MiR-21-5p alleviates trigeminal neuralgia in rats through down-regulation of voltage-gated potassium channel Kv1.1. / MiR-21-5p通过下调电压门控钾离子通道Kv1.1è¡¨è¾¾å‡è½»å¤§é¼ ä¸‰å‰ç¥žç»ç—›.

OBJECTIVES: Trigeminal neuralgia (TN) is a common neuropathic pain. Voltage-gated potassium channel (Kv) has been confirmed to be involved in the occurrence and development of TN, but the specific mechanism is still unclear. MicroRNA may be involved in neuropathic pain by regulating the expression of Kv channels and neuronal excitability in trigeminal ganglion (TG). This study aims to explore the relationship between Kv1.1 and miR-21-5p in TG with a TN model, evaluate whether miR-21-5p has a regulatory effect on Kv1.1, and to provide a new target and experimental basis for the treatment of TN. METHODS: A total of 48 SD rats were randomly divided into 6 groups: 1) a sham group (n=12), the rats were only sutured at the surgical incision without nerve ligation; 2) a sham+agomir NC group (n=6), the sham rats were microinjected with agomir NC through stereotactic brain injection in the surgical side of TG; 3) a sham+miR-21-5p agomir group (n=6), the sham rats were microinjected with miR-21-5p agomir via stereotactic brain injection in the surgical side of TG; 4) a TN group (n=12), a TN rat model was constructed using the chronic constriction injury of the distal infraorbital nerve (dIoN-CCI) method with chromium intestinal thread; 5) a TN+antagonist NC group (n=6), TN rats were microinjected with antagonist NC through stereotactic brain injection method in the surgical side of TG; 6) a TN+miR-21-5p antagonist group (n=6), TN rats were microinjected with miR-21-5p antagonist through stereotactic brain injection in the surgical side of TG. The change of mechanical pain threshold in rats of each group after surgery was detected. The expressions of Kv1.1 and miR-21-5p in the operative TG of rats were detected by Western blotting and real-time reverse transcription polymerase chain reaction. Dual luciferase reporter genes were used to determine whether there was a target relationship between Kv1.1 and miR-21-5p and whether miR-21-5p directly affected the 3'-UTR terminal of KCNA1. The effect of brain stereotaxic injection was evaluated by immunofluorescence assay, and then the analogue of miR-21-5p (agomir) and agomir NC were injected into the TG of rats in the sham group by brain stereotaxic apparatus to overexpress miR-21-5p. The miR-21-5p inhibitor (antagomir) and antagomir NC were injected into TG of rats in the TN group to inhibit the expression of miR-21-5p. The behavioral changes of rats before and after administration were observed, and the expression changes of miR-21-5p and Kv1.1 in TG of rats after intervention were detected. RESULTS: Compared with the baseline pain threshold, the facial mechanical pain threshold of rats in the TN group was significantly decreased from the 5th to 15th day after the surgery (P<0.05), and the facial mechanical pain threshold of rats in the sham group was stable at the normal level, which proved that the dIoN-CCI model was successfully constructed. Compared with the sham group, the expression of Kv1.1 mRNA and protein in TG of the TN group was down-regulated (both P<0.05), and the expression of miR-21-5p was up-regulated (P<0.05). The results of dual luciferase report showed that the luciferase activity of rno-miR-21-5p mimics and KCNA1 WT transfected with 6 nmol/L or 20 nmol/L were significantly decreased compared with those transfected with mimic NC and wild-type KCNA1 WT, respectively (P<0.001). Compared with low dose rno-miR-21-5p mimics (6 nmol/L) co-transfection group, the relative activity of luciferase in the high dose rno-miR-21-5p mimics (20 nmol/L) cotransfection group was significantly decreased (P<0.001). The results of immunofluorescence showed that drugs were accurately injected into TG through stereotaxic brain. After the expression of miR-21-5p in the TN group, the mechanical pain threshold and the expression of Kv1.1 mRNA and protein in TG were increased. After overexpression of miR-21-5p in the sham group, the mechanical pain threshold and the expression of Kv1.1 mRNA and protein in TG were decreased. CONCLUSIONS: Both Kv1.1 and miR-21-5p are involved in TN and miR-21-5p can regulate Kv1.1 expression by binding to the 3'-UTR of KCNA1.

Shenshuai Yingyang Jiaonang ameliorates chronic kidney disease-associated muscle atrophy in rats by inhibiting ferroptosis mediated by the HIF-1α/SLC7A11 pathway.

Objective: Shenshuai Yingyang Jiaonang (SSYYJN), a traditional Chinese medicine formula, can ameliorate muscle atrophy associated with chronic kidney disease (CKD). However, its mechanisms of action remain unclear. This study is to investigate the molecular mechanisms involved in the effects of SSYYJN in ameliorating muscle atrophy associated with CKD in rats. Methods: The chemical compounds of SSYYJN were identified by UPLC-Q-Orbitrap HRMS. Considering the dose-response relationship of the identified compounds, male SD rats were randomly divided into Sham, Model, SSYYJN, and α-Keto Acid (KA) groups. Subsequently, we assessed the therapeutic and anti-ferroptotic effects of SSYYJN. Network pharmacology studies were used to predict the molecular mechanism of SSYYJN on ferroptosis and were further verified for accuracy. Results: A total of 42 active compounds were identified from SSYYJN. SSYYJN alleviated muscle atrophy caused by CKD, as evidenced by changes in body weight, serum biochemical indices, mass and histopathology of the skeletal muscle, and the levels of MuRF1. SSYYJN reduced the levels of iron, MDA, and ROS, increased the levels of GSH, NAPDH, and Gpx4. Network pharmacology analysis indicated that SSYYJN exerted anti-ferroptotic effects that were closely related to the HIF-1α signaling pathway. Molecular protein and genetic test results showed that SSYYJN increased HIF-1α protein and increased SLC7A11. Conclusions: SSYYJN attenuates muscle atrophy in CKD by inhibiting ferroptosis through the activation of the HIF-1α/SLC7A11 pathway and might be a promising traditional Chinese medicine for muscle atrophy in CKD.

Qingguang'an-induced autophagy in TFs inhibits scar formation: A follow-up in vivo mechanistic investigation.

Purpose: To investigate the mechanism by which Qingguang'an inhibits scar formation in rabbits administered glaucoma filtering surgery (GFS). Methods: Combined trabeculectomy was performed in 100 rabbits diagnosed with glaucoma, which were assigned to five groups, including the no surgery, surgery only, mitomycin C (MMC; positive control), Qingguang'an (experimental) and PBS (negative control) groups. The animals were followed up at postoperative days 1-28. Ultrastructure was observed under a transmission electron microscope (TEM). Real-Time Polymerase Chain Reaction (RT-PCR), Western blot, Hematoxylin and Eosin (H&E) staining, Masson's trichrome staining and Immuno-histochemistry (IHC) were performed to assess the harvested blocks. Results: In the Qingguang'an group, intraocular pressure (IOP) on postoperative D28 was significantly lower than values in the no surgery, surgery only and PBS groups (P < 0.05). Its blebs kept better filtering function and less complications in follow-up, which be detected to have less fibroblasts and collagen deposition histologically. Compared with the PBS group, ATG5, Beclin1 and LC3-II mRNA levels were significantly increased while P62 was downregulated in the Qingguang'an group (P < 0.05). Correspondingly, ATG5 and Beclin1 protein amounts in the Qingguang'an group were increased while P62 was downregulated. The LC3-II/Ⅰ ratio tended to rise to the process of autophagy. Abundant autophagosomes were captured under TEM in this condition. Conclusions: Qingguang'an granules can inhibit scar formation in rabbits after GFS and restrain IOP increase by inducing autophagy in TFs.

Effects of non-pharmacological interventions on pain in wound patients during dressing change: A systematic review.

BACKGROUND: Changes to the wound dressing frequently cause pain. Some adverse side effects of pharmacologic pain management may cause problems or even impede wound healing. There is no systematic study of non-pharmacologic therapies for pain during wound dressing changes, despite the gradual promotion of non-pharmacologic pain reduction methods. OBJECTIVES: To give clinical wound pain management a new direction, locating and assessing non-pharmacological interventions regarding pain brought on by wound dressing changes are necessary. METHOD: The researchers conducted a comprehensive literature review on non-pharmacological interventions for pain during wound dressing changes across five databases: PubMed, Web of Science, Medline, Embase, and the Cochrane Library spanning the period from January 2010 to September 2022. The evaluation of literature and data extraction was carried out independently by two researchers, and in cases of disagreement, a third researcher participated in the deliberation. To assess the risk of bias in the literature, the researchers utilised the Cochrane Handbook for Reviews of Interventions, version 5.1.0. RESULTS: In total, 951 people were involved in 11 investigations covering seven non-pharmacological therapies. For pain triggered by dressing changes, virtual reality (VR) distraction, auditory and visual distractions, foot reflexology, religious and spiritual care, and guided imaging demonstrated partially positive effects, with hypnosis therapy and jaw relaxation perhaps having a weak effect. CONCLUSION: The key to managing wounds is pain management. According to our review, there is some indication that non-pharmacologic interventions can help patients feel less discomfort when having their wound dressings changed. However, the evidence supporting this view is weak. It needs to be corroborated by future research studies with multicentre and large samples. To promote and use various non-pharmacologic interventions in the future, it is also necessary to build standardised and homogenised paths for their implementation.

Electroacupuncture promotes the repair of the damaged spinal cord in mice by mediating neurocan-perineuronal net.

AIMS: This study aimed to investigate the effect of perineuronal net (PNN) and neurocan (NCAN) on spinal inhibitory parvalbumin interneuron (PV-IN), and the mechanism of electroacupuncture (EA) in promoting spinal cord injury (SCI) repair through neurocan in PNN. METHODS: A mouse model of SCI was established. Sham-operated mice or SCI model mice were treated with chondroitin sulfate ABC (ChABC) enzyme or control vehicle for 2 weeks (i.e., sham+veh group, sham+ChABC group, SCI+veh group, and SCI+ChABC group, respectively), and then spinal cord tissues were taken from the T10 lesion epicenter for RNA sequencing (RNA-seq). MSigDB Hallmark and C5 databases for functional analysis, analysis strategies such as differential expression gene analysis (DEG), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI). According to the results of RNA-seq analysis, the expression of NCAN was knocked down or overexpressed by virus intervention, or/and EA intervention. Polymerase chain reaction (PCR), immunofluorescence, western blot, electrophysiological, and behavioral tests were performed. RESULTS: After the successful establishment of SCI model, the motor dysfunction of lower limbs, and the expression of PNN core glycan protein at the epicenter of SCI were reduced. RNA-seq and PCR showed that PNN core proteoglycans except NCAN showed the same expression trend in normal and injured spinal cord treated with ChABC. KEGG and GSEA showed that PNN is mainly associated with inhibitory GABA neuronal function in injured spinal cord tissue, and PPI showed that NCAN in PNN can be associated with inhibitory neuronal function through parvalbumin (PV). Calcium imaging showed that local parvalbumin interneuron (PV-IN) activity decreased after PNN destruction, whether due to ChABC treatment or surgical bruising of the spinal cord. Overexpression of neurocan in injured spinal cord can enhance local PV-IN activity. PCR and western blot suggested that overexpression or knockdown of neurocan could up-regulate or down-regulate the expression of GAD. At the same time, the activity of PV-IN in the primary motor cortex (M1) and the primary sensory cortex of lower (S1HL) extremity changed synchronously. In addition, overexpression of neurocan improved the electrical activity of the lower limb and promoted functional repair of the paralyzed hind limb. EA intervention reversed the down-regulation of neurocan, enhanced the expression of PNN in the lesioned area, M1 and S1HL. CONCLUSION: Neurocan in PNN can regulate the activity of PV-IN, and EA can promote functional recovery of mice with SCI by upregulating neurocan expression in PNN.

Click-Reaction-Mediated Chemotherapy and Photothermal Therapy Synergistically Inhibit Breast Cancer in Mice.

The development of functional materials for tumor immunogenicity enhancement is desirable for overcoming the low therapeutic efficiency and easy metastasis during tumor treatments. Herein, the thermoresponsive nanoparticles composed of photothermal agent (PTA) and click reactive reagent are developed for enhanced immunotherapy application. A Ni-bis(dithiolene)-containing PTA with intense near-infrared absorption and efficient photothermal conversion is developed for thermoresponsive nanoparticles construction. The generated heat by encapsulated PTA further induces the phase transition of thermoresponsive nanoparticles with the release of chemotherapy reagent to react with the amino groups on functional proteins, realizing PTT and chemotherapy simultaneously. Moreover, the immunogenic cell death (ICD) of cancer cells evoked by PTT could be further enhanced by the released reactive reagent. As a result, the synergistic effect of photothermal treatment and reaction-mediated chemotherapy can suppress the growth of a primary tumor, and the evoked ICD could further activate the immune response with the suppression of a distant tumor. This synergistic treatment strategy provides a reliable and promising approach for cancer immunotherapy in clinic.

The Developments of Surface-Functionalized Selenium Nanoparticles and Their Applications in Brain Diseases Therapy.

Selenium (Se) and its organic and inorganic compounds in dietary supplements have been found to possess excellent pharmacodynamics and biological responses. However, Se in bulk form generally exhibits low bioavailability and high toxicity. To address these concerns, nanoscale selenium (SeNPs) with different forms, such as nanowires, nanorods, and nanotubes, have been synthesized, which have become increasingly popular in biomedical applications owing to their high bioavailability and bioactivity, and are widely used in oxidative stress-induced cancers, diabetes, and other diseases. However, pure SeNPs still encounter problems when applied in disease therapy because of their poor stability. The surface functionalization strategy has become increasingly popular as it sheds light to overcome these limitations in biomedical applications and further improve the biological activity of SeNPs. This review summarizes synthesis methods and surface functionalization strategies employed for the preparation of SeNPs and highlights their applications in treating brain diseases.

Efficacy of Tai Chi on lower limb function of Parkinson's disease patients: A systematic review and meta-analysis.

Background: At present, the effect of Tai Chi (TC) on lower limb function in patients with Parkinson's disease (PD) is controversial. Therefore, we conducted a meta-analysis on the influence of TC on lower limb function in PD patients. Methods: According to the PRISMA guidelines, seven databases were searched. Randomized controlled trials (RCTS) were selected and screened according to inclusion and exclusion criteria. We assessed the quality of the studies using the Cochrane Risk of Bias tool and then extracted the characteristics of the included studies. The random effect model was adopted, and heterogeneity was measured by I 2 statistic. Results: A total of 441 articles were screened, and 10 high-quality RCTs were with a total of 532 patients with PD met Our inclusion criteria. Meta-analysis showed that compared To control groups TC improved several outcomes. TC significantly improved motor function (SMD = -0.70; 95% CI = -0.95, -0.45; p < 0.001; I 2 = 35%), although The results were not statistically significant for The subgroup analysis of TC duration (SMD = -0.70; 95% CI = -0.95, -0.45; p = 0.88; I 2 = 0%;). TC significantly improved balance function (SMD = 0.89; 95% CI = 0.51, 1.27; p < 0.001; I 2 = 54%), functional walking capacity (SMD = -1.24; 95% CI = -2.40, -0.09; p = 0.04; I 2 = 95%), and gait velocity (SMD = 0.48; 95% CI = -0.02, 0.94; p = 0.04; I 2 = 78%), But Did Not improve endurance (SMD = 0.31; 95% CI = -0.12, 0.75; p = 0.16; I 2 = 0%), step length (SMD = 0.01; 95% CI = -0.34, 0.37; p = 0.94; I 2 = 29%), and cadence (SMD = 0.06; 95% CI = -0.25, 0.36; p = 0.70; I 2 = 0%). Conclusion: TC has beneficial effects on motor function, balance function, functional walking ability, and gait velocity, but does not improve walking endurance, stride length, and cadence.

NIR luminogen for low-temperature photothermal therapy by triggering HSP90α down-regulation.

A near-infrared (NIR) luminogen TST was designed and used to efficiently trigger HSP90α protein knockdown through photo-thermal conversion based on a gene interference strategy, by which in vitro and in vivo tumor ablation were significantly acquired at low-temperature.

Mindfulness-based stress reduction with acupressure for sleep quality in breast cancer patients with insomnia undergoing chemotherapy: A randomized controlled trial.

PURPOSE: The objective of this randomized controlled trial was to evaluate and compare the effectiveness of mindfulness-based stress reduction (MBSR), acupressure, and MBSR combined with acupressure in improving sleep quality in breast cancer patients with sleep disorders, as well as the potential effects of these interventions on relieving fatigue, anxiety, and depression. METHODS: A four-arm parallel-group randomized controlled trial was conducted in a tertiary hospital in Fujian between July 2019 and January 2021. A total of 147 breast cancer patients were randomly assigned to a usual care group (n = 34), a MBSR group (n = 38), an acupressure group (n = 36), or a combined group (n = 39). We assessed patients' sleep quality (Pittsburgh Sleep Quality Index-PSQI and 6 actigraphy indices), fatigue, anxiety, and depression at baseline and at the mid-intervention (fourth week) and the end of intervention (eighth week). RESULTS: The ANOVA showed a significant difference (p < 0.05) in PSQI, and all sleep parameters measured by wrist actigraphy, and anxiety between groups. The three active treatments led to better PSQI outcomes (p < 0.001), reduced fatigue (p < 0.001), decreased anxiety (p < 0.05), and improved sleep measured by all actigraphy indices with two exceptions (MBSR did not differ from control on Sleep Latency (p = 0.235) and mean waking by time (MWBT) (p = 0.058)). Both acupressure and the combined intervention outperformed MBSR on four actigraphy indices: Sleep Efficiency (SE), Sleep Latency (SL), Totatl Sleep Time (TST), and Wake after sleep onset (WASO) (p < 0.05), and the combined intervention further outperformed MBSR on PSQI (p = 0.03) and Number of awakings (NOA) (p = 0.003). Moreover, there was no significant difference across all outcomes between acupressure and combined intervention (p ≥ 0.05). CONCLUSIONS: MBSR, acupressure, and combined therapy all show a remarkable advantages in allemiating sleep quality, fatigue, and anxiety. Acupressure and combined therapy outperformed MBSR in improving sleep quality.

Gynostemma Glycosides Protect Retinal Ganglion Cells in Rats with Chronic High Intraocular Pressure by Regulating the STAT3/JAK2 Signaling Pathway and Inhibiting Astrocyte and Microglia Activation.

Objective: To observe the protective effect of gynostemma glycosides on retinal ganglion cells in rats with chronically high intraocular pressure. Materials and Methods: A total of 60 rats were randomly divided into group A (the blank group, 10 rats) and chronic high IOP model group (50 rats). The IOP model group (IOP above 22 mmHg) was then randomly divided into an additional 5 groups (10 rats per group): group B (negative control group) treated with normal saline; group C treated with gynostemma glycosides 25 mg/(kg-d); group D treated with gynostemma glycosides 50 mg/(kg-d); group E treated with gynostemma glycosides 100 mg/(kg-d); and group F (positive control group) treated with VitB1 and VitB12. The eyes of each rat were monitored from day 1 to 14 (D1-D14). On day 14, rats were euthanized, after which retinal tissue and optic nerve were examined using real-time PCR, western blot, HE staining, LFB staining, and TUNEL assay. Results: Groups A, C, D, E, and F had significantly lower expression of CD11b, GFAP, Brn3α, and more TUNEL cells than in group B (all P < 0.05). Moreover, the relative expression of STAT3 mRNA and JAK2 (mRNA and protein) in groups A, C, D, E, and F was significantly lower than in group B (P < 0.05), while in group E, the expression was lower than in group D (P < 0.05). Conclusion: Gynostemma glycosides protect retinal ganglion cells in rats with chronically high intraocular pressure possibly associated with the STAT3/JAK2 signaling pathway.

Effects of Acupuncture on Neuropathic Pain Induced by Spinal Cord Injury: A Systematic Review and Meta-Analysis.

Introduction: Neuropathic pain is a commonly seen symptom and one of the most intractable comorbidities following spinal cord injury (SCI). Acupuncture has been widely used for neuropathic pain after SCI in clinical settings. There is no systematic review or meta-analysis evaluating the efficacy of acupuncture in the treatment of SCI-induced neuropathic pain. Thus, this study aimed to conduct a systematic review and meta-analysis to assess the efficacy of acupuncture on SCI-induced neuropathic pain. Methods: Seven databases were comprehensively searched, including PubMed, the Cochrane Library, the Web of Science, the China National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature Service System (SinoMed), the Wanfang Database, and the Chinese Scientific Journals Database (VIP) from their inception to 30 September 2021. Two independent reviewers evaluated the eligibility of the data retrieved based on the pre-established eligibility criteria and assessed the methodological quality of the included studies using the Cochrane Risk of Bias Tool. The outcome indexes in this study included the visual analogue scale, the numeric rating scale, the present pain intensity, and the pain region index. Sensitivity and subgroup analyses were also performed to specifically evaluate the intervention effects. In addition, publication bias was analyzed. Results: Six randomized controlled trials (145 participants in the experimental groups and 141 participants in the control groups) were identified that evaluated the application of acupuncture for neuropathic pain after SCI and were included in this study. The results of our study revealed that acupuncture had a positive effect on the pain severity (standardized mean difference (SMD): -1.40, 95% confidence interval (CI): -2.23; -0.57), the present pain intensity (MD = -0.61, 95% CIs = -0.98; -0.23), and the pain region index (MD = -3.04, 95% CI = -3.98; -2.11). In addition, sensitivity analyses showed that these results were robust and stable. Subgroup analyses indicated that electroacupuncture (EA) had better effects on SCI-induced neuropathic pain. However, a publication bias was observed. Conclusion: Available evidence appears to suggest that acupuncture may have a role in SCI-induced neuropathic pain management, but this remains to be determined.

[Effect of parent-child cooperative music therapy on children with autism spectrum disorder and their mothers: a prospective randomized controlled study]. / äº²å­åˆä½œå¼éŸ³ä¹ç–—æ³•å¯¹å­¤ç‹¬ç—‡è°±ç³»éšœç¢å„¿ç«¥åŠå ¶æ¯äº²å½±å“çš„å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To study the effect of parent-child cooperative music therapy on the core symptoms of children with autism spectrum disorder (ASD) and their mothers. METHODS: In this prospective study, 112 children with ASD and their mothers were divided into a music therapy group and an applied behavior analysis (ABA) group using a random number table (n=56 each). The children in the ABA group were treated with ABA, and those in the music therapy group were given parent-child cooperative music therapy in addition to the ABA treatment. The duration of intervention was 8 weeks for both groups. Childhood Autism Rating Scale (CARS), Autism Behavior Checklist (ABC), Parenting Stress Index-Short form (PSI-SF), Family APGAR Index, and Herth Hope Index (HHI) were used to evaluate the core symptoms of children with ASD and the parenting stress, family APGAR index, and hope level of mothers before and after intervention. RESULTS: A total of 100 child-mother dyads completed the whole study, with 50 child-mother dyads in each group. After intervention, the children in the music therapy group had significantly lower total score of ABC scale and scores of sensation, social interaction, and somatic movement, as well as a significantly lower total score of CARS than those in the ABA group (P<0.05). After intervention, compared with the mothers in the ABA group, the mothers in the music therapy group had significantly higher total score of PSI-SF and score of parent-child dysfunctional interaction, significantly higher total score of HHI and scores of each dimension, and significantly higher total score of APGAR and scores of cooperation and intimacy (P<0.05). CONCLUSIONS: Parent-child cooperative music therapy combined with ABA can alleviate the core symptoms of children with ASD, reduce the parenting stress of their mothers, and improve family APGAR index and hope level.

Electroacupuncture Inhibits NLRP3 Activation by Regulating CMPK2 After Spinal Cord Injury.

Objectives: This study aimed to evaluate the expression of cytosine monophosphate kinase 2 (CMPK2) and activation of the NLRP3 inflammasome in rats with spinal cord injury (SCI) and to characterize the effects of electroacupuncture on CMPK2-associated regulation of the NLRP3 inflammasome. Methods: An SCI model was established in Sprague-Dawley (SD) rats. The expression levels of NLRP3 and CMPK2 were measured at different time points following induction of SCI. The rats were randomly divided into a sham group (Sham), a model group (Model), an electroacupuncture group (EA), an adeno-associated virus (AAV) CMPK2 group, and an AAV NC group. Electroacupuncture was performed at jiaji points on both sides of T9 and T11 for 20 min each day for 3 consecutive days. In the AAV CMPK2 and AAV NC groups, the viruses were injected into the T9 spinal cord via a microneedle using a microscope and a stereotactic syringe. The Basso-Beattie-Bresnahan (BBB) score was used to evaluate the motor function of rats in each group. Histopathological changes in spinal cord tissue were detected using H&E staining, and the expression levels of NLRP3, CMPK2, ASC, caspase-1, IL-18, and IL-1ß were quantified using Western blotting (WB), immunofluorescence (IF), and RT-PCR. Results: The expression levels of NLRP3 and CMPK2 in the spinal cords of the model group were significantly increased at day 1 compared with those in the sham group (p < 0.05). The expression levels of NLRP3 and CMPK2 decreased gradually over time and remained low at 14 days post-SCI. We successfully constructed AAV CMPK2 and showed that CMPK2 was significantly knocked down following 2 dilutions. Finally, treatment with EA or AAV CMPK2 resulted in significantly increased BBB scores compared to those in the model group and the AAV NC group (p < 0.05). The histomorphology of the spinal cord in the EA and AAV CMPK2 groups was significantly different than that in the model and AAV NC groups. WB, IF, and PCR analyses showed that the expression levels of CMPK2, NLRP3, ASC, caspase-1, IL-18, and IL-1ß were significantly lower in the EA and AAV CMPK2 groups compared with those in the model and AAV NC groups (p < 0.05). Conclusion: Our study showed that CMPK2 regulated NLRP3 expression in rats with SCI. Activation of NLRP3 is a critical mechanism of inflammasome activation and the inflammatory response following SCI. Electroacupuncture downregulated the expression of CMPK2 and inhibited activation of NLRP3, which could improve motor function in rats with SCI.

Effects of exercise interventions for physical fitness, fatigue, and quality of life in adult hematologic malignancy patients without receiving hematopoietic stem cell transplantation: a systematic review and meta-analysis.

PURPOSE: To investigate the effects of exercise interventions on the physical fitness, fatigue, and quality of life (QOL) in adults with hematological malignancy (HM) who did not receive hematopoietic stem cell transplantation (HSCT). METHODS: We performed a systematic review with meta-analysis and qualitative evidence synthesis. We systematically searched 10 electronic databases including Medline, Allied and Complementary Medicine Database, Cochrane Central Register of Controlled Trials, Embase, CINAHL complete, SPORTDiscus, Web of Science, China Wan Fang Database, China National Knowledge Internet, and China Science and Technology Journal Database from their inception up to March 2021. The Cochrane guideline was followed, and a PRISMA checklist for reporting systematic reviews was completed. RESULTS: Fifteen studies were included in this systematic review, of which 11 were included in the meta-analysis. There was a significant increase in the physical fitness between the exercise group and the control group, in terms of the 6-min walk test and peak oxygen consumption. There was a significant change in the peak oxygen consumption from the baseline to the endpoint in the exercise group. In the between-group analyses, there were no significant differences in the effect of exercise on the grip strength, fatigue, and QOL; however, in the within-group analysis, QOL was significantly increased in the combination exercise group. CONCLUSION: Both aerobic exercise and combination exercise appear safe and feasible and can improve physical fitness in adult patients with HM who have not received HSCT. The combination exercise may have potential benefits for their QOL.

YIV-906 enhances nuclear factor of activated T-cells (NFAT) activity of T cells and promotes immune checkpoint blockade antibody action and CAR T-cell activity.

YIV-906 is a systems biology botanical cancer drug, inspired by a traditional Chinese herbal formulation. Results from eight Phase I/II to II clinical studies demonstrated the potential of YIV-906 to prolong survival and improve the quality of life of cancer patients. As an immunomodulator in the tumor microenvironment, YIV-906 can turn cold tumors hot and potentiate anti-tumor activity for different classes of anticancer agents; and as a cytoprotector in the GI, YIV-906 can reduce non-hematological side effects and speed up damaged tissue recovery. YIV-906 enhanced anti-PD1 action against hepatoma in mice by stimulating both innate and adaptive immunity. In a Jurkat cell-staphylococcal superantigen E (SEE)-Raji cell culture model, YIV-906 promoted T cell activation with upregulation of CD69 by enhancing NFAT activity, with or without PD1-PD-L1 interaction. YIV-906 could trigger the phosphorylation of TCR downstream signaling cascades without the involvement of TCR. YIV-906 could inhibit SHP1 and SHP2 activities, which dephosphorylates TCR downstream proteins due to the PD1-PD-L1 interaction. Therefore, YIV-906 could enhance anti-PD1 action to rescue the depressed NFAT activity of Jurkat cells due to the PD1-PD-L1 interaction. In addition, YIV-906 enhanced the NFAT activity and killing capability of Jurkat cells expressing chimeric antigen receptor (CAR-CD19-CD3z) toward CD19 expressing cells, such as Raji cells, with or without PD1-PD-L1 overexpression. Ingredient herb S (Scutellaria baicalensis Georgi) of YIV-906 and some S compounds were found to play key roles in these activities. In conclusion, YIV-906 modulates adaptive immunity by activating T effector cells mainly through its action on SHP1/2. YIV-906 could also facilitate immune checkpoint blockade therapy or CAR-T cell therapy for cancer treatment.

Electroacupuncture attenuates LPS-induced depression-like behavior through kynurenine pathway.

Background: A growing body of evidence suggests that inflammation and changes in glutamate neurotransmission are two pathophysiological mechanisms underlying depression. Electroacupuncture (EA) is a common therapeutic tool for the treatment of depression. However, the potential antidepressant mechanism of EA remains obscure. The change of the kynurenine pathway (KP) is the research priority of antidepressant mechanisms. This study will investigate the role of EA on lipopolysaccharide (LPS)-induced depression-like behavior and explore its possible mechanism of action. Methods: Lipopolysaccharide was used to induce depression-like behavior, and EA was given at Hegu (L14) and Taichong (LR3) acupoints in C57BL/6J mice. Depression-like behaviors were measured by behavioral tests, including tail suspension test (TST), sucrose preference test (SPT), force swim test (FST), and open field test (OFT). The levels of inflammatory cytokines IL-1ß, IL-6, and TNF-α, and KP enzyme IDO1 were measured by qPCR and enzyme-linked immunosorbent assay (ELISA), while high-performance liquid chromatography (HPLC) was performed to detect the content of prefrontal cortex and hippocampal as well as serum glutamate, tryptophan (TRP), kynurenic (KYN), and quinolinic acid (QA). Results: The results showed that (1) as evidenced by increased spontaneous locomotor activities, decreased immobility duration, and a stronger preference for sucrose in the sucrose preference test, EA reversed LPS-challenged depressive-like behavior. (2) EA at L14 and LR3 decreased the levels of inflammatory cytokines, inhibited IDO1, and regulated KP metabolisms, as well as lowered the concentration of glutamate. (3) EA may exert anti-depression effects by acting on the kynurenine pathway. Conclusion: This study evaluated the effects of EA on depression-like behaviors induced by lipopolysaccharide (LPS) and its regulation of inflammation and the glutamatergic system. Our results suggest that EA can ameliorate depression-like behaviors, lower the level of inflammation, and reduce the release of glutamate, possibly through the regulation of the kynurenine pathway in the brain.

YIV-906 potentiated anti-PD1 action against hepatocellular carcinoma by enhancing adaptive and innate immunity in the tumor microenvironment.

YIV-906 (PHY906) is a standardized botanical cancer drug candidate developed with a systems biology approach-inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. In combination with chemotherapy and/or radiation therapy, preclinical and clinical results suggest that YIV-906 has the potential to prolong survival and improve quality of life for cancer patients. Here, we demonstrated that YIV-906 plus anti-PD1 could eradicate all Hepa 1-6 tumors in all tumor bearing mice. YIV-906 was found to have multiple mechanisms of action to enhance adaptive and innate immunity. In combination, YIV-906 reduced PD1 or counteracted PD-L1 induction caused by anti-PD1 which led to higher T-cell activation gene expression of the tumor. In addition, YIV-906 could reduce immune tolerance by modulating IDO activity and reducing monocytic MDSC of the tumor. The combination of anti-PD1 and YIV-906 generated acute inflammation in the tumor microenvironment with more M1-like macrophages. YIV-906 could potentiate the action of interferon gamma (IFNg) to increase M1-like macrophage polarization while inhibiting IL4 action to decrease M2 macrophage polarization. Flavonoids from YIV-906 were responsible for modulating IDO activity and potentiating IFNg action in M1-like macrophage polarization. In conclusion, YIV-906 could act as an immunomodulator and enhance the innate and adaptive immune response and potentiate anti-tumor activity for immunotherapies to treat cancer.

High-dose vitamin D3 supplementation ameliorates renal fibrosis by vitamin D receptor activation and inhibiting TGF-ß1/Smad3 signaling pathway in 5/6 nephrectomized rats.

Renal fibrosis is the pathological consequence of progressive chronic kidney disease. Although it has been reported that vitamin D3 exerts antifibrotic effects, the underlying mechanisms remain unclear. This study is aimed at investigating the effects and molecular mechanisms in high-dose vitamin D3 treatment on renal fibrosis. A model of chronic kidney disease was established by 5/6 nephrectomy in rats characterised by high levels of serum creatine, urea nitrogen, and urinary protein. Serum 25-dihydroxyvitamin D3, calcium and parathormone levels were measured to evaluate vitamin D levels. Hematoxylin and eosin, periodic acid Schiff and Mallory's Trichrome staining were used to evaluate histopathological changes in rats. Moreover, the expression of vimentin, collagen I, α-smooth muscle actin and E-cadherin were analyzed at molecular and histopathological levels. Our results showed that exposure to vitamin D3 decreased the levels of serum creatine, urea nitrogen and urine protein and restored the homeostasis of calcium and parathormone. Vitamin D3 also downregulated the expression of vimentin, collagen I and α-smooth muscle actin and attenuated renal fibrosis and epithelial to mesenchymal transition in the kidney. Importantly, vitamin D3 treatment increased the expression of the vitamin D receptor and inhibited Transforming growth factor-ß1 (TGF-ß1)/Smad3 signaling pathway in rats kidneys with chronic kidney disease. Mechanistically, the upregulation of TGF-ß1 and phosphorylation of Smad3 induced by vitamin D3 was reversed by activation of the vitamin D receptor. Our findings indicated that vitamin D3 is a potential antifibrotic drug in chronic kidney disease via the vitmin D receptor and inhibiting TGF-ß1/Smad3 signaling pathway.

Highly modified nor-clerodane diterpenoids from Croton yanhuii.

Phytochemical investigation of the leaves and twigs of Croton yanhuii led to the isolation of seven highly modified nor-clerodane diterpenoids (1-7), including three new ones, croyanoids A-C (1-3), along with four known analogues (4-7). Compound 1 incorporates a 5,12-epoxy ring, forming a unique cage-like, 6/6/6/5-fused tetracyclic ring system. Their structures were established by extensive spectroscopic analysis, and the absolute configurations of 1-4 were determined by a combination of circular dichroism (CD) analysis and single-crystal X-ray diffraction. All compounds were tested in an array of bioassays, but were inactive. Crotoeurin A (7), a nor-clerodane dimer with a high yield of 0.2‰ isolated in current study, was considered as a chemotaxonomic marker for this species.