0D/2D heterojunctions, especially quantum dots (QDs)/nanosheets (NSs) have attracted significant attention for use of photoexcited electrons/holes due to their high charge mobility. Herein, ...unprecedent heterojunctions of vanadate (AgVO3, BiVO4, InVO4 and CuV2O6) QDs/graphitic carbon nitride (g‐C3N4) NSs exhibiting multiple unique advances beyond traditional 0D/2D composites have been developed. The photoactive contribution, up‐conversion absorption, and nitrogen coordinating sites of g‐C3N4 NSs, highly dispersed vanadate nanocrystals, as well as the strong coupling and band alignment between them lead to superior visible‐light‐driven photoelectrochemical (PEC) and photocatalytic performance, competing with the best reported photocatalysts. This work is expected to provide a new concept to construct multifunctional 0D/2D nanocomposites for a large variety of opto‐electronic applications, not limited in photocatalysis.
Vanadate quantum dots including AgVO3, BiVO4, InVO4, and CuV2O6 were strongly coupled with graphitic carbon nitride nanosheets using an in situ growth strategy. These quantum dots displayed a much better visible‐light‐driven photoelectrochemical activity and photocatalytic degradation efficiency than single vanadate quantum dots, carbon nitride nanosheets or previously reported highly active photocatalysts.
Background and Aims
No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to ...treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof‐of‐concept strategy by combining the regulation of leukocyte cell‐derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin‐like and epidermal growth factor–like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling.
Approach and Results
The CCl4‐induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno‐associated viral vector serotype 9 (AAV9)–LECT2–short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9‐LECT2‐shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects.
Conclusions
Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9‐LECT2‐shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.
Abstract
Photocatalytic reduction of CO
2
is a promising approach to achieve solar-to-chemical energy conversion. However, traditional catalysts usually suffer from low efficiency, poor stability, ...and selectivity. Here we demonstrate that a large porous and stable metal-organic framework featuring dinuclear Eu(III)
2
clusters as connecting nodes and Ru(phen)
3
-derived ligands as linkers is constructed to catalyze visible-light-driven CO
2
reduction. Photo-excitation of the metalloligands initiates electron injection into the nodes to generate dinuclear {Eu(II)}
2
active sites, which can selectively reduce CO
2
to formate in a two-electron process with a remarkable rate of 321.9 μmol h
−1
mmol
MOF
−1
. The electron transfer from Ru metalloligands to Eu(III)
2
catalytic centers are studied via transient absorption and theoretical calculations, shedding light on the photocatalytic mechanism. This work highlights opportunities in photo-generation of highly active lanthanide clusters stabilized in MOFs, which not only enables efficient photocatalysis but also facilitates mechanistic investigation of photo-driven charge separation processes.
Microglial polarization is one of the most promising therapeutic strategies for multiple central nervous system (CNS) disorders. However, safe, effective, and controllable microglial regulation still ...faces formidable challenges. Although some anti‐inflammatory factors promote microglia polarization, their short half‐life, high cost, unpredictable in vivo behavior, and complex delivery operations, hamper their clinical application. Here, inspired by the natural microhemorrhage cleaning mechanism, an MG1 peptide and RVG29 peptide engineered nanoerythrocyte (NEMR) that can reprogram microglia are developed from classical M1 toward alternative M2 by inducing heme oxygenase‐1 (HO‐1), stimulating Notch1/Hes1/Stat3 signaling, and further inhibiting NF‐κB p65 translocation. Moreover, anti‐inflammatory carbon monoxide (CO) and bilirubin produced by endogenous metabolism of heme further reinforces the anti‐inflammatory effect. In middle cerebral artery occlusion and experimental autoimmune encephalomyelitis models, a satisfactory prognosis is achieved, with precise regulation of inflammatory microglia in lesion sites, increased expression of anti‐inflammatory factors, reduced blood–brain barrier permeability, as well as promotion of neurogenesis and functional recovery. Furthermore, NEMR can be integrated with clinical therapeutic agents, which facilitates precise drug delivery to enhance therapeutic effects. Hence, the natural nanoerythrocytes, as a feasible, efficient, safe, and practical tool, provides a new strategy for rebalancing of the immune environment in the CNS disorders.
Microglia are the main regulator of inflammatory response in ischemic stroke and multiple sclerosis. An engineered nanoerythrocyte immunosuppressive platform is developed for precise targeting and efficient reprogramming of M1 microglia. The regulation of microglia function, protection of the blood–brain barrier, and neurons are realized through upregulation of heme oxygenase‐1 and reinforcement by intrinsic metabolism to generate anti‐inflammatory substances CO and bilirubin.
Colorectal cancer (CRC) is the second most common cause of cancer incidence worldwide. Oral drug delivery systems (ODDS) have shown great promise for CRC therapy, but the delivery efficiency is still ...challenged by the dense intestinal mucus barrier and nonspecific interception of abnormally proliferated pathogenic bacteria. Herein, self‐thermophoretic nanoparticles (CTPB) is presented to enhance intestinal mucus penetration and reduce pathogenic bacteria interception in CRC for efficient drug delivery. The nanoplatform introduces hollow mesoporous copper sulfide and is asymmetrically sprayed with titanium dioxide as the self‐thermophoretic matrix. Based on the close relationship between pathogenic bacteria and CRC, the nanoplatform is camouflaged by the biomimetic membrane of Staphylococcus aureus to precisely anchor in the intestinal segment of CRC. After near‐infrared laser irradiation, CTPB can effectively increase the intestinal mucus penetration efficiency by 2.7 folds, and decrease the pathogenic bacterial interception by 3.5 folds via the self‐thermophoretic propulsion force. In orthotopic CRC‐bearing mice, CTPB vastly improved the drug delivery efficiency to CRC after oral administration, thus showing a 99.4% antitumor rate after three weeks of treatment, which provides new insight into oral drug delivery for CRC therapy.
The delivery efficiency of oral nanoparticles is always limited by intestinal mucus and pathogenic bacteria interception. A self‐thermophoretic nanoparticle is developed for colorectal cancer therapy through penetrating intestinal mucus and detaching from pathogenic bacteria. With improved delivery efficiency, the nanoparticles showed a 99.4% antitumor efficiency in vivo, and provides a new strategy for orally targeted therapy of colorectal cancer.
• Basic helix–loop–helix (bHLH) proteins are involved in transcriptional networks controlling a number of biological processes in plants. However, little information is known on the roles of bHLH ...proteins in cotton fibre development so far.
• Here, we show that a cotton bHLH protein (GhFP1) positively regulates fibre elongation. GhFP1 transgenic cotton and Arabidopsis plants were generated to study how GhFP1 regulates fibre cell elongation.
• Fibre length of the transgenic cotton overexpressing GhFP1 was significantly longer than that of wild-type, whereas suppression of GhFP1 expression hindered fibre elongation. Furthermore, overexpression of GhFP1 in Arabidopsis promoted trichome development. Expression of the brassinosteroid (BR)-related genes was markedly upregulated in fibres of GhFP1 overexpression cotton, but downregulated in GhFP1-silenced fibres. BR content in the transgenic fibres was significantly altered, relative to that in wild-type. Moreover, GhFP1 protein could directly bind to the promoters of GhDWF4 and GhCPD to activate expression of these BR-related genes.
• Therefore, our data suggest that GhFP1 as a positive regulator participates in controlling fibre elongation by activating BR biosynthesis and signalling. Additionally, homodimerisation of GhFP1 may be essential for its function, and interaction between GhFP1 and other cotton bHLH proteins may interfere with its DNA-binding activity.
Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological activity, which has led to the ...discovery of numerous broad-spectrum therapeutic agents. In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer's), ciclopirox (ringworm and athlete's foot), crizotinib (cancer), nifedipine (Raynaud's syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. Their remarkable therapeutic applications have encouraged researchers to prepare a larger number of biologically active compounds decorated with pyridine or dihydropyridine, expandeing the scope of finding a cure for other ailments. It is thus anticipated that myriad new pharmaceuticals containing the two heterocycles will be available in the forthcoming decade. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development.
Delta-secretase cleaves both APP and Tau to mediate the formation of amyloid plaques and neurofibrillary tangle in Alzheimer's disease (AD). However, how aging contributes to an increase in ...delta-secretase expression and AD pathologies remains unclear. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression in mediating pathogenesis in AD mouse models. We find that C/EBPβ regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBPβ in young 3xTg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.
Abstract
Currently, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been reported in almost all countries globally. No effective ...therapy has been documented for COVID-19, and the role of convalescent plasma therapy is unknown. In the current study, 6 patients with COVID-19 and respiratory failure received convalescent plasma a median of 21.5 days after viral shedding was first detected, all tested negative for SARS-CoV-2 RNA within 3 days after infusion, and 5 eventually died. In conclusion, convalescent plasma treatment can end SARS-CoV-2 shedding but cannot reduce the mortality rate in critically ill patients with end-stage COVID-19, and treatment should be initiated earlier.
Six patients with coronavirus 2019 disease and respiratory failure received convalescent plasma a median of 21.5 days after first detected viral shedding, all tested negative for severe acute respiratory syndrome coronavirus 2 within 3 days after infusion, and 5 eventually died.
Alzheimer's disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and ...synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy.
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