GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation.

Disturbances in intestinal immune homeostasis predispose susceptible individuals to type 1 diabetes (T1D). G-protein-coupled receptor 41 (GPR41) is a receptor for short-chain fatty acids (SCFAs) mainly produced by gut microbiota, which plays key roles in maintaining intestinal homeostasis. In this study, we investigated the role of GPR41 in the progression of T1D. In non-obese diabetic (NOD) mice, we found that aberrant reduction of GPR41 expression in the pancreas and colons was associated with the development of T1D. GPR41-deficient (Gpr41-/-) mice displayed significantly exacerbated streptozotocin (STZ)-induced T1D compared to wild-type mice. Furthermore, Gpr41-/- mice showed enhanced gut immune dysregulation and increased migration of gut-primed IFN-γ+ T cells to the pancreas. In bone marrow-derived dendritic cells from Gpr41-/- mice, the expression of suppressor of cytokine signaling 3 (SOCS) was significantly inhibited, while the phosphorylation of STAT3 was significantly increased, thus promoting dendritic cell (DC) maturation. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (BMDC) from Gpr41-/- mice accelerated T1D in irradiated NOD mice. We conclude that GPR41 is essential for maintaining intestinal and pancreatic immune homeostasis and acts as a negative regulator of DC maturation in T1D. GPR41 may be a potential therapeutic target for T1D.

Rps6ka2 enhances iMSC chondrogenic differentiation to attenuate knee osteoarthritis through articular cartilage regeneration in mice.

Articular cartilage (AC) is most susceptible to degeneration in knee osteoarthritis (OA); however, the existing treatments for OA do not target the core link of the pathogenesis-"decreased tissue cell function activity and extracellular matrix (ECM) metabolic disorders" for effective intervention. iMSC hold lower heterogeneity and great promise in biological research and clinical applications. Rps6ka2 may play an important role in the iMSC to treat OA. In this study, the CRISPR/Cas9 gene editing Rps6ka2-/- iMSC were obtained. Effect of Rps6ka2 on iMSC proliferation and chondrogenic differentiation was evaluated in vitro. An OA model was constructed in mice by surgical destabilization of medial meniscus (DMM). The Rps6ka2-/- iMSC and iMSC were injected into the articular cavity twice-weekly for 8 weeks. In vitro experiments showed that Rps6ka2 could promote iMSC proliferation and chondrogenic differentiation. In vivo results further confirmed that Rps6ka2 could improve iMSC viability to promote ECM production to attenuate OA in mice.

Adriamycin induces cardiac fibrosis in mice via PRMT5-mediated cardiac fibroblast activation.

Long-term treatment with adriamycin (ADR) is associated with higher incidences of cumulative cardiotoxicity manifest as heart failure. ADR-induced cardiomyopathy is characterized by extensive fibrosis that is caused by cardiac fibroblast activation. To date, however, no specific treatment is available to alleviate ADR-induced cardiotoxicity. Protein arginine methyltransferase 5 (PRMT5), a major enzyme responsible for methylation of arginine, regulates numerous cellular processes such as cell differentiation. In the present study we investigated the role of PRMT5 in cardiac fibrosis. Mice were administered ADR (3 mg/kg, i.p., every 2 days) for 2 weeks. We showed that aberrant PRMT5 expression was largely co-localized with α-SMA-positive activated cardiac fibroblasts in ADR-injected mice and in ADR-treated cardiac fibroblasts in vitro. PRMT5-overexpression exacerbated, whereas PRMT5 knockdown alleviated ADR-induced cardiac fibrosis in vivo and TGF-ß1-induced cardiac fibroblast activation in vitro. We demonstrated that PRMT5-overexpression enhanced methylated-Smad3 levels in vivo and in vitro. Pretreatment with a specific PRMT5 inhibitor EPZ015666 (5 nM) or overexpression of a catalytically inactive mutant of PRMT5, PRMT5(E444Q), reduced PRMT5-induced methylation of Smad3, thus suppressing PRMT5-mediated cardiac fibroblast activation in vitro. Furthermore, ADR activated cardiac fibroblasts was depending on autocrine TGF-ß1. Taken together, our results demonstrate that PRMT5 promotes ADR-induced cardiac fibrosis via activating cardiac fibroblasts, suggesting that it may be a potential therapeutic target of ADR-caused cardiotoxicity.

Gut microbiota in pancreatic diseases: possible new therapeutic strategies.

Pancreatic diseases such as pancreatitis, type 1 diabetes and pancreatic cancer impose substantial health-care costs and contribute to marked morbidity and mortality. Recent studies have suggested a link between gut microbiota dysbiosis and pancreatic diseases; however, the potential roles and mechanisms of action of gut microbiota in pancreatic diseases remain to be fully elucidated. In this review, we summarize the evidence that supports relationship between alterations of gut microbiota and development of pancreatic diseases, and discuss the potential molecular mechanisms of gut microbiota dysbiosis in the pathogenesis of pancreatic diseases. We also propose current strategies toward gut microbiota to advance a developing research field that has clinical potential to reduce the cost of pancreatic diseases.

M860, a Monoclonal Antibody against Human Lactoferrin, Enhances Tumoricidal Activity of Low Dosage Lactoferrin via Granzyme B Induction.

Lactoferrin (LF) is a soluble glycoprotein of the transferring family found in most biological fluids, functioning as a major first line defense molecule against infection in mammals. It also shows certain anti-tumor activity, but its clinical application in tumor therapy is limited because high dosage is required. In this study, we demonstrate that M860, a monoclonal antibody against human LF (hLF), could significantly increase the anti-tumor potential of low dosage hLF by forming LF-containing immune complex (IC). Human monocytes primed with LF-IC, but not hLF or M860 alone, or control ICs, showed strong tumoricidal activity on leukemia cell lines Jurkat and Raji through induction of secreted Granzyme B (GzB). LF-IC is able to colligate membrane-bound CD14 (a TLR4 co-receptor) and FcγRIIa (a low affinity activating Fcγ receptor) on the surface of human monocytes, thereby triggering the Syk-PI3K-AKT-mTOR pathway leading to GzB production. Our work identifies a novel pathway for LF-mediated tumoricidal activity and may extend the clinical application of LF in tumor therapy.

Natural Killer Cell-Based Cancer Immunotherapy: A Review on 10 Years Completed Clinical Trials.

NK cell cancer immunotherapy is an emerging anti-tumour therapeutic strategy that explores NK cell stimulation. In this review, we address strategies developed to circumvent limitations to clinical application of NK cell-based therapies, and comprehensively review the design and results of clinical trials conducted in the past 10 years (2008-2018) to test their therapeutic potential. NK cell-based immunotherapy of solid cancers remains controversial, but merit further detailed investigation.

Variations in energy metabolism along the pericardium meridian and its relationship with visceral function adjustments during electroacupuncture.

BACKGROUND: Electroacupuncture (EA) is a traditional Chinese medicine treatment guided by meridian theory. As it gradually gains more worldwide acceptance, a clarification of its mechanisms is extremely urgent. We observed variations in transcutaneous oxygen pressure/carbon dioxide pressure (tcpO2/tcpCO2) and microcirculation blood perfusion units (BPU) along the pericardium meridian, and cardiac function during EA at Neiguan (PC6) to explore variations in energy metabolism and its relationship with visceral function adjustments during EA. METHODS: Twenty-two healthy volunteers participated in this study. Three channel laser Doppler flowmetry and tcpO2/tcpCO2 detection systems were used to detect tcpO2/tcpCO2 and microcirculation BPU along the pericardium meridian. A hemodynamic monitor was used to detect cardiac function. RESULTS: In the normal state, the microcirculatory BPU along the pericardium meridian were significantly higher than that of their bilateral corresponding control points (p < 0.05). During EA at PC6, the values of the microcirculatory BPU along the pericardium meridian did not vary, and few increased. In the normal state, the values of tcpO2 along the pericardium meridian were significantly higher than those of their bilateral corresponding control points (p < 0.05). In addition, the values of tcpCO2 along the pericardium meridian were lower than those of their bilateral corresponding control points. In comparison with the normal state, EA could decrease tcpO2 along the meridian significantly (p < 0.05) and increase tcpCO2. During EA at PC6 in healthy volunteers treated by artificial acute mild hypoxia, cardiac output and cardiac index (p < 0.05) decreased and systemic vascular resistance increased significantly (p < 0.05). CONCLUSIONS: In the normal state, the values of microcirculatory BPU and tcpO2 along the pericardium meridian were both higher than those of their bilateral corresponding control points. Energy metabolism was vigorous along the meridian. During EA, the decrease in oxygen partial pressure along the pericardium meridian might be a result of strengthened energy metabolism of associated tissue and increased oxygen consumption. The variations in energy metabolism along the pericardium meridian during the course of EA had a close relationship with visceral function adjustments. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTRTRC13003193.

Effect of electroacupuncture on myocardial electrical remodeling in rats with acute myocardial infarction. / ç”µé’ˆå¯¹æ€¥æ€§å¿ƒè‚Œæ¢—æ­»å¤§é¼ å¿ƒè‚Œç”µé‡æž„çš„å½±å“åŠå ¶æœºåˆ¶ç ”ç©¶.

OBJECTIVES: To investigate the mechanism of electroacupuncture (EA) at "Neiguan" (PC6) in impro-ving myocardial electrical remodeling in rats with acute myocardial infarction (AMI) by enhancing transient outward potassium current. METHODS: A total of 30 male SD rats were randomly divided into control, model and EA groups, with 10 rats in each group. The AMI model was established by subcutaneous injection with isoprenaline (ISO, 85 mg/kg). EA was applied to left PC6 for 20 min, once daily for 5 days. Electrocardiogram (ECG) was recorded after treatment. TTC staining was used to observe myocardial necrosis. HE staining was used to observe the pathological morphology of myocardial tissue and measure the cross-sectional area of myocardium. Potassium ion-related genes in myocardial tissue were detected by RNA sequencing. The mRNA and protein expressions of Kchip2 and Kv4.2 in myocardial tissue were detected by real-time fluorescence quantitative PCR and Western blot, respectively. RESULTS: Compared with the control group, cardiomyocyte cross-sectional area in the model group was significantly increased (P<0.01), the ST segment was significantly elevated (P<0.01), and QT, QTc, QTd and QTcd were all significantly increased (P<0.05, P<0.01). After EA treatment, cardiomyocyte cross-sectional area was significantly decreased (P<0.01), the ST segment was significantly reduced (P<0.01), and the QT, QTc, QTcd and QTd were significantly decreased (P<0.01, P<0.05). RNA sequencing results showed that a total of 20 potassium ion-related genes co-expressed by the 3 groups were identified. Among them, Kchip2 expression was up-regulated most notablely in the EA group. Compared with the control group, the mRNA and protein expressions of Kchip2 and Kv4.2 in the myocardial tissue of the model group were significantly decreased (P<0.01, P<0.05), while those were increased in the EA group (P<0.01, P<0.05). CONCLUSIONS: EA may improve myocardial electrical remodeling in rats with myocardial infarction, which may be related to its functions in up-regulating the expressions of Kchip2 and Kv4.2.

Microbial­induced carbonate precipitation (MICP) technology: a review on the fundamentals and engineering applications.

The microbial­induced carbonate precipitation (MICP), as an emerging biomineralization technology mediated by specific bacteria, has been a popular research focus for scientists and engineers through the previous two decades as an interdisciplinary approach. It provides cutting-edge solutions for various engineering problems emerging in the context of frequent and intense human activities. This paper is aimed at reviewing the fundaments and engineering applications of the MICP technology through existing studies, covering realistic need in geotechnical engineering, construction materials, hydraulic engineering, geological engineering, and environmental engineering. It adds a new perspective on the feasibility and difficulty for field practice. Analysis and discussion within different parts are generally carried out based on specific considerations in each field. MICP may bring comprehensive improvement of static and dynamic characteristics of geomaterials, thus enhancing their bearing capacity and resisting liquefication. It helps produce eco-friendly and durable building materials. MICP is a promising and cost-efficient technology in preserving water resources and subsurface fluid leakage. Piping, internal erosion and surface erosion could also be addressed by this technology. MICP has been proved suitable for stabilizing soils and shows promise in dealing with problematic soils like bentonite and expansive soils. It is also envisaged that this technology may be used to mitigate against impacts of geological hazards such as liquefaction associated with earthquakes. Moreover, global environment issues including fugitive dust, contaminated soil and climate change problems are assumed to be palliated or even removed via the positive effects of this technology. Bioaugmentation, biostimulation, and enzymatic approach are three feasible paths for MICP. Decision makers should choose a compatible, efficient and economical way among them and develop an on-site solution based on engineering conditions. To further decrease the cost and energy consumption of the MICP technology, it is reasonable to make full use of industrial by-products or wastes and non-sterilized media. The prospective direction of this technology is to make construction more intelligent without human intervention, such as autogenous healing. To reach this destination, MICP could be coupled with other techniques like encapsulation and ductile fibers. MICP is undoubtfully a mainstream engineering technology for the future, while ecological balance, environmental impact and industrial applicability should still be cautiously treated in its real practice.

Effects of electroacupuncture on rats with cognitive impairment: An iTRAQ-based proteomics analysis.

OBJECTIVE: The study explores the effects of electroacupuncture (EA) at the governing vessel (GV) on proteomic changes in the hippocampus of rats with cognitive impairment. METHODS: Healthy male rats were randomly divided into 3 groups: sham, model and EA. Cognitive impairment was induced by left middle cerebral artery occlusion in the model and EA groups. Rats in the EA group were treated with EA at Shenting (GV24) and Baihui (GV20) for 7 d. Neurological deficit was scored using the Longa scale, the learning and memory ability was detected using the Morris water maze (MWM) test, and the proteomic profiling in the hippocampus was analyzed using protein-labeling technology based on the isobaric tag for relative and absolute quantitation (iTRAQ). The Western blot (WB) analysis was used to detect the proteins and validate the results of iTRAQ. RESULTS: Compared with the model group, the neurological deficit score was significantly reduced, and the escape latency in the MWM test was significantly shortened, while the number of platform crossings increased in the EA group. A total of 2872 proteins were identified by iTRAQ. Differentially expressed proteins (DEPs) were identified between different groups: 92 proteins were upregulated and 103 were downregulated in the model group compared with the sham group, while 142 proteins were upregulated and 126 were downregulated in the EA group compared with the model group. Most of the DEPs were involved in oxidative phosphorylation, glycolipid metabolism and synaptic transmission. Furthermore, we also verified 4 DEPs using WB technology. Although the WB results were not exactly the same as the iTRAQ results, the expression trends of the DEPs were consistent. The upregulation of heat-shock protein ß1 (Hspb1) was the highest in the EA group compared to the model group. CONCLUSION: EA can effect proteomic changes in the hippocampus of rats with cognitive impairment. Hspb1 may be involved in the molecular mechanism by which acupuncture improves cognitive impairment.

A rare left ventricular cardiac myxoma mimicking fibroma.

BACKGROUND: In most cases, it is not difficult to differentiate common left ventricular (LV) cardiac myxomas from fibromas because they are different disease entities and have different imaging findings. Herein, we present a case of a tumor with histological characteristics of a LV cardiac myxoma even though its imaging and macroscopical views were similar to that of fibroma. CASE PRESENTATION: A 65-year-old woman was admitted to the hospital with chest tightness and palpitations which persisted for 2 years. Transthoracic echocardiogram and transesophageal echocardiography revealed a 23 mm × 8 mm, polyp-like-shaped, homogeneous, firm, solitary, mobile and solitary LV mass, which protruded into the left atrium during systole, resulting in mild mitral regurgitation. LV contrast-enhanced echocardiography revealed that there was little contrast agent filling in the LV mass. To further clarify the nature of the mass, non-enhanced and contrast-enhanced coronary computed tomography (CT) angiograms showed a 19 mm × 8 mm relatively homogeneous low density with punctate calcifications mass and no significant enhancement. Thus, we preoperatively diagnosed her condition as a LV fibroma and performed excision of the tumor under cardiopulmonary by-pass by using port-access approach through right mini-thoracotomy. The postoperative pathological diagnosis of the tumor was in fact a LV myxoma. CONCLUSIONS: LV cardiac myxomas mimicking fibroma makes diagnosis difficult, and sonographers should be aware of this imaging changes.

Tibial cortex transverse transport accelerates wound healing via enhanced angiogenesis and immunomodulation.

AIMS: Treatment for delayed wound healing resulting from peripheral vascular diseases and diabetic foot ulcers remains a challenge. A novel surgical technique named 'tibial cortex transverse transport' (TTT) has been developed for treating peripheral ischaemia, with encouraging clinical effects. However, its underlying mechanisms remain unclear. In the present study, we explored the potential biological mechanisms of TTT surgery using various techniques in a rat TTT animal model. METHODS: A novel rat model of TTT was established with a designed external fixator, and effects on wound healing were investigated. Laser speckle perfusion imaging, vessel perfusion, histology, and immunohistochemistry were used to evaluate the wound healing processes. RESULTS: Gross and histological examinations showed that TTT technique accelerated wound closure and enhanced the quality of the newly formed skin tissues. In the TTT group, haematoxylin and eosin (H&E) staining demonstrated a better epidermis and dermis recovery, while immunohistochemical staining showed that TTT technique promoted local collagen deposition. The TTT technique also benefited to angiogenesis and immunomodulation. In the TTT group, blood flow in the wound area was higher than that of other groups according to laser speckle imaging with more blood vessels observed. Enhanced neovascularization was seen in the TTT group with double immune-labelling of CD31 and α-Smooth Muscle Actin (α-SMA). The number of M2 macrophages at the wound site in the TTT group was also increased. CONCLUSION: The TTT technique accelerated wound healing through enhanced angiogenesis and immunomodulation. Cite this article: Bone Joint Res 2022;11(4):189-199.

Baicalein mediates the anti-tumor activity in Osteosarcoma through lncRNA-NEF driven Wnt/ß-catenin signaling regulatory axis.

Background: Osteosarcoma (OS) is a common type of malignant bone tumor in adolescents with high risk of metastasis. However, the clinical management still remains unsatisfactory. Traditional Chinese medicine (TCM) has been widely considered as an alternative treatment, and their extracts have proved to possess great potential for drug discovery. Baicalein (BA), the active pharmaceutical ingredient of rhizoma coptidis, was proved to have anti-tumor properties in OS, but the mechanism remains poorly understood. Methods: The potential anti-cancer effects on cell growth, cell cycle, apoptosis and migration were examined in OS cells. Moreover, the lncRNA-Neighboring Enhancer of FOXA2 (lncRNA-NEF) and Wnt/ß-catenin signaling were detected by qPCR and Western blotting assays. The in vivo effect of GA on tumor growth was investigated using a xenograft mice model. Results: In the present study, BA was found to significantly suppress tumor growth in vitro and in vivo. And it was also found to inhibit the invasion and metastasis as well. As for the mechanism investigation, lncRNA-NEF was obviously upregulated by BA in OS cells, and thus induced the inactivation of Wnt/ß-catenin signaling. Moreover, lncRNA-NEF knockdown partially reversed the BA-induced anti-cancer activities; and successfully compensated the suppressive effect on Wnt/ß-catenin signaling. We therefore suggested that BA induced the inactivation of Wnt/ß-catenin signaling through promoting lncRNA-NEF expression. Conclusions: In conclude, our results demonstrated that BA suppressed tumor growth and metastasis in vitro and in vivo through an lncRNA-NEF driven Wnt/ß-catenin regulatory axis, in which lncRNA-NEF was upregulated by BA, and thus induced the inactivation of Wnt/ß-catenin signaling. The Translational potential of this article: The findings derived from this study validates the anti-cancer activity of BA in OS and provides a novel underlying mechanism, which suggest that BA may be a potential candidate to develop the effective drug for OS patients.

Effects of Interactive Dynamic Scalp Acupuncture on Motor Function and Gait of Lower Limbs after Stroke: A Multicenter, Randomized, Controlled Clinical Trial.

OBJECTIVE: To evaluate the effects of interactive dynamic scalp acupuncture (IDSA), simple combination therapy (SCT), and traditional scalp acupuncture (TSA) on motor function and gait of the lower limbs in post-stroke hemiplegia patients. METHODS: A total of 231 patients with post-stroke hemiplegia was randomly divided into IDSA (78 cases), SCT (78 cases), and TSA (75 cases) groups by a random number table. Scalp acupuncture (SA) and lower-limb robot training (LLRT) were both performed in the IDSA and SCT groups. The patients in the TSA group underwent SA and did not receive LLRT. The treatment was administered once daily and 6 times weekly for 8 continuous weeks, each session lasted for 30 min. The primary outcome measures included Fugl-Meyer assessment of the lower extremity (FMA-LE), berg balance scale (BBS), modified barthel index (MBI), and 6-min walking test (6MWT). The secondary outcome measures included stride frequency (SF), stride length (SL), stride width (SW), affected side foot angle (ASFA), passive range of motion (PROM) of the affected hip (PROM-H), knee (PROM-K) and ankle (PROM-A) joints. The patients were evaluated before treatment, at 1- and 2-month treatment, and 1-, and 2-month follow-up visits, respectively. Adverse events during 2-month treatment were observed. RESULTS: Nineteen patients withdrew from the trial, with 8 in the IDSA and 5 in the SCT groups, 6 in the TSA group. The FMA-LE, BBS, 6MWT and MBI scores in the IDSA group were significantly increased after 8-week treatment and 2 follow-up visits compared with the SCT and TSA groups (P<0.05 or P<0.01). Compared with pre-treatment, the grade distribution of BBS and MBI scores in the 3 groups were significantly improved at 1, 2-month treatment and 2 follow-up visits (P<0.05 or P<0.01). The SF, PROM-H, PROM-K and PROM-A in the IDSA group was significantly increased compared with the SCT and TSA groups after 8-week of treatment (P<0.05 or P<0.01). Compared with the SCT group, ASFA of the IDSA group was significantly reduced after 8-week of treatment (P<0.05). SF, SL, PROM-K and PROM-A were significantly increased at the 2nd follow-up visit whereas the ASFA was significantly reduced in the IDSA group compared with the SCT groups at 1st follow-up visit (P<0.05 or P<0.01). The SF was significantly increased in the SCT group compared with the TSA group after 8-week treatment (P<0.05). Compared with the TSA group, PROM-K, PROM-A were significantly increased at the 2nd follow-up visit (P<0.05). CONCLUSIONS: The effects of IDSA on lower-limb motor function and walking ability of post-stroke patients were superior to SCT and TSA. The SCT was comparable to TSA treatment, and appeared to be superior in improving the motion range of the lower extremities. (Registration No. ChiCTR1900027206).

Effect of Interactive Dynamic Scalp Acupuncture on Post-Stroke Cognitive Function, Depression, and Anxiety: A Multicenter, Randomized, Controlled Trial.

OBJECTIVE: To compare the clinical effects of interactive dynamic scalp acupuncture (IDSA), simple combination therapy (SCT), and traditional scalp acupuncture (TSA) on cognitive function, depression and anxiety in patients with post-stroke cognitive impairment. METHODS: A total of 660 patients with post-stroke cognitive impairment who were admitted to 3 hospitals in Shenzhen City between May 2017 and May 2020 were recruited and randomly assigned to the IDSA (218 cases), SCT (222 cases) and TSA groups (220 cases) according to a random number table. All the patients received conventional drug therapy for cerebral stroke and exercise rehabilitation training. Scalp acupuncture and computer-based cognitive training (CBCT) were performed simultaneously in the IDSA group, but separately in the morning and in the afternoon in the SCT group. The patients in the TSA group underwent scalp acupuncture only. The course of treatment was 8 weeks. Before treatment (M0), 1 (M1) and 2 months (M2) after treatment, as well as follow-up at 1 (M3) and 2 months (M4), the cognitive function of patients was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA) Scales; depression, anxiety, sleep quality, and self-care ability of patients were assessed using Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), Pittsburgh Sleep Quality Index (PSQI), and Modified Barthel Index (MBI), respectively. During this trial, all adverse events (AEs) were accurately recorded. RESULTS: There were no significant differences in the MMSE, MoCA, HAMD, HAMA, PSQI, and MBI scores among the 3 groups at M0 (all P>0.05). In the IDSA group, the MMSE, MoCA and MBI scores from M2 to M4 were significantly higher than those in the SCT and TSA groups, while the HAMD, HAMA and PSQI scores were significantly reduced (all P<0.01). The changes of all above scores (M2-M0, M4-M0) were significantly superior to those in the SCT and TSA groups (all P<0.01, except M4-M0 of HAMD). At M2, the severity of MMSE, HAMD, HAMA, PSQI and MBI in the IDSA group was significantly lower than that in the SCT and TSA groups (all P<0.01). There was no serious AE during this trial. CONCLUSIONS: IDSA can not only significantly improve cognitive function, but also reduce depression, anxiety, which finally improves the patient's self-care ability. The effect of IDSA was significantly better than SCT and TSA. (Trial registration No. ChiCTR1900027206).

Hypoxia is essential for bone-tendon junction healing: the molecular biological evidence.

Bone-tendon junction (BTJ) injury is difficult to cure due to its special anatomical structure. Most methods applied for BTJ injury treatment cannot lead to the perfect restoration of the fibrocartilage zone and perfect vascular regeneration, which are two important facets of BTJ reconstruction. Based on current research, hypoxia, which has been discovered to induce chondrogenesis and angiogenesis in vivo, plays an essential role in the tissue repair process. Consequently, it is reasonable to confirm that a hypoxic environment is the prerequisite condition to obtain physiological healing of BTJ injury. In this paper, the potential relationship between hypoxia and BTJ healing is discussed. Moreover, an operation model and possible drug application to obtain hypoxic conditions are delineated.

Troxerutin Stimulates Osteoblast Differentiation of Mesenchymal Stem Cell and Facilitates Bone Fracture Healing.

Troxerutin (TRX), a semi-synthetic derivative of the natural bioflavonoid rutin, is a bioactive flavonoid widely abundant in various fruits and vegetables. Known as vitamin P4, TRX has been demonstrated to have several activities including anti-inflammation, anti-oxidants, vasoprotection, and immune support in various studies. Although rutin, the precursor of troxerutin, was reported to have a protective role against bone loss, the function of TRX in skeletal system remains unknown. In the present study, we found that TRX promoted osteogenic differentiation of human mesenchymal stem cells (MSCs) in a concentration-dependent manner by stimulating the alkaline phosphatase (ALP) activity, calcium nodule formation and osteogenic marker genes expression in vitro. The further investigation demonstrated that TRX stimulated the expression of the critical transcription factor ß-catenin and several downstream target genes of Wnt signaling, thus activated Wnt/ß-catenin signaling. Using a femur fracture rats model, TRX was found to stimulate new bone formation and accelerate the fracture healing in vivo. Collectively, our data demonstrated that TRX could promote osteogenesis in vitro and facilitate the fracture healing in vivo, indicating that TRX may be a promising therapeutic candidate for bone fracture repair.

[Scalp acupuncture combined with lower-limb intelligent feedback training for lower-limb motor dysfunction after stroke: a randomized controlled trial].

OBJECTIVE: To compare the efficacy of scalp acupuncture combined with lower-limb intelligent feedback training and lower-limb intelligent feedback training alone for lower-limb motor dysfunction after stroke. METHODS: A total of 154 patients with lower-limb motor dysfunction after stroke were randomly divided into an observation group (76 cases, 6 cases dropped off) and a control group (78 cases, 8 cases dropped off). The patients in both groups were treated with conventional medication and exercise rehabilitation training. In addition, the patients in the observation group were treated with scalp acupuncture combined with lower-limb intelligent feedback training. The scalp acupuncture was given at upper 1/5 of the anterior oblique line of parietal temporal area and upper 1/5 of the posterior oblique line of parietal temporal area. The patients in the control group were treated with lower-limb intelligent feedback training alone. All the treatment was given once a day, 6 days a week, totaling for 8 weeks. The affected-side lower-limb Brunnstrom stage and modified Ashworth scale (MAS) grade, 6-minute walk test (6MWT), Berg balance scale (BBS) score and modified Barthel index (MBI) score were evaluated before and after treatment in the two groups. The plantar pressure was measured by gait function evaluation system. RESULTS: Compared before treatment, the Brunnstrom stage in the two groups was improved after treatment (P<0.01); the MAS grade in the observation group was improved after treatment (P<0.01); the Brunnstrom stage and MAS grade in the observation group were superior to those in the control group (P<0.01, P<0.05). After treatment, the 6MWT, BBS and MBI scores in the two groups were increased (P<0.05), and those in the observation group were higher than those in the control group (P<0.05). After treatment, the touchdown area of health-side hind foot, affected-side front-hind foot and bilateral full foot in the observation group was increased (P<0.05), and the touchdown area of affected-side front-hind foot and full foot in the observation group was larger than that in the control group (P<0.05). The weight-bearing ratio of health-side forefoot and full foot in the observation group was decreased after treatment (P<0.05), and the weight-bearing ratio of affected-side forefoot, hind foot and full foot was increased after treatment (P<0.05). The weight-bearing ratio of health-side forefoot and full foot in the observation group was lower than that in the control group (P<0.05), and the weight-bearing ratio of health-side hind foot, affected-side forefoot and affected-side full foot in the observation group was higher than that in the control group (P<0.05). CONCLUSION: The scalp acupuncture combined with lower-limb intelligent feedback training could reduce the muscle tension of lower limbs, promote the separation movement mode of lower limbs, improve the plantar pressure distribution, and improve the balance ability and walking ability in stroke patients, and the curative effect is better than lower-limb intelligent feedback training alone.

IgG Immunocomplexes Drive the Differentiation of a Novel Subset of Osteoclasts Independent of RANKL and Inflammatory Cytokines.

Potentiation of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis by IgG immunocomplexes (ICs) is generally considered an important pathway leading to cartilage and bone destruction in rheumatoid arthritis (RA). However, whether IgG ICs possess pro-osteoclastogenic potential independent of RANKL and inflammatory cytokines is unclear. Here we demonstrate that by fully cross-linking human FcγRIIa (hFcγRIIa) or co-ligating hFcγRIIa and TLR4, IgG ICs alone could drive the differentiation of human blood monocytes into nuclear factor of activated T cells cytoplasmic 1 (NFATc1-negative nonclassical osteoclasts (NOCs). Surprisingly, IgG ICs could also overrule RANKL-induced classical osteoclast (COC) differentiation in vitro. In mouse model of collagen-induced arthritis, hFcγRIIa-transgenic, but not nontransgenic control, mice suffered from cartilage/bone destruction accompanied by the presence of NFATc1- NOCs lining the eroded cartilage surface in affected joints. Our results not only identify a novel subset of IC-induced NOCs but also provide a possible explanation for the uncoupling of FcγR-mediated cartilage destruction from RANKL-related bone erosion in autoinflammatory arthritis. © 2021 American Society for Bone and Mineral Research (ASBMR)..

New therapeutic approaches for the treatment of rheumatoid arthritis may rise from the cholinergic anti-inflammatory pathway and antinociceptive pathway.

Due to the complex etiology of rheumatoid arthritis (RA), it is difficult to be completely cured at the current stage although many approaches have been applied in clinics, especially the wide application of nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). New drug discovery and development via the recently discovered cholinergic anti-inflammatory and antinociceptive pathways should be promising. Based on the above, the nicotinic acetylcholine receptor agonists maintain the potential for the treatment of RA. Therefore, new therapeutic approaches may rise from these two newly discovered pathways. More preclinical experiments and clinical trials are required to confirm our viewpoint.