"Swiss Army Knife" black phosphorus-based nanodelivery platform for synergistic antiparkinsonian therapy via remodeling the brain microenvironment.

The combination of excessive reactive oxygen species (ROS) levels, neuroinflammation, and pathogenic protein aggregation disrupt the homeostasis of brain microenvironment, creating conditions conducive to the progression of Parkinson's disease (PD). Restoring homeostasis by remodeling the brain microenvironment could reverse this complex pathological progression. However, treatment strategies that can induce this effect are currently unavailable. Herein, we developed a "Swiss Army Knife" nanodelivery platform consisting of matrine (MT) and polyethylene glycol-modified black phosphorus nanosheets (BP) that enables PD treatment by restoring brain microenvironment homeostasis. Under NIR irradiation, the photothermal effect induced by BP allowed the nanomedicine to cross the blood-brain barrier (BBB) and entered the brain parenchyma. In PD brains, the biological effects of BP and MT resulted in the removal of excess ROS, effective reduction of neuroinflammation, decreased aggregation of pathogenic proteins, and improved neurotransmitter delivery, eventually restoring dopamine levels in the striatum. This study demonstrated the effective capacity of a BP-based nanodelivery platform to enter the brain parenchyma and trigger multiple neuropathological changes in PD brains. The platform serves as a safe and effective anti-PD nanomedicine with immense clinical potential.

Programmed Stimuli-Responsive Carbon Dot-Nanogel Hybrids for Imaging-Guided Enhanced Tumor Phototherapy.

For harmonizing the contradiction of nanotheranostic agents between enhanced tumor accumulation and penetration, efficient cell internalization and fast elimination are key tactics for promoting their clinical applications. Herein, programmed stimuli-responsive poly(N-isopropylacrylamide)-carbon dot (PNIPAM-CD) hybrid nanogels are designed to address the abovementioned conflicts. The enlarged particle size of PNIPAM-CDs enables one to effectively improve their accumulation at tumor sites. Once the hybrid nanogels are docked in tumors and exposed to deep-red-light (660 nm) irradiation, heat and reactive oxygen species (ROS) are generated from the CDs, consequently activating photothermal therapy (PTT) and photodynamic therapy (PDT) effects and meanwhile inducing partial degradation of PNIPAM-CDs for deep tissue penetration. Further, enhanced cellular internalization of the functional components can be achieved owing to the pH-responsive charge reversal and temperature-dependent hydrophilic/hydrophobic conversion characteristics of PNIPAM-CDs. Finally, the overexpressed glutathione (GSH) in tumor cells would trigger further cleavage of the partially degraded hybrid nanogels, which is beneficial for their rapid clearance from the body. This work not only proposed a novel strategy to fabricate nanotheranostic agents using just a single functional component (i.e., the versatile CDs) to simplify the preparation process but also achieved effective delivery of agents into tumor cells by overcoming the multiple biological barriers to enhance therapeutic efficacy and decrease side effects.

Iron parameters in pregnant women with beta-thalassaemia minor combined with iron deficiency anaemia compared to pregnant women with iron deficiency anaemia alone demonstrate the safety of iron supplementation in beta-thalassaemia minor during pregnancy.

In patients with beta-thalassaemia intermedia or major, hepcidin induces iron overload by continuously promoting iron absorption. There have been no studies in pregnant women with beta-thalassaemia minor combined with iron deficiency anaemia (IDA), examining whether hepcidin is inhibited by GDF15, as may occur in patients with beta-thalassaemia intermedia or major, or whether the iron metabolism characteristics and the effect of iron supplementation are consistent with simple IDA in pregnancy. We compared and analysed routine blood parameters, iron metabolism parameters, the GDF15 levels, and the hepcidin levels among four groups, namely the beta-thalassaemia (ß) + IDA, ß, IDA, and normal groups. In addition, the ß + IDA and IDA groups received iron supplementation for four weeks. We found no statistically significant correlation between hepcidin and GDF15 in any group, but a positive correlation was observed between hepcidin and ferritin. After iron supplementation, the routine blood parameters and iron metabolism parameters in the ß + IDA group were improved, and the hepcidin content was significantly increased. These results suggest that in pregnant women with beta-thalassaemia minor, hepcidin functions normally to maintain iron homeostasis, and that iron supplementation is effective and safe.

Discovery of Novel and Potent N-Methyl-d-aspartate Receptor Positive Allosteric Modulators with Antidepressant-like Activity in Rodent Models.

N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+ and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.

Brain-targeted delivery shuttled by black phosphorus nanostructure to treat Parkinson's disease.

The treatment of Parkinson's disease (PD) is hampered by the blood-brain barrier (BBB). As such, there is an urgent need for the development of a novel nanoplatform capable of penetrating the BBB in order to effectively treat PD. In the present study, we utilized black phosphorus nanosheets (BP) containing the brain-targeting ligand lactoferrin (Lf) and loaded with Paeoniflorin (Pae) to obtain Lf-BP-Pae. Through an effective photo-thermal effect, these Lf-BP-Pae particles were capable of traversing the BBB and effectively treating PD in a targeted manner. Importantly, this BP-based nanoplatform was capable of achieving satisfactory biocompatibility and biosafety with excellent anti-Parkinsonian efficacy, making it ideal for clinical applications.

Biomimetic cell-cell adhesion capillary electrophoresis for studying Gu-4 antagonistic interaction between cell membrane receptor and ligands.

We report a new method: biomimetic cell-cell adhesion capillary electrophoresis (BCCACE) to screen drugs targeting interactions between cell membrane receptors and ligands under an environment close to physiological conditions, in which the cell membrane receptors/ligands can maintain their natural conformations and bioactivity without being isolated and purified. Firstly, we screened twenty-one lactose derivatives by cell-immobilized capillary electrophoresis and obtained Gu-4 with the best activity (K = 3.58 ±â€¯0.22 × 104) targeting macrophage antigen-1 (Mac-1). Then, BCCACE was performed as follows: HEK 293 cells overexpressed with receptor (intercellular adhesion molecules-1, ICAM-1) were cultured and immobilized on the inner wall of capillaries as stationary phase, which simulated the endothelial cells lining on the inner surface of blood vessels. HEK 293 cells overexpressed with ligand Mac-1 as samples were used to simulate the neutrophils cells in blood vessels. And Gu-4 added into the running buffer solution as the antagonist was used to simulate the drug in blood. The results showed that Gu-4 (40 µM) could selectively inhibit cell-cell adhesion by targeting the interaction between Mac-1 and ICAM-1. Finally, the pharmaceutical efficacy assays of Gu-4 at cellular and animal levels were carried out using the concentration of 40 µM and the dose of 20 mg kg-1 respectively, which showed the anti-cancer metastasis activity of Gu-4 and the validity of the method. This method simulated a complete three-dimensional vascular model, which can easily obtain the suitable blood concentration of drugs. This system simulated the interaction between leukocytes and vascular endothelial cells in the bloodstream antagonized by drugs, and obtained the effective concentration of the antagonist. It can be used as an accuracy and efficient drug screening method and will be expected to become a new method to screen drugs targeting cell-cell adhesion.

Ce6-Modified Carbon Dots for Multimodal-Imaging-Guided and Single-NIR-Laser-Triggered Photothermal/Photodynamic Synergistic Cancer Therapy by Reduced Irradiation Power.

Photomediated cancer therapy, mainly including photothermal (PT) therapy (PTT) and photodynamic therapy (PDT), has attracted tremendous attention in recent years thanks to its noninvasive and stimuli-responsive features. The single mode of PTT or PDT, however, has obvious drawbacks, either requiring high-power laser irradiation to generate enough heat or only providing limited efficacy due to the hypoxia nature inside tumors. In addition, the reported synergistic PTT/PDT generally utilized two excitation sources to separately activate PTT and PDT, and the problem of high-power laser irradiation for PTT was still not well solved. Herein, a new concept, loading a small amount of photosensitizers onto a PTT agent (both of them can be triggered by a single-near-infrared (NIR) laser), was proposed to evade the shortcomings of PTT and PDT. To validate this idea, minute quantities of photosensitizer chlorin e6 (Ce6) (0.56% of mass) were anchored onto amino-rich red emissive carbon dots (RCDs) that possess superior photothermal (PT) character under 671 nm NIR laser (PT conversion efficiency to be 46%), and meanwhile the PDT of Ce6 can be activated by this laser irradiation as well. The findings demonstrate that Ce6-modified RCDs (named Ce6-RCDs) offer much higher cancer therapy efficacy under a reduced laser power density (i.e., 0.50 W cm-2 at 671 nm) in vitro and in vivo than the equivalent RCDs or Ce6 under the same irradiation conditions. Besides, the Ce6-RCDs also exhibit multimodal imaging capabilities (i.e., fluorescence (FL), photoacoustic (PA), and PT), which can be employed for guidance of the phototherapy process. This study suggests not only a strategy to enhance cancer phototherapy efficacy but also a promising candidate (i.e., Ce6-RCDs) for multimodal FL/PA/PT imaging-guided and single-NIR-laser-triggered synergistic PTT/PDT for cancers by a reduced irradiation power.

Conceptually Novel Black Phosphorus/Cellulose Hydrogels as Promising Photothermal Agents for Effective Cancer Therapy.

Black phosphorus (BP) has recently emerged as an intriguing photothermal agent in photothermal therapy (PTT) against cancer by virtue of its high photothermal efficiency, biocompatibility, and biodegradability. However, naked BP is intrinsically characterized by easy oxidation (or natural degradation) and sedimentation inside the tumor microenvironment, leading to a short-term therapeutic and inhomogeneous photothermal effect. Development of BP-based nanocomposites for PTT against cancer therefore remains challenging. The present work demonstrates that green and injectable composite hydrogels based on cellulose and BP nanosheets (BPNSs) are of great efficiency for PTT against cancer. The resultant cellulose/BPNS-based hydrogel possesses 3D networks with irregular micrometer-sized pores and thin, strong cellulose-formed walls and exhibits an excellent photothermal response, enhanced stability, and good flexibility. Importantly, this hydrogel nanoplatform is totally harmless and biocompatible both in vivo and in vitro. This work may facilitate the development of BP-polymer-based photothermal agents in the form of hydrogels for biomedical-related clinic applications.

Black phosphorus nanosheets for rapid microRNA detection.

Herein, for the first time, a sensitive sensing platform for rapid detection of microRNA was developed by employing black phosphorus nanosheets as the fluorescence quenching material. The biosensor displayed a good linear response to microRNA ranging from 10 nM to 1000 nM. Moreover, the biosensor could distinguish triple nucleotide polymorphism.

Novel concept of the smart NIR-light-controlled drug release of black phosphorus nanostructure for cancer therapy.

A biodegradable drug delivery system (DDS) is one the most promising therapeutic strategies for cancer therapy. Here, we propose a unique concept of light activation of black phosphorus (BP) at hydrogel nanostructures for cancer therapy. A photosensitizer converts light into heat that softens and melts drug-loaded hydrogel-based nanostructures. Drug release rates can be accurately controlled by light intensity, exposure duration, BP concentration, and hydrogel composition. Owing to sufficiently deep penetration of near-infrared (NIR) light through tissues, our BP-based system shows high therapeutic efficacy for treatment of s.c. cancers. Importantly, our drug delivery system is completely harmless and degradable in vivo. Together, our work proposes a unique concept for precision cancer therapy by external light excitation to release cancer drugs. If these findings are successfully translated into the clinic, millions of patients with cancer will benefit from our work.

Antimonene Quantum Dots: Synthesis and Application as Near-Infrared Photothermal Agents for Effective Cancer Therapy.

Photothermal therapy (PTT) has shown significant potential for cancer therapy. However, developing nanomaterials (NMs)-based photothermal agents (PTAs) with satisfactory photothermal conversion efficacy (PTCE) and biocompatibility remains a key challenge. Herein, a new generation of PTAs based on two-dimensional (2D) antimonene quantum dots (AMQDs) was developed by a novel liquid exfoliation method. Surface modification of AMQDs with polyethylene glycol (PEG) significantly enhanced both biocompatibility and stability in physiological medium. The PEG-coated AMQDs showed a PTCE of 45.5 %, which is higher than many other NMs-based PTAs such as graphene, Au, MoS2 , and black phosphorus (BP). The AMQDs-based PTAs also exhibited a unique feature of NIR-induced rapid degradability. Through both in vitro and in vivo studies, the PEG-coated AMQDs demonstrated notable NIR-induced tumor ablation ability. This work is expected to expand the utility of 2D antimonene (AM) to biomedical applications through the development of an entirely novel PTA platform.

A new natural lactone from Dimocarpus longan Lour. seeds.

A new natural product named longanlactone was isolated from Dimocarpus longan Lour. seeds. Its structure was determined as 3-(2-acetyl-1H--pyrrol-1-yl)-5-(prop-2-yn-1-yl)dihydrofuran-2(3H)-one by spectroscopic methods and HRESIMS.

Therapeutic effects of lactosyl derivative Gu-4 in a collagen-induced arthritis rat model.

Rheumatoid arthritis (RA) is an inflammatory disorder that is characterized by persistent recurrence of joint inflammation leading to cartilage and bone destruction. The present anti-arthritis therapies failed to achieve satisfactory remission in all patients; therefore, it is still necessary to develop novel approaches to fulfill the demand in clinic. Here, we reported the therapeutic effects of lactosyl derivative Gu-4, a synthetic compound that was previously identified as a selective inhibitor against leukocyte integrin CD11b, in a bovine type II collagen induced arthritis (CIA) rat model. First, prophylactic administration of Gu-4 (1.2728 mg/kg) to rats by intraperitoneal injection every 2 days from the first day of collagen immunization significantly decreased the incidence of CIA, diminished the mean paw volume increase, and reduced the number of swollen paws. Second, administration of Gu-4 (1.2728 mg/kg) to rats at early-onset stage of CIA prevented the progression of the pathological process of RA, accelerated the remission of paw edema, and declined the arthritis score; after 5 weeks treatment, X-ray and histological examinations were carried out, the ankle joint of hind limb of Gu-4 treated CIA rats exhibited slighter bone erosion and much less inflammatory cell infiltration compared to those of saline treated animals; furthermore, Gu-4 remarkably attenuated the production of rheumatoid factor (RF) in the serum of CIA rats as determined by ELISA. Moreover, we performed in vitro lymphocyte proliferation assay and found that Gu-4 significantly inhibited the proliferation of splenic lymphocytes isolated from CIA rats in a dose-dependent manner. Our results suggest that Gu-4 can effectively ameliorate CIA and might be an alternative option for the treatment of RA.

Suspended graphene sensors with improved signal and reduced noise.

We report enhanced performance of suspended graphene field effect transistors (Gra-FETs) as sensors in aqueous solutions. Etching of the silicon oxide (SiO(2)) substrate underneath graphene was carried out in situ during electrical measurements of devices, which enabled systematic comparison of transport properties for same devices before and after suspension. Significantly, the transconductance of Gra-FETs in the linear operating modes increases 1.5 and 2 times when the power of low-frequency noise concomitantly decreases 12 and 6 times for hole and electron carriers, respectively, after suspension of graphene in solution from the SiO(2) substrate. Suspended graphene devices were further demonstrated as direct and real-time pH sensors, and complementary pH sensing with the same nanodevice working as either a p-type or n-type transistor was experimentally realized by offsetting the electrolyte gate potential in solution. Our results highlight the importance to quantify fundamental parameters that define resolution of graphene-based bioelectronics and demonstrate that suspended nanodevices represent attractive platforms for chemical and biological sensors.

[Analysis and suggestion management system of wild medicinal resources].

The present paper introduced the management status of wild medicinal resources (WMR) including the law system, the government system and the rule system, and analyzed the main problems and their reasons for WMR management. It pointed out that the old management system for WMR was not fit the need of conversation and management of WMR. It suggested to revise the "the Law of Conversation and Manage System of Wild Medicinal Resources", and discussed the law type, the objective and the principle he government system, management field and rule system for the revised law in details.

A study on the immune receptors for polysaccharides from the roots of Astragalus membranaceus, a Chinese medicinal herb.

The immunopotentiating effect of the roots of Astragalus membranaceus, a medicinal herb, has been associated with its polysaccharide fractions (Astragalus polysaccharides, APS). We herein demonstrate that APS activates mouse B cells and macrophages, but not T cells, in terms of proliferation or cytokine production. Fluorescence-labeled APS (fl-APS) was able to selectively stain murine B cells, macrophages and a also human tumor cell line, THP-1, as determined in flow cytometric analysis and confocal laser scanning microscopy. The specific binding of APS to B cells and macrophages was competitively inhibited by bacterial lipopolysaccharides. Rabbit-anti-mouse immunoglobulin (Ig) antibody was able to inhibit APS-induced proliferation of, and APS binding to, mouse B cells. Additionally, APS effectively stimulated the proliferation of splenic B cells from C3H/HeJ mice that have a mutated TLR4 molecule incapable of signal transduction. These results indicate that APS activates B cells via membrane Ig in a TLR4-independent manner. Interestingly, macrophages from C3H/HeJ mice were unable to respond to APS stimulation, suggesting a positive involvement of the TLR4 molecule in APS-mediated macrophage activation. Monoclonal Ab against mouse TLR4 partially inhibited APS binding with macrophages, implying direct interaction between APS and TLR4 on cell surface. These results may have important implications for our understanding on the molecular mechanisms of immunopotentiating polysaccharides from medicinal herbs.