherapy. The doxorubicin (DOX) and photosensitizer methyl pyropheophorbide-a (MPPa) are loaded into the nano-drug delivery system as DPSPFA/MPPa/DOX. In response to near-infrared (NIR) laser, the drugs were quickly released to the cancer cells. The MPPa produces reactive oxygen species (ROS) under the action of photodynamics. Unsaturated fatty acids with ROS promotes lipid peroxidation and the combination of chemotherapy and photodynamic therapy. The data shows that the DPSPFA/MPPa/DOX has a spherical shape, good dispersibility and stability, and the particle size is roughly 200 nm. The drug loading capability of DOX is about 13 %. Both of MCF7 cell model in vitro and breast cancer model in vivo, DPSPFA/MPPa/DOX showed an excellent anti-tumor effect of 86.9 % and without any obvious side effects. These findings might offer potential for a new approach for breast cancer treatment.

Carboxymethyl Chitosan/Sodium Alginate/Chitosan Quaternary Ammonium Salt Composite Hydrogel Supported 3J for the Treatment of Oral Ulcer.

Oral ulcer is a common inflammatory disease of oral mucosa, causing severe burning pain and great inconvenience to daily life. In this study, compound 3J with anti-inflammatory activity was synthesized beforehand. Following that, an intelligent composite hydrogel supported 3J was designed with sodium alginate, carboxymethyl chitosan, and chitosan quaternary ammonium salt as the skeleton, and its therapeutic effect on the rat oral ulcer model was investigated. The results show that the composite hydrogel has a dense honeycomb structure, which is conducive to drug loading and wound ventilation, and has biodegradability. It has certain antibacterial effects and good anti-inflammatory activity. When loaded with 3J, it reduced levels of TNF-α and IL-6 in inflammatory cells by up to 50.0%. It has excellent swelling and water retention properties, with a swelling rate of up to 765.0% in a pH 8.5 environment. The existence of a large number of quaternary ammonium groups, carboxyl groups, and hydroxyl groups makes it show obvious differences in swelling in different pH environments, which proves that it has double pH sensitivity. It is beneficial to adapt to the highly dynamic changes of the oral environment. Compared with single hydrogel or drug treatment, the drug-loaded hydrogel has a better effect on the treatment of oral ulcers.

Preparation of injectable porcine skin-derived collagen and its application in delaying skin aging by promoting the adhesion and chemotaxis of skin fibroblasts.

Collagen, as the main component of human skin, plays a vital role in maintaining dermal integrity. Its loss will lead to dermis destruction and collapse, resulting in skin aging. At present, injection of exogenous collagen is an important means to delay skin aging. In this study, high-purity collagen was extracted from porcine skin. Our research revealed that it can effectively promote the adhesion and chemotaxis of HSF cells. It can also reduce the expression of ß-galactosidase, decrease ROS levels, and increase the expression of the collagen precursors, p53 and p16 in HSF cells during senescence. After local injection into the aging skin of rats, it was found that the number of cells and type I collagen fibers in the dermis increased significantly, and the arrangement of these fibers became more uniform and orderly. Moreover, the important thing is that it is biocompatible. To sum up, the porcine skin collagen we extracted is an anti-aging biomaterial with application potential.

Tumor cell-derived extracellular vesicles for breast cancer specific delivery of therapeutic P53.

Breast cancer has consistently had the highest incidence among women in the world. Tumor cell-derived extracellular vesicles (EV) have been leveraged as drug carriers for cancer treatment. Herein, we developed an efficient theranostic platform for breast cancer-specific delivery of lipophilic triphenylphosphonium (TPP)-modified therapeutic recombinant P53 proteins (TPP/P53) by breast cancer cell-derived EVs. We observed that the EVs were routinely captured by their patent cells, so when, TPP/P53 was loaded into the EVs (TPP/P53@EVs), TPP/P53 was targeted to the mitochondria of breast cancer cells, where it caused signal amplification and induced the death of breast cancer cells. Our findings demonstrated that the TPP/P53@EVs showed good tumor-targeting capability and efficiently destroyed the tumor tissues without any obvious toxicity in vivo. Therefore, our TPP/P53@EVs might provide a "drug-free" strategy for future applications in breast cancer therapy.

Glucose sensitive konjac glucomannan/concanavalin A nanoparticles as oral insulin delivery system.

Compared with injection, oral drug delivery is a better mode of administration because of its security, low pain and simplicity. Insulin is the first choice for clinical treatment of type 1 diabetes, but, because insulin inability to resist gastrointestinal (GI) digestion results in poor oral bioavailability of insulin. Herein, we developed a targeted oral delivery system for diabetes. ConA-INS-KGM nanoparticles were prepared, loaded with insulin, fabricated from konjac glucomannan (KGM) and concanavalin A (ConA) through a crosslinking method, as an insulin oral delivery system in response to different blood glucose levels. The size of nanoparticles was characterized by TEM, which showed that these nanoparticles were formed spherical particles with a diameter of about 500 nm. In vitro release of insulin from these nanoparticles was studied, which indicated that insulin release is reversible at different glucose concentrations. In vivo tests demonstrated that they are safe and have high biocompatibility. Using the nanoparticles to treat diabetic mice, we found that they can control blood sugar levels for 6 h, retaining their glucose-sensitive properties during this time. Therefore, these nanoparticles have significant potential as glucose-responsive systems for diabetes and show great applications in biomedical fields.

Nano-MgO composites containing plasmid DNA to silence SNCA gene displays neuroprotective effects in Parkinson's rats induced by 6-hydroxydopamine.

Parkinson's disease (PD) always causes dyskinesia and cognitive impairments. The alpha-synuclein (α-syn) accumulation, one of the main pathological characteristics of PD, may impair synaptic structural and synaptic functions. Nano-MgO composites has been reported to interfere α-syn expression. The present study is aim to investigate the roles of nano-MgO composites on cognitive impairments in PD rats. PD rats were formed by 6-hydroxydopamine (6-OH DA) and α-syn expression were evaluated by Western blot. Hippocampal dendritic morphology was examined by Golgi staining. Morris water maze (MWM) test was applied to evaluate learning and memory abilities and population spike was recorded by electrophysiological records in vivo. The results showed that: 6-OH DA-treated up-regulated α-syn levels in striatum and hippocampus and increased the rotational times by APO, but nano-MgO composites could down-regulated α-syn levels. The overall length of dendritic and the total number of intersections were reduced by 6-OH DA, accompanied by the decrease of the dendritic spine density in hippocampal CA1, CA3 and DG regions. Interestingly, nano-MgO composites could alleviate the morphological damages of dendrites. In the MWM test, the escape latencies and the swimming distances in PD rats were increased as compared to the sham group, and nano-MgO composites could reduce the escapes latencies and the swimming distances. Furthermore, 6-OH DA reduced the amplitudes of long-term potentiation (LTP) in hippocampal CA1 region, and 6 mg/kg nano-MgO composites could improve LTP amplitudes. In conclusion, the current findings would be helpful to explore the roles of nano-MgO composites on neuroprotection in PD.

Multi-ligand modified PC@DOX-PA/EGCG micelles effectively inhibit the growth of ER+, PR+ or HER2+ breast cancer.

Breast cancer is one of the most common cancers in the world with tumor heterogeneity. Currently, cancer treatment mainly relies on surgical intervention, chemotherapy, and radiotherapy, for which the side effects, drug resistance and cost need to be resolved. In this study, we develop a natural medicine targeted therapy system. Phosphatidylcholine (PC), doxorubicin (DOX), procyanidin (PA), and epigallocatechin gallate (EGCG) are assembled and PC@DOX-PA/EGCG nanoparticles (NPs) are obtained. In addition, the HER2, ER and PR ligands were grafted on the surface of the NPs to acquire the targeted nanoparticles NP-ER, NP-ER-HER2, and NP-ER-HER2-PR. The physicochemical properties of the nanoparticles were detected and it was found that the nanoparticles are spherical and less than 200 nm in diameter. Furthermore, in vitro and in vivo results indicate that the nanoparticles can target BT-474, MCF-7, EMT-6, and MDA-MB-231 breast cancer cells, effectively inhibiting the growth of the breast cancer cells. In short, this research will provide some strategies for the treatment of heterogeneous breast cancer.

Fabrication of Resveratrol-Loaded Scaffolds and Their Application for Delaying Cell Senescence In Vitro.

In this research, resveratrol (RSV)-loaded scaffolds have been prepared to control the release of resveratrol and used to delay hepatic stellate cell (HSC) senescence in vitro. The functional carboxyl group-COOH is first introduced to the surface of poly(ε-caprolactone/d,l-lactide) (P(CL-DLLA)) under the coadministration of ultra-violet (UV) treatment and photo initiator and then resveratrol are conjugated onto the surface of the modified scaffolds through esterification. The characterization of the structure of RSV-AA-P(CL-DLLA) shows that resveratrol has been successfully conjugated onto the modified surface. Cell growth exhibits a higher level of cell viability and much more obvious agglomeration on the surface of the synthetic RSV-AA-P(CL-DLLA). Meanwhile the activity of senescence-associated ß-galactosidase (SA-ß-gal) and reactive oxygen species (ROS) is downgulated for cells on RSV-AA-P(CL-DLLA), which suggests that cell senescence is delayed on RSV-AA-P(CL-DLLA). And then it is attested that cells have a lower level of p53 but SIRT1 expression is upregulated on RSV-AA-P(CL-DLLA), which might be related to resveratrol release from RSV-AA-P(CL-DLLA). It also suggested cell senescence on RSV-AA-P(CL-DLLA) has been regulated by p53 and the SIRT1 signaling pathway. In all, the present study shows that RSV-AA-P(CL-DLLA) can be successfully prepared to promote cell growth and delay cell senescence and could be used for cell-based therapy in tissue engineering.

Construction of a double-responsive modified guar gum nanoparticles and its application in oral insulin administration.

The use of intelligent insulin delivery systems has become more important for treating diabetes. In this study, a dual-responsive oral insulin delivery nanocarrier that responds to glucose and pH has been developed. First, the oleic acid hydrophobic modified guar gum (GG) was synthesized by the esterification reaction, and the γ-polyglutamic acid (γ-PGA) was coupled with GG by the amidation reaction. The obtained pH-responsive copolymer (γ-PGA-GG) was cross-linked by concanavalin A to obtain pH/glucose dual-responsive nanocarriers, and insulin was effectively loaded into the dual-responsive nanocarriers. The insulin-loaded nanoparticles can achieve effective pH and glucose responses, releasing insulin on demand. In vitro and in vivo studies demonstrated the dual-responsive nanoparticles can protect insulin against the pH changes in the digestive tract and deliver insulin into the body to exert a hypoglycemic effect. Moreover, the dual-responsive nanoparticles have significant potential to be employed for oral insulin delivery.

NIR-Assisted MgO-Based Polydopamine Nanoparticles for Targeted Treatment of Parkinson's Disease through the Blood-Brain Barrier.

The blood-brain barrier (BBB) is a major limiting factor that prevents the treatment of Parkinson's disease (PD). In the present study, MgOp@PPLP nanoparticles are explored by using MgO nanoparticles as a substrate, polydopamine as a shell, wrapping anti-SNCA plasmid inside, and modifying polyethylene glycol, lactoferrin, and puerarin on the surface to improve the hydrophilicity, brain targeting and antioxidant properties of the particles, respectively. MgOp@PPLP exhibits superior near-infrared radiation (NIR) response. Under the guidance of photothermal effect, these MgOp@PPLP particles are capable of penetrating the BBB and be taken up by neuronal cells to exert gene therapy and antioxidant therapy. In both in vivo and in vitro models of PD, MgOp@PPLP exhibits good neuroprotective effects. Therefore, combined with noninvasive NIR radiation, MgOp@PPLP nanoplatform with good biocompatibility becomes an ideal material to combat neurodegenerative diseases.