Bibliometric Analysis of Brain Stimulation Technologies in Sleep Disorders.

BACKGROUND Sleep disorders are a common disease faced by people today and can lead to fatigue, lack of concentration, impaired memory, and even death. In recent years, the development of brain stimulation techniques has provided a new perspective for the treatment of sleep disorders. However, there is a lack of bibliometric analyses related to sleep disorders and brain stimulation techniques. Therefore, this study analyzed the application status and trend of brain stimulation technology in sleep disorder research. MATERIAL AND METHODS Articles and reviews published between 1999 and 2023 were retrieved from the Web of Science. CiteSpace was used to visually analyze the publications, countries, institutions, journals, authors, references, and keywords. RESULTS A total of 459 publications were obtained. The number of studies was shown to be on a general upward trend. The country with the largest number of publications was the United States; UDICE-French Research Universities had the highest number of publications; Neurology had the highest citation frequency; 90% of the top 10 references cited were from Journal Citation Reports Q1; Brigo was the author with the highest number of publications; and the most frequent keywords were "transcranial magnetic stimulation", "deep brain stimulation", and "Parkinson disease". CONCLUSIONS Our study used CiteSpace software to analyze 459 studies published since 1999 on brain stimulation techniques for the treatment of sleep disorders, revealing research trends and the current state of the field. Our results will help researchers to understand the existing research quickly and provide direction for future research.

Weak acid-initiated slow release of Dexamethasone from hydrogel to treat orbital inflammation.

Rationale: Orbital inflammation is a prevalent and prolonged ocular disease that poses a significant challenge to clinicians. Glucocorticoid Dexamethasone sodium phosphate (Dex) has demonstrated efficacy in the clinical treatment of nonspecific orbital inflammation. However, frequent administration is required due to the short half-life of Dex, which may lead to drug waste and adverse side effects. Methods: In this study, we co-assembled Dex with a weak acid responsive hydrogelator Py-Phe-Phe-Lys-Lys-OH (K) to obtain a novel supramolecular hydrogel Dex/K that could release Dex in a slow manner to treat orbital inflammation. The therapeutic effect of Gel Dex/K on orbital inflammation was verified by in vitro and in vivo experiments. Results: In vitro experiments indicated that co-assembly of Dex with K significantly increased mechanic strength of the hydrogel, enabling a continuous release of 40% of total Dex within 7 days. In vivo experiments further demonstrated that sustained release of Dex from Gel Dex/K could effectively alleviate the infiltration of inflammatory cells and the release of inflammatory factors in the orbit of mice, improving symptoms such as increased intraocular pressure and proptosis. Additionally, Gel Dex/K mitigated the degree of tissue fibrosis and fatty infiltration by reducing the development of local inflammation in the orbit. Conclusions: Our research results indicate that Gel Dex/K could more efficiently achieve responsive drug release in orbit, providing an innovative method for treating orbital inflammation.

Branched hydrophobic tails in lipid nanoparticles enhance mRNA delivery for cancer immunotherapy.

Efficient and safe delivery of vulnerable mRNA is a long-standing challenge for the broad application of the emerging mRNA-based therapeutics. Herein, a combinatorial library containing 119 novel lipids was constructed via sequential aza-Michael addition reactions of arylates and varying amines to tackle the ongoing challenge in mRNA delivery. Through in vitro screening of the lipid library on IGROV 1 cells, we identified several synthetic lipids with superior mRNA delivery efficacy. The delivery capability of these lipids was verified by the potent expression of luciferase in BALB/c mice upon intravenous administration of luciferase-encoding mRNA lipid nanoparticles (LNPs). Further investigations on the structure-activity relationship revealed that lipids with branched hydrophobic tails were better at delivering mRNA than those containing linear tails at the similar total number of carbons. In comparison to linear tails, the branched tails endowed LNPs with less inner hydrophobicity, fewer surface charges, and proper stability, which benefits the cellular uptake of LNPs and the intracellular trafficking of mRNA, thus improves the delivery efficacy of mRNA. The therapeutical potential of the lead LNPs was evaluated by delivering ovalbumin (OVA)-encoding mRNA to mice bearing B16-OVA melanoma tumors. The results demonstrated that the administration of OVA mRNA LNPs significantly activated CD8+ T cells in tumor microenvironment and substantially prohibited the growth of the aggressive B16-OVA tumors. The robust antitumor efficacy highlights the great potential of these LNPs in cancer immunotherapy.

Intracellular Construction of Cathepsin B-Guided Gadolinium Nanoparticles for Enhanced T2 -Weighted MR Tumor Imaging.

Magnetic resonance imaging (MRI) is a superior and noninvasive imaging technique with unlimited tissue penetration depth and superb spatiotemporal resolution, however, using intracellular self-assembly of Gd-containing nanoparticles to enhance the T2 -weighted MR contrast of cancer cells in vivo for precise tumor MRI is rarely reported. The lysosomal cysteine protease cathepsin B (CTSB) is regarded as an attractive biomarker for the early diagnosis of cancers and metastasis. Herein, taking advantage of a biocompatible condensation reaction, a "smart" Gd-based CTSB-responsive small molecular contrast agent VC-Gd-CBT is developed, which can self-assemble into large intracellular Gd-containing nanoparticles by glutathione reduction and CTSB cleavage to enhance the T2 -weighted MR contrast of CTSB-overexpressing MDA-MB-231 cells at 9.4 T. In vivo T2 -weighted MRI studies using MDA-MB-231 murine xenografts show that the T2 -weighted MR contrast change of tumors in VC-Gd-CBT-injected mice is distinctly larger than the mice injected with the commercial agent gadopentetate dimeglumine, or co-injected with CTSB inhibitor and VC-Gd-CBT, indicating that the accumulation of self-assembled Gd-containing nanoparticles at tumor sites effectively enhances the T2 -weighted MR tumor imaging. Hence, this CTSB-targeted small molecule VC-Gd-CBT has the potential to be employed as a T2 contrast agent for the clinical diagnosis of cancers at an early stage.

Quality of clinical practice guidelines relevant to rehabilitation of knee osteoarthritis: A systematic review.

OBJECTIVE: This systematic review summarized the rehabilitation recommendations for treating and managing knee osteoarthritis (OA) in practice guidelines and evaluated their applicability and quality using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. DATA SOURCES: PubMed, the Cochrane Library, EMBASE, CINAHL, PEDro, Guideline central, Guideline International Network and Agency for Healthcare Research and Quality (AHRQ) were used to search for relevant studies published between 1 January 2008 and 31 May 2022. METHODS: AGREE II was used to evaluate the included guidelines quality, SPSS 25.0 statistical software was used for data analysis, and the intra-group correlation coefficient value was calculated to verify the consistency between the raters. The two-way random effects model was used to calculate concordance scores, and each domain's total scores were calculated. Additionally, the median and interquartile range for domain and total scores were calculated. RESULTS: Twenty-four guidelines recommending knee OA rehabilitation were included. Inter-rater consistency evaluation ranged from 0.62 to 0.90. The domains where the guideline's overall and rehabilitation parts scored highest and lowest were scope and purpose (domain 1) and applicability (domain 5), respectively. The highly recommended rehabilitation opinions included aerobic exercise programs (21/24), weight control (16/24), self-education and management (16/24), gait/walking aids (7/24), and tai chi (6/24). However, the orthopedic insole and hot/cold therapy roles remain controversial. CONCLUSION: The clinical practice guidelines' overall quality for knee OA rehabilitation is good; however, the applicability is slightly poor. Therefore, we should improve the promoting factors and hindering factors, guideline application recommendations, tools, and resources when developing relevant guidelines.

V1-Cal hydrogelation enhances its effects on ventricular remodeling reduction and cardiac function improvement post myocardial infarction.

Myocardial infarction (MI) is a major cause of disability and mortality worldwide. A cell permeable peptide V1-Cal has shown remarkable therapeutic effects on ML However, using V1-Cal to improve long-term cardiac function after MI is presently limited by its short half-life. Herein, we co-assembled V1-Cal with a well-known hydrogelator Nap-Phe-Phe-Tyr (NapFFY) to obtain a new supramolecular hydrogel V1-Cal/NapFFY. We found that the hydrogel could significantly enhance the therapeutic effects of V1-Cal on ventricular remodeling reduction and cardiac function improvement in a myocardial infarction rat model. In vitro experiments indicated that co-assembly of V1-Cal with NapFFY significantly increased mechanic strength of the hydrogel, enabling a sustained release of V1-Cal for more than two weeks. In vivo experiments supported that sustained release of V1-Cal from V1-Cal/NapFFY hydrogel could effectively decrease the expression and activation of TRPV1, reduce apoptosis and the release of inflammatory factors in a MI rat model. In particular, V1-Cal/NapFFY hydrogel significantly decreased infarct size and fibrosis, while improved cardiac function 28 days post MI. We anticipate that V1-Cal/NapFFY hydrogel could be used clinically to treat MI in the near future.

Structural Exploration of Polycationic Nanoparticles for siRNA Delivery.

RNA interference (RNAi) is a promising approach to the treatment of genetic diseases by the specific knockdown of target genes. Functional polymers are potential vehicles for the effective delivery of vulnerable small interfering RNA (siRNA), which is required for the broad application of RNAi-based therapeutics. The development of methods for the facile modulation of chemical structures of polymeric carriers and an elucidation of detailed delivery mechanisms remain important areas of research. In this paper, we synthesized a series of methacrylate-based polymers with controllable structures and narrow distributions by atom transfer radical polymerization using various combinations of cationic monomers (2-dimethylaminoethyl methacrylate, 2-diethylaminoethyl methacrylate, and 2-dibutylaminoethyl methacrylate) and hydrophobic monomers (2-butyl methacrylate (BMA), cyclohexyl methacrylate, and 2-ethylhexyl methacrylate). These polymers exhibited varying hydrophobicities, charge densities, and pKa values, enabling the discovery of effective carriers for siRNA by in vitro delivery assays. For the polymers with BMA segments, 50% of cationic segments were beneficial to the formation of siRNA nanoparticles (NPs) and the in vitro delivery of siRNA. The optimal ratio varied for different combinations of cationic and hydrophobic segments. In particular, 20k PMB 0.5, PME 0.5, and PEB 1.0 showed >75% luciferase knockdown. Efficacious delivery was dependent on high siRNA binding, the small size of NPs, and balanced hydrophobicity and charge density. Cellular uptake and endosomal escape experiments indicated that carboxybetaine modification of 20k PMB 0.5 did not remarkably affect the internalization of corresponding NPs after incubation for 6 h but significantly reduced the endosomal escape of NPs, which leads to the notable decrease in delivery efficacy of polymers. These results provide insights into the mechanism of polymer-based siRNA delivery and may inspire the development of novel polymeric carriers.

Lysosome-Targeted and Fluorescence-Turned "On" Cytotoxicity Induced by Alkaline Phosphatase-Triggered Self-Assembly.

Selectively inducing lysosomal membrane permeabilization (LMP) is a promising strategy for cancer therapy. But integrating alkaline phosphatase (ALP)-instructed self-assembly and lysosome-targeting to induce LMP for selective killing of cancer cells was not reported. Herein, a pyrene-peptide conjugate Py-Phe-Phe-Glu-Tyr(H2 PO3 )-Gly-lyso (Py-Yp-Lyso) is rationally designed and demonstrated for its lysosome-targeting cytotoxicity on cancer cells, together with its pyrene (Py) excimer fluorescence turning "on" at 480 nm. In vitro results showed that, Py-Yp-Lyso is efficiently dephosphorylated by ALP to yield Py-Phe-Phe-Glu-Tyr-Gly-lyso (Py-Y-Lyso) which self-assembles into nanofibers. Cell experiments verified that, after being taken up by HeLa cells, the excimer fluorescence of Py-Yp-Lyso assemblies has turned "on" and the assemblies specifically target the lysosomes, inducing LMP and ultimate cancer cell death. In vivo experiments indicated that Py-Yp-Lyso has the highest inhibition effect on HeLa tumors among the four compounds studied. This is anticipated for applying Py-Yp-Lyso to treat cancers in the clinic in the future.

Functional Muscle Network in Post-stroke Patients during Quiet Standing.

The overall muscle activation of post-stroke patients during standing has not been well understood. Functional muscle network provides a tool to quantify the functional synchronization across a large number of muscles. In order to investigating the functional muscle network of stroke survivors during quiet standing, we recruited 8 post-stroke hemiplegic patients and required them to stand still for 30 s with eyes open and closed. Surface electromyography signals were recorded from 16 muscles in abdomen, buttocks and lower limbs. The functional muscle networks of paretic side and healthy side were built by multiplex recurrence network approach. The topological characteristics of functional muscle network was quantified by parameters of multiplex network and weighted network. The results showed that the dynamical similarities of muscles on paretic side were reduced, and the dynamical connections of muscles on paretic side were weakened. Without visual feedback, the muscles activated in a more similar mode. The stroke led to lower synchronization of the muscle activation, and decreased efficiency of information transmission between muscles. When subjects stood with eyes closed, the muscles activated in a more deterministic pattern. The research opens new horizons to detect the overall muscle activation when stroke patients stand quietly, and can provide a theoretical basis for understanding the motor dysfunction caused by stroke.

Alkaline phosphatase-triggered self-assembly of near-infrared nanoparticles for the enhanced photoacoustic imaging of tumors.

In this chapter, we discuss the need for the development of enzyme-activatable probes in the field of tumor-targeted photoacoustic (PA) imaging, then we give a brief description of the innovation of designing alkaline phosphatase (ALP)-activatable probes for PA imaging. After that, we provide detailed protocols for the syntheses and characterizations of a near-infrared photoacoustic imaging probe, 1P, developed in our research group. With this tool, 1P could form nanoparticles 1-NPs under the catalysis of ALP and thus could be used to enhance PA imaging both in vitro and in vivo.

Bioluminescence Imaging of Urokinase-Type Plasminogen Activator Activity in Vitro and in Tumors.

Urokinase-type plasminogen activator (uPA) is a cell-secreted serine protease and plays a significant role in numerous biological processes. Overexpression of uPA has been proved to be relevant to some malignant tumors as well as poor prognosis. However, bioluminescence (BL) probes for selectively sensing uPA activity have not been reported up to now. Herein, we designed a BL probe, GGR-AmLuc, to detect uPA in vitro and sense uPA both inside cells and in tumors. In vitro studies demonstrated that GGR-AmLuc was able to selectively detect uPA with a limit of detection (LOD) of 1.37 µg/L. Moreover, GGR-AmLuc was successfully applied to image uPA in living subjects with excellent sensitivity. We anticipate that probe GGR-AmLuc could be applied for highly sensitive diagnosis of cancers overexpressing uPA and provide guidance for cancer treatment in the near future.

A Golgi-Targeting and Dual-Color "Turn-On" Probe for Spatially Precise Imaging of Furin.

Development of fluorescence probes for highly accurate detection of cancer-related enzyme activity is important in early cancer diagnosis. Herein, we report a Golgi-targeting and dual-color "Turn-On" probe Q-RVRR-DCM for imaging furin with high spatial precision. By integrating the principles of Förster resonance energy transfer and intramolecular charge transfer, the probe was designed to be non-fluorescent. Upon furin cleavage, Q-RVRR-DCM was converted into Q-RVRR and DCM-NH2, turning the dual fluorescence color "On" at 420 and 640 nm without spectral cross-talk. In furin-overexpressing HCT116 cells, Q-RVRR-DCM showed not only furin-specific, dual-color "Turn-On" fluorescence but also superior colocalization with a Golgi tracker than the single-color "Turn-On" probe RVRR-DCM. We envision that, with the excellent properties of Golgi-targeting and dual fluorescence color "Turn-On", our furin probe Q-RVRR-DCM could be applied for accurate early diagnosis of cancer in the near future.

Sustained Release of Two Bioactive Factors from Supramolecular Hydrogel Promotes Periodontal Bone Regeneration.

Intact and stable bone reconstruction is ideal for the treatment of periodontal bone destruction but remains challenging. In research, biomaterials are used to encapsulate stem cells or bioactive factors for periodontal bone regeneration, but, to the best of our knowledge, using a supramolecular hydrogel to encapsulate bioactive factors for their sustained release in bone defect areas to promote periodontal bone regeneration has not been reported. Herein, we used a well-studied hydrogelator, NapFFY, to coassemble with SDF-1 and BMP-2 to prepare a supramolecular hydrogel, SDF-1/BMP-2/NapFFY. In vitro and in vivo results indicated that these two bioactive factors were ideally, synchronously, and continuously released from the hydrogel to effectively promote the regeneration and reconstruction of periodontal bone tissues. Specifically, after the bone defect areas were treated with our SDF-1/BMP-2/NapFFY hydrogel for 8 weeks using maxillary critical-sized periodontal bone defect model rats, a superior bone regeneration rate of 56.7% bone volume fraction was achieved in these rats. We anticipate that our SDF-1/BMP-2/NapFFY hydrogel could replace bone transplantation in the clinic for the repair of periodontal bone defects and periodontally accelerated osteogenic orthodontics in the near future.

Facile syntheses of conjugated polymers for photothermal tumour therapy.

Development of photothermal materials which are able to harness sunlight and convert it to thermal energy seems attractive. Besides carbon-based nanomaterials, conjugated polymers are emerging promising photothermal materials but their facile syntheses remain challenging. In this work, by modification of a CBT-Cys click condensation reaction and rational design of the starting materials, we facilely synthesize conjugated polymers poly-2-phenyl-benzobisthiazole (PPBBT) and its dihexyl derivative with good photothermal properties. Under the irradiation of either sunlight-mimicking Xe light or near-infrared laser, we verify that PPBBT has comparable photothermal heating-up speed to that of star material single-wall carbon nanotube. Moreover, PPBBT is used to fabricate water-soluble NPPPBBT nanoparticles which maintain excellent photothermal properties in vitro and photothermal therapy effect on the tumours exposed to laser irradiation. We envision that our synthetic method provides a facile approach to fabricate conjugated polymers for more promising applications in biomedicine or photovoltaics in the near future.

Alkaline Phosphatase-Triggered Self-Assembly of Near-Infrared Nanoparticles for the Enhanced Photoacoustic Imaging of Tumors.

Photoacoustic (PA) imaging is advantageous for the diagnosis of superficial cancer with high spatial resolution. However, to the best of our knowledge, using an alkaline phosphatase (ALP)-activatable probe for the enhanced PA imaging of tumors has not been reported. In this work, we rationally designed a NIR probe IR775-Phe-Phe-Tyr(H2PO3)-OH (1P) for PA imaging ALP activity in vitro and in tumor. Under the catalysis of ALP, 1P was efficiently converted to IR775-Phe-Phe-Tyr-OH (1), which self-assembled into the nanoparticles 1-NPs. The formation of 1-NPs induced a 6.4-fold enhancement of the 795 nm PA signal of 1P. In vivo tumor PA imaging results indicated that, compared to that in the ALP inhibitor-treated control group, PA contrast in the experimental group enhanced 2.3 folds at 4 h after 1P injection. By replacing the Phe-Phe-Tyr(H2PO3)-OH motif in 1P with other enzyme-cleavable ones, we hope that more PA probes could be developed for the precise diagnoses of their corresponding cancers in the near future.

Tandem Enzymatic Self-Assembly and Slow Release of Dexamethasone Enhances Its Antihepatic Fibrosis Effect.

Many chronic liver diseases will advance to hepatic fibrosis and, if without timely intervention, liver cirrhosis or even hepatocellular carcinoma. Anti-inflammation could be a standard therapeutic strategy for hepatic fibrosis treatment, but a "smart" strategy of hepatic fibrosis-targeted, either self-assembly or slow release of an anti-inflammation drug ( e.g., dexamethasone, Dex), has not been reported. Herein, we rationally designed a hydrogelator precursor Nap-Phe-Phe-Lys(Dex)-Tyr(H2PO3)-OH (1-Dex-P) and proposed a tandem enzymatic strategy of self-assembly and slow release of Dex, with which the precursor exhibited much stronger antihepatic fibrosis effect than Dex both in vitro and in vivo. Enzymatic and cell experiments validated that 1-Dex-P was first dephosphorylated by alkaline phosphatase to yield Nap-Phe-Phe-Lys(Dex)-Tyr-OH (1-Dex), which self-assembled into nanofiber 1-Dex. The nanofiber was then hydrolyzed by esterase to transform into nanofiber 1, accompanied by slow release of Dex. We anticipate that our "smart" tandem enzymatic strategy could be widely employed to design more sophisticated drug delivery systems to achieve enhanced therapeutic efficacy than free drugs in the future.

Fluorine substitution enhances the self-assembling ability of hydrogelators.

When supramolecular hydrogels are applied as tissue culture scaffolds, their mechanical strength and biocompatibility are the two most important factors that must be considered. However, systematic studies on the structure-mechanical property (or structure-cytotoxicity) relationship of hydrogels are rare. Herein, we rationally designed three hydrogelators and their corresponding phosphate precursors, and systematically studied their self-assembling ability and cytotoxicity. The results indicated that fluorine substitution, but not trifluoromethyl substitution with more fluorine atoms, to the phenylalanine motif enhanced the self-assembling ability and cytotoxicity of the hydrogelators (or precursors). We envision that our preliminary study of hydrogelator fluorination would provide a strategy for the development of supramolecular hydrogels for wider biomedical applications.

Intracellular synthesis of d-aminoluciferin for bioluminescence generation.

d-Luciferin is the most widely used substrate for bioluminescence (BL) applications but its low chemical stability always affects its performance. Herein, we rationally designed two chemically stable precursor molecules CBT-d-cystine-CBT (d-1) and CBT-l-cystine-CBT (l-1), and subjected them to reduction-controlled condensation to form 1-oligomer and subsequent proteolysis to yield d-aminoluciferin for BL generation in cells and in vivo. We envision that our precursor molecules might serve as d-luciferin alternatives for a wide range of BL applications in the near future.

Cell Environment-Differentiated Self-Assembly of Nanofibers.

Employing cellular environment for the self-assembly of supramolecular nanofibers for biological applications has been widely explored. But using one precursor to differentiate the extra- and intracellular environments to self-assemble into two different nanofibers remains challenging. With the knowledge that the extracellualr environment of some cancer cells contains large amounts of alkaline phosphatase (ALP) while their intracellular environment is glutathione (GSH)-abundant in mind, we rationally designed a precursor Cys(SEt)-Glu-Tyr(H2PO3)-Phe-Phe-Gly-CBT (1) that can efficiently yield amphiphilic 2 and 2-D to self-assemble into two different nanofibers in hydrogels under the sequential treatment of ALP and GSH. We envision that, by employing a click condensation reaction, this work offers a platform for facilely postmodulation of supramolecular nanofibers, and the versatile precursor 1 could be used to kill two birds with one stone.