Effect of Tan Tui combined with kinesio taping on the posture control of patients with PFPS: protocol for a randomized controlled trial.

BACKGROUND: Patellofemoral pain syndrome (PFPS) is a chronic disease. Its early symptoms are mild and can be relieved by rest after the pain. If there is no effective rehabilitation, it may develop into patellofemoral arthritis. Physiotherapy and appropriate exercise intervention can improve PFPS and postural control during exercise. Tan Tui (TT) is an effective means to improve postural control. Whether combined kinesio taping (KT) can be used as an effective treatment for PFPS patients' recovery has not yet been confirmed. METHODS/DESIGN: Seventy-two eligible patients with early-stage PFPS will be recruited and randomized into 4 groups: TT + KT group (n = 18), TT + KTp group (n = 18), KT group (n = 18), and CON group (n = 18). The TT + KT group was treated with TT combined with KT intervention; the TT + KTp group was treated with TT and KT placebo technical intervention; the KT group was treated with KT intervention alone; the CON group was treated with routine activities. All 4 groups received 30 min, three times a week, for a total of 6 weeks of intervention training. Measurements will be performed at baseline, mid-intervention (4 weeks), and post-intervention (6 weeks) with visual analog scale/score, (VAS), Knee joint Lysholm function score (Lysholm), UniPedal Stance Test (UST), Star Excursion Balance Test ( SEBT), Relative Peak Torque, (RPT), and Knee joint Position PercePtion (KJPP), to check the maintenance of the effect of any intervention. DISCUSSION: For the first time in this trial, the impact will be evaluated. If the results are the same as expected, they will provide evidence that TT combined with KT sticking intervention can promote the posture control of patients with early PFPS. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100051166. Registered on 15 September 2021.

Effect of Tai Chi combined with Kinesio taping on posture control of football players with FAI: protocol for a randomized controlled trial.

BACKGROUND: Functional ankle instability (FAI) of college football players is an important risk factor affecting their training and competition. Physical therapy and appropriate sports intervention can improve the stability of FAI patients. Previous studies have shown that Tai Chi (TC) and Kinesio taping (KT) can improve the posture control ability of FAI patients. However, whether Tai Chi combined with Kinesio taping effect patch can be used as an effective exercise for rehabilitation of college football players with FAI is not yet proven. METHODS/DESIGN: Fifty-three FAI college football players were randomly assigned to 3 groups: TC+KT (n = 20); TC+KTp (placebo Kinesio taping, KTp, placebo) (n = 17), and KT (n = 16). The TC+KT group received TC and KT functional correction technical intervention, the TC+KTp group received TC and placebo KT technical intervention, and the KT group received KT functional correction technical intervention. Each of the three groups received 30 min each time, 3 times a week, for a total of 6 weeks of intervention training. Star Excursion Balance Test (SEBT) and UniPedal Stance Test (UST) at baseline (before), 4 weeks after intervention (middle), and 6 weeks after intervention (after) and Toe Touch Test (TTT) were evaluated. DISCUSSION: For the first time in this trial, the impact will be evaluated. If the results are the same as expected, they will provide evidence that Tai Chi combined with Kinesio taping sticking intervention can promote the posture control of college football players with FAI. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027253 . Registered on 6 November 2019.

Amphiphilic mPEG-Modified Oligo-Phenylalanine Nanoparticles Chemoenzymatically Synthesized via Papain.

Amphiphilic mPEG-modified peptide nanoparticles were developed from oligo-phenylalanine (OPhe) nanoparticles (NPs) synthesized via papain. Tyndall effects indicate that OPhe NPs are amphiphobic. Addition of protein perturbants, sodium dodecyl sulfate (SDS), and urea, in the dispersion solution of OPhe NPs can significantly reduce the R h,m value of NPs, from approximately 749.2 nm to about 200 nm. Therefore, the hydrophobic interaction and hydrogen bonding play major roles in maintaining the aggregation of OPhe NPs. Using the "grafting to" method, the methoxypolyethylene-modified OPhe NPs (mPEG-g-OPhe NPs) were synthesized and characterized by Fourier transform infrared spectroscopy (FTIR), 1H NMR, electrospray ionization mass spectrometry (ESI-MS), and dynamic light scattering (DLS). The attenuated total reflectance (ATR) spectrum of OPhe NPs and mPEG-g-OPhe NPs demonstrate that the secondary structures of these NPs are mainly ß-type. mPEG-g-OPhe NPs can self-aggregate into spherical micelles both in water and cyclohexane. Increasing the chain length of the mPEG moiety, the critical micellar concentrations of mPEG-g-OPhe NPs increased in water but decreased in cyclohexane. The light stability, thermal stability, hydrolysis stability, and encapsulation stability of curcumin were significantly promoted by encapsulation in the micelles formed by mPEG-g-OPhe NPs. The protective effects regularly varied with the variations in the mPEG chain length of mPEG-g-OPhe NPs.

miR­122 and miR­199 synergistically promote autophagy in oral lichen planus by targeting the Akt/mTOR pathway.

The aim of the present study was to characterize the roles of two microRNAs (miRNAs), miR­122 and miR­199, in oral lichen planus (OLP). miRNA microarray analysis was performed to detect potential miRNAs involved in OLP, while in­silicon analysis, reverse transcription­quantitative polymerase chain reaction (RT­qPCR), western blot and immunohistochemistry (IHC) analyses were utilized to explore the molecular mechanisms underlying the roles of miR­199 and miR­122 in OLP. The results from the microarray and RT­qPCR analyses demonstrated that the expression levels of miR­122 and miR­199 were significantly decreased in the peripheral blood mononuclear cells (PBMCs) collected from the OLP group compared with the control group. In addition, miR­122 and miR­199 directly targeted AKT serine/threonine kinase 1 (AKT1) and mammalian target of rapamycin (mTOR), respectively, by binding to their 3' UTRs. AKT1 and mTOR were highly expressed in PBMCs derived from OLP patients. In fact, a negative regulatory relationship was observed between miR­122 and AKT1, and between miR­199 and mTOR, with negative correlation coefficients of ­0.41 and ­0.51, respectively. Furthermore, the protein levels of AKT1, mTOR and microtubule associated protein 1 light chain 3ß (LC3B) were upregulated in the OLP group compared with the control group. Finally, overexpression of miR­122 inhibited the expression of AKT1 and LC3B, while overexpression of miR­199 reduced the levels of mTOR and LC3B. In conclusion, the present study demonstrated that miR­199 and miR­122 are implicated in the pathogenesis of OLP by regulating the expression of mTOR and AKT1.

MicroRNA Microarray-Based Identification of Involvement of miR-155 and miR-19a in Development of Oral Lichen Planus (OLP) by Modulating Th1/Th2 Balance via Targeting eNOS and Toll-Like Receptor 2 (TLR2).

BACKGROUND A wide range of microRNAs (miRNAs) have been shown to play a significant role in disease regulation. The objective of this study was to explore the role of miR-155 and miR-19a in the regulation of oral lichen planus (OLP). MATERIAL AND METHODS Microarray assay, real-time PCR, Western blot assay, computational analysis, luciferase assay, ELISA, and immunohistochemistry analysis were carried out to investigate the role of miR-155 and miR-19a in OLP. RESULTS According to microarray assay and real-time PCR results, the expression of miR-155 was most significantly decreased among the 16 candidate miRNAs in the OLP group, whereas the expression of miR-19a was most significantly increased. MiR-155 and miR-19a directly targeted endothelial nitric oxide synthase (eNOS) and TLR2, respectively, since only the cells co-transfected with miR-155/wild-type eNOS 3'UTR or cells co-transfected with miR-19a/wild-type TLR2 3'UTR exhibited decreased luciferase activity. In addition, the expression of TLR2 was highly upregulated in OLP, whereas the expression of eNOS was significantly downregulated. A negative correlation was found between miR-19a and TLR2 mRNA, with a coefficient value of -0.40. Similarly, a negative correlation was found between miR-155 and eNOS mRNA, with a coefficient value of -0.54. A lower level of NO, IL-4, IL-5, and IL-10 was observed in OLP, which was also accompanied by a higher level of TNF-α and IFN-γ. Finally, the upregulation in miR-155 directly decreased the expression of eNOS and further inhibited the production of NO. Downregulation of miR-19a directly increased the expression of TLR2. The inhibition of NO production and the enhancement in TLR2 expression synergistically increased the production of TNF-α and IFN-γ, while decreasing the levels of IL-4, IL-5, and IL-10. CONCLUSIONS In this study, the peripheral blood mononuclear cells (PBMCs) from subjects with or without OLP were collected and their gene expression profiles were compared. It was found that OLP changed the expression profile of miR-155 and miR-19a, which in turn directly affected the production of eNOS and TLR2, respectively. In addition, by synergistically inducing an imbalance between Th1 and Th2, the simultaneous deregulation of miR-155/eNOS and miR-19a/TLR2 was responsible for an elevated risk of OLP.

Integrated Mechanical, Thermal, Data, and Power Transfer Interfaces for Future Space Robotics.

In-situ connectability among modules of a space system can provide significantly enhanced flexibility, adaptability, and robustness for space exploration and servicing missions. Connection of modules in extra-terrestrial environment is hence a topic of rising importance in modern orbital or planetary missions. As an example, the increasing number of satellites sent to space have introduced a large set of connections of various type, for transferring mechanical loads, data, electrical power and heat from one module to another. This paper provides a comprehensive review of published work in space robotic connections and presents the different transfer types developed and used to date in robotic applications for orbital and extra-terrestrial planetary missions. The aims of this paper are to present a detailed analysis of the state of the art available technologies, to make an analysis of and comparison among different solutions to common problems, to synthesize and identify future connectability research, and to lay the foundation for future European space robotic connectability effort and work for a complex and growing important future space missions. All types are described in their base characteristics and evaluated for orbital and planetary environments. This analysis shows that despite the large number of connectors developed for each of the four functionalities (mechanical, thermal, data, and electrical power) here considered, the trend is that researchers are integrating more than one functionalizes into a single equipment or device, to reduce costs and improve standardization. The outcomes of this literature review have contributed toward the design of a future multifunctional, standard and scalable interface at the early stage of the Standard Interface for Robotic Manipulation of Payloads in Future Space Missions (SIROM) project, a European Commission funded Horizon 2020 project. SIROM interfaces will be employed by European prime contractors in future extra-terrestrial missions.

A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity.

The selectivity of an enzyme inhibitor is a key determinant of its usefulness as a tool compound or its safety as a drug. Yet selectivity is never assessed comprehensively in the early stages of the drug discovery process, and only rarely in the later stages, because technical limitations prohibit doing otherwise. Here, we report EnPlex, an efficient, high-throughput method for simultaneously assessing inhibitor potency and specificity, and pilot its application to 96 serine hydrolases. EnPlex analysis of widely used serine hydrolase inhibitors revealed numerous previously unrecognized off-target interactions, some of which may help to explain previously confounding adverse effects. In addition, EnPlex screening of a hydrolase-directed library of boronic acid- and nitrile-containing compounds provided structure-activity relationships in both potency and selectivity dimensions from which lead candidates could be more effectively prioritized. Follow-up of a series of dipeptidyl peptidase 4 inhibitors showed that EnPlex indeed predicted efficacy and safety in animal models. These results demonstrate the feasibility and value of high-throughput, superfamily-wide selectivity profiling and suggest that such profiling can be incorporated into the earliest stages of drug discovery.

Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs.

The protease fibroblast activation protein (FAP) is a specific marker of activated mesenchymal cells in tumour stroma and fibrotic liver. A specific, reliable FAP enzyme assay has been lacking. FAP's unique and restricted cleavage of the post proline bond was exploited to generate a new specific substrate to quantify FAP enzyme activity. This sensitive assay detected no FAP activity in any tissue or fluid of FAP gene knockout mice, thus confirming assay specificity. Circulating FAP activity was ∼20- and 1.3-fold less in baboon than in mouse and human plasma, respectively. Serum and plasma contained comparable FAP activity. In mice, the highest levels of FAP activity were in uterus, pancreas, submaxillary gland and skin, whereas the lowest levels were in brain, prostate, leukocytes and testis. Baboon organs high in FAP activity included skin, epididymis, bladder, colon, adipose tissue, nerve and tongue. FAP activity was greatly elevated in tumours and associated lymph nodes and in fungal-infected skin of unhealthy baboons. FAP activity was 14- to 18-fold greater in cirrhotic than in non-diseased human liver, and circulating FAP activity was almost doubled in alcoholic cirrhosis. Parallel DPP4 measurements concorded with the literature, except for the novel finding of high DPP4 activity in bile. The new FAP enzyme assay is the first to be thoroughly characterised and shows that FAP activity is measurable in most organs and at high levels in some. This new assay is a robust tool for specific quantitation of FAP enzyme activity in both preclinical and clinical samples, particularly liver fibrosis.

A general method for making peptide therapeutics resistant to serine protease degradation: application to dipeptidyl peptidase IV substrates.

Bioactive peptides have evolved to optimally fulfill specific biological functions, a fact which has long attracted attention for their use as therapeutic agents. While there have been some recent commercial successes fostered in part by advances in large-scale peptide synthesis, development of peptides as therapeutic agents has been significantly impeded by their inherent susceptibility to protease degradation in the bloodstream. Here we report that incorporation of specially designed amino acid analogues at the P1' position, directly C-terminal of the enzyme cleavage site, renders peptides, including glucagon-like peptide-1 (7-36) amide (GLP-1) and six other examples, highly resistant to serine protease degradation without significant alteration of their biological activity. We demonstrate the applicability of the method to a variety of proteases, including dipeptidyl peptidase IV (DPP IV), dipeptidyl peptidase 8 (DPP8), fibroblast activation protein α (FAPα), α-lytic protease (αLP), trypsin, and chymotrypsin. In summary, the "P1' modification" represents a simple, general, and highly adaptable method of generating enzymatically stable peptide-based therapeutics.

A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy.

Multimodality therapy consisting of surgery, chemotherapy, and radiation will fail in approximately 40% of patients with pediatric sarcomas and result in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (dipeptidyl peptidase IV activity and/or structural homologs) enzymes can mediate tumor regression by immune-mediated mechanisms. Herein, we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b) cells, particularly myeloid DCs, to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11bLy6-CLy6-G) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared with either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies, particularly as an adjuvant to tumor vaccines and ACT.

Identification of selective and potent inhibitors of fibroblast activation protein and prolyl oligopeptidase.

Fibroblast activation protein (FAP) is a serine protease selectively expressed on reactive stromal fibroblasts of epithelial carcinomas. It is widely believed to play a role in tumor invasion and metastasis and therefore to represent a potential new drug target for cancer. Investigation into its biological function, however, has been hampered by the current unavailability of selective inhibitors. The challenge has been in identifying inhibitors that are selective for FAP over both the dipeptidyl peptidases (DPPs), with which it shares exopeptidase specificity, and prolyl oligopeptidase (PREP), with which it shares endopeptidase specificity. Here, we report the first potent FAP inhibitor with selectivity over both the DPPs and PREP, N-(pyridine-4-carbonyl)-d-Ala-boroPro (ARI-3099, 6). We also report a similarly potent and selective PREP inhibitor, N-(pyridine-3-carbonyl)-Val-boroPro (ARI-3531, 22). Both are boronic acid based inhibitors, demonstrating that high selectivity can be achieved using this electrophile. The inhibitors are stable, easy to synthesize, and should prove to be useful in helping to elucidate the biological functions of these two unique and interesting enzymes, as well as their potential as drug targets.

4-Substituted boro-proline dipeptides: synthesis, characterization, and dipeptidyl peptidase IV, 8, and 9 activities.

The boroProline-based dipeptidyl boronic acids were among the first DPP-IV inhibitors identified, and remain the most potent known. We introduced various substitutions at the 4-position of the boroProline ring regioselectively and stereoselectively, and incorporated these aminoboronic acids into a series of 4-substituted boroPro-based dipeptides. Among these dipeptidyl boronic acids, Arg-(4S)-boroHyp (4q) was the most potent inhibitor of DPP-IV, DPP8 and DPP9, while (4S)-Hyp-(4R)-boroHyp (4o) exhibited the most selectivity for DPP-IV over DPP8 and DPP9.

Chemical and biological evaluation of dipeptidyl boronic acid proteasome inhibitors for use in prodrugs and pro-soft drugs targeting solid tumors.

Bortezomib, a dipeptidyl boronic acid and potent inhibitor of the 26S proteasome, is remarkably effective against multiple myeloma (MM) but not against solid tumors. Dose-limiting adverse effects from "on target" inhibition of the proteasome in normal cells and tissues appear to be a key obstacle. Achieving efficacy against solid tumors therefore is likely to require making the inhibitor more selective for tumor tissue over normal tissues. The simplest strategy that might provide such tissue specificity would be to employ a tumor specific protease to release an inhibitor from a larger, noninhibitory structure. However, such release would necessarily generate an inhibitor with a free N-terminal amino group, raising a key question: Can short peptide boronic acids with N-terminal amino groups have the requisite properties to serve as warheads in prodrugs? Here we show that dipeptides of boroLeu, the smallest plausible candidates for the task, can indeed be sufficiently potent, cell-penetrating, cytotoxic, and stable to degradation by cellular peptidases to serve in this capacity.

Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety.

Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents.

Asymmetric synthesis of four isomers of 2-C-trifluoromethylerythritol.

Optically active 2-C-trifluoromethylerythritols, analogues of 2-C-methylerythritol, which is a key intermediate in the biosynthesis of isoprenoid with a mevalonate-independent route, were conveniently synthesized from 1,1,1-trifluoro-2,3-epoxypropane.

Solvent-controlled asymmetric Strecker reaction: stereoselective synthesis of alpha-trifluoromethylated alpha-amino acids.

[reaction: see text] Stereoselective approaches to alpha-trifluoromethylated alpha-amino acids (alpha-Tfm AAs) have been developed. The stereoconfigurations of the resulting alpha-Tfm AA precursors were well controlled by using different solvents. The optically active (S)-2-amino-2-phenyl-1,1,1-trifluoropropanoic acid was synthesized by this method.

High stereoselective preparation of O-protected 2-trifluoromethyl 3-bromoallylic alcohols from 1,1-dibromo-1-alkenes.

A highly stereoselective lithium-bromine exchange reaction of 2-trifluoromethyl-3,3-dibromoallylic alcohols is described. (E)- and (Z)-2-trifluoro-3-bromoallylic alcohols were obtained in THF and hexane, respectively. The lithium carbenoid intermediate was stable even at -40 degrees C and could be trapped by various electrophiles to afford functionalized 2-trifluoromethyl-3-bromoallylic alcohols. [reaction: see text]