Schisandrin B from Schisandra chinensis alleviated pain via glycine receptors, Nav1.7 channels and Cav2.2 channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis, the dried and ripe fruit of the magnolia family plant Schisandra chinensis (Turcz.) Baill, was commonly used in traditional analgesic prescription. Studies have shown that the extract of Schisandra chinensis (SC) displayed analgesic activity. However, the analgesic active component and the exact mechanisms have yet to be revealed. AIM OF THE STUDY: The present study was to investigate the anti-nociceptive constituent of Schisandra chinensis, assess its analgesic effect, and explore the potential molecular mechanisms. MATERIALS AND METHODS: The effects of a series of well-recognized compounds from SC on glycine receptors were investigated. The analgesic effect of the identified compound was evaluated in three pain models. Mechanistic studies were performed using patch clamp technique on various targets expressed in recombinant cells. These targets included glycine receptors, Nav1.7 sodium channels, Cav2.2 calcium channels et al. Meanwhile, primary cultured spinal dorsal horn (SDH) neurons and dorsal root ganglion (DRG) neurons were also utilized. RESULTS: Schisandrin B (SchB) was a positive allosteric modulator of glycine receptors in spinal dorsal horn neurons. The EC50 of SchB on glycine receptors in spinal dorsal horn neurons was 2.94 ± 0.28 µM. In three pain models, the analgesic effect of SchB was comparable to that of indomethacin at the same dose. Besides, SchB rescued PGE2-induced suppression of α3 GlyR activity and alleviated persistent pain. Notably, SchB could also potently decrease the frequency of action potentials and inhibit sodium and calcium channels in DRG neurons. Consistent with the data from DRG neurons, SchB was also found to significantly block Nav1.7 sodium channels and Cav2.2 channels in recombinant cells. CONCLUSION: Our results demonstrated that, Schisandrin B, the primary lignan component of Schisandra chinensis, may exert its analgesic effect by acting on multiple ion channels, including glycine receptors, Nav1.7 channels, and Cav2.2 channels.

RIIß-PKA in GABAergic Neurons of Dorsal Median Hypothalamus Governs White Adipose Browning.

The RIIß subunit of  cAMP-dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RIIß-knockout mice show leanness and increased UCP1 in brown adipose tissue. The authors have previously reported that RIIß reexpression in hypothalamic GABAergic neurons rescues the leanness. However, whether white adipose tissue (WAT) browning contributes to the leanness and whether RIIß-PKA in these neurons governs WAT browning are unknown. Here, this work reports that RIIß-KO mice exhibit a robust WAT browning. RIIß reexpression in dorsal median hypothalamic GABAergic neurons (DMH GABAergic neurons) abrogates WAT browning. Single-cell sequencing, transcriptome sequencing, and electrophysiological studies show increased GABAergic activity in DMH GABAergic neurons of RIIß-KO mice. Activation of DMH GABAergic neurons or inhibition of PKA in these neurons elicits WAT browning and thus lowers body weight. These findings reveal that RIIß-PKA in DMH GABAergic neurons regulates WAT browning. Targeting RIIß-PKA in DMH GABAergic neurons may offer a clinically useful way to promote WAT browning for treating obesity and other metabolic disorders.

Neural circuit control of innate behaviors.

All animals possess a plethora of innate behaviors that do not require extensive learning and are fundamental for their survival and propagation. With the advent of newly-developed techniques such as viral tracing and optogenetic and chemogenetic tools, recent studies are gradually unraveling neural circuits underlying different innate behaviors. Here, we summarize current development in our understanding of the neural circuits controlling predation, feeding, male-typical mating, and urination, highlighting the role of genetically defined neurons and their connections in sensory triggering, sensory to motor/motivation transformation, motor/motivation encoding during these different behaviors. Along the way, we discuss possible mechanisms underlying binge-eating disorder and the pro-social effects of the neuropeptide oxytocin, elucidating the clinical relevance of studying neural circuits underlying essential innate functions. Finally, we discuss some exciting brain structures recurrently appearing in the regulation of different behaviors, which suggests both divergence and convergence in the neural encoding of specific innate behaviors. Going forward, we emphasize the importance of multi-angle and cross-species dissections in delineating neural circuits that control innate behaviors.

A brain-to-spinal sensorimotor loop for repetitive self-grooming.

Self-grooming is a complex behavior with important biological functions and pathological relevance. How the brain coordinates with the spinal cord to generate the repetitive movements of self-grooming remains largely unknown. Here, we report that in the caudal part of the spinal trigeminal nucleus (Sp5C), neurons that express Cerebellin-2 (Cbln2+) form a neural circuit to the cervical spinal cord to maintain repetitive orofacial self-grooming. Inactivation of Cbln2+ Sp5C neurons blocked both sensory-evoked and stress-induced repetitive orofacial self-grooming. Activation of these neurons triggered short-latency repetitive forelimb movements that resembled orofacial self-grooming. The Cbln2+ Sp5C neurons were monosynaptically innervated by both somatosensory neurons in the trigeminal ganglion and paraventricular hypothalamic neurons. Among the divergent projections of Cbln2+ Sp5C neurons, a descending pathway that innervated motor neurons and interneurons in the cervical spinal cord was necessary and sufficient for repetitive orofacial self-grooming. These data reveal a brain-to-spinal sensorimotor loop for repetitive self-grooming in mice.

FDA Approval Summary: Tivozanib for Relapsed or Refractory Renal Cell Carcinoma.

On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75-1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.

The complete chloroplast genome sequence of medicinal plant, Artemisia Montana.

The complete chloroplast genome sequence of Artemisia montana was characterized from Illumina pair-end sequencing. The chloroplast genome of A. montana was 151,130 bp in length, containing a large single-copy region (LSC) of 80,975 bp, a small single-copy region (SSC) of 16,011 bp, and two inverted repeat (IR) regions of 27,162 bp. The overall GC content is 30.70%, while the correponding values of the LSC, SSC, and IR regions are 64.6%, 69.2%, and 60.1%, respectively. The genome contains 131 complete genes, including 86 protein-coding genes (62 protein-coding gene species), 37 tRNA genes (29 tRNA species) and 8 rRNA genes (4 rRNA species). The Neighbour-joining phylogenetic analysis showed that A. montana and Artemisia lavandulaefolia YC clustered together as sisters to other Artemisia species.

Applying Complex Network and Cell-Cell Communication Network Diagram Methods to Explore the Key Cytokines and Immune Cells in Local Acupoint Involved in Acupuncture Treating Inflammatory Pain.

Manual acupuncture (MA) can effectively treat a variety of diseases, but its specific mechanism remains unclear. The "acupoint network" activated by MA participates in MA signal transduction, in which immune-related cells and cytokines play an important role. However, which cells and cytokines in the acupoint have changed after MA? What is the network relationship between them? Which cells and cytokines may play the most important role in MA effect? These problems are unclear. In this study, on the basis of affirming the analgesic, detumescence, and anti-inflammatory effect of MA, the concentration of 24 cytokines in ST36 acupoint in rats with inflammatory pain after MA treatment was detected by multiplex immunoassay technology. Then, using statistical and complex network and cell-cell communication (CCC) network diagram method to analyze the detected data depicts the network relationship between the cytokines and related cells objectively and establishes cytokine connection network and CCC network, respectively. The results showed that MA reinforced communication intensity between cells while reducing the overall correlation intensity. On this basis, the key cytokines and key cells at three MA time-points were screened out, cytokines IL-6, MCP-1, fibroblasts cell, and monocyte macrophage screened by the three methods at three MA time-points might be the key cytokines or key cells. After that, we detected the macrophages in ST36 acupoint by flow cytometry and immunofluorescence and found that the relative amount of macrophages increased significantly after MA, especially the macrophage of the dermis of skin. This study provided a basis for revealing the initiated mechanism of MA effect.

Efficacy of Acupuncture at the Sphenopalatine Ganglion in the Treatment of Persistent Allergic Rhinitis.

Objective: The aim of this research was to explore the hypothesis that acupuncture at the sphenopalatine ganglion (SPG), a new a new method of acupuncture, would be more efficacious and safe than traditional acupuncture in the treatment of persistent allergic rhinitis (PAR). Materials and Methods: For this study, 120 patients with PAR were randomly assigned to SPG acupuncture, traditional acupuncture (Yingxiang [LI 20], Hegu [LI 4], and Yintang [Ex-HN 3]), or drug treatment (budesonide nasal spray). Efficacy was assessed by using single symptoms, including sneezing, rhinorrhea, nasal obstruction and nasal itch, a total nasal symptoms score (TNSS), and a Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) before treatment, the day treatment ended, and 4-, 8-, 12-weeks later, respectively. Results: Four weeks after treatment ended, the effectiveness rate in the SPG-acupuncture group was superior to that of the traditional-acupuncture group (P = 0.033) but was still lower than that of the drug-treatment group (P = 0.039), with mean effectiveness rates of 69.70%, 44.44%, and 71.43%, respectively. However, these rates gradually decreased in each group during weeks 8 through 16. Moreover, statistically significant improvements in TNSS', and reductions in nasal congestion and sneezing symptoms were observed in the SPG-acupuncture group, compared with those in the traditional-acupuncture group as early as the day treatment ended and this continued throughout the observation period (P < 0.05). However, the improvement did not continue for sneezing, during weeks 8 through weeks 12 after treatment ended. The RQLQ of the SPG-acupuncture group was lower than that of the traditional-acupuncture group at week 12; however, there were no differences at weeks 8 and 16. Conclusions: The data generated by this study confirmed that acupuncture at the SPG alleviated the symptoms of PAR rapidly and safely, especially nasal obstruction, and improved the patients' life quality. These results were worthy of clinical promotion.

The complete chloroplast genome sequence of Salvia miltiorrhiza, a medicinal plant for preventing and treating vascular dementia.

S. miltiorrhiza is a perennial herb of the genus Salvia (Lamiaceae), which is an important medicinal plant for preventing and treating vascular dementia. The complete chloroplast genome sequence of Salvia miltiorrhiza was characterized from Illumina pair-end sequencing. The chloroplast genome of S. miltiorrhiza was 152,680 bp in length, containing a large single-copy region (LSC) of 84,104 bp, a small single-copy region (SSC) of 17,638 bp, and two inverted repeat (IR) regions of 25,469 bp. The overall GC content is 38.70%, while the correponding values of the LSC, SSC, and IR regions are 36.2%, 31.9%, and 43.2%, respectively. The genome contains 131 complete genes, including 86 protein-coding genes (62 protein-coding gene species), 37 tRNA genes (29 tRNA species) and 8 rRNA genes (4 rRNA species). The Neighbour-joining phylogenetic analysis showed that S. miltiorrhiza and Salvia przewalskii clustered together as sisters to other Salvia species.

Comparison of volatile profiles and bioactive components of sun-dried Pu-erh tea leaves from ancient tea plants on Bulang Mountain measured by GC-MS and HPLC.

To explore the volatile profiles and the contents of ten bioactive components (polyphenols and caffeine) of sun-dried Pu-erh tea leaves from ancient tea plants on Bulang Mountain, 17 samples of three tea varieties were analyzed by headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) and high-performance liquid chromatography (HPLC). A total of 75 volatile components were tentatively identified. Laomaner (LME), Laobanzhang (LBZ), and other teas on Bulang Mountain (BL) contained 70, 53, and 71 volatile compounds, respectively. Among the volatile compounds, alcohols (30.2%-45.8%), hydrocarbons (13.7%-17.5%), and ketones (12.4%-23.4%) were qualitatively the most dominant volatile compounds in the different tea varieties. The average content of polyphenol was highest in LME (102.1 mg/g), followed by BL (98.7 mg/g) and LBZ (88.0 mg/g), while caffeine showed the opposite trend, 27.3 mg/g in LME, 33.5 mg/g in BL, and 38.1 mg/g in LBZ. Principal component analysis applied to both the volatile compounds and ten bioactive components showed a poor separation of samples according to varieties, while partial least squares-discriminant analysis (PLS-DA) showed satisfactory discrimination. Thirty-four volatile components and five bioactive compounds were selected as major discriminators (variable importance in projection (VIP) >1) among the tea varieties. These results suggest that chromatographic data combined with multivariate analysis could provide a useful technique to characterize and distinguish the sun-dried Pu-erh tea leaves from ancient tea varieties on Bulang Mountain.

Plant morphology, physiological characteristics, accumulation of secondary metabolites and antioxidant activities of Prunella vulgaris L. under UV solar exclusion.

BACKGROUND: Prunella vulgaris L. has been an important medicinal plant for the treatment of thyroid gland malfunction and mastitis in China for over 2000 years. There is an urgent need to select effective wavelengths for greenhouse cultivation of P. vulgaris as light is a very important factor in P. vulgaris growth. Here, we described the effects of natural light (control) and UV solar exclusion on the morphological and physiological traits, secondary metabolites contents and antioxidant activities of P. vulgaris. RESULTS: The results showed that UV solar exclusion resulted in remarkable alterations to morphological and biomass traits; significantly reduced the chlorophyll a, chlorophyll b and total chlorophyll contents; significantly enhanced the ratio of chlorophyll a to b; and significantly increased the carotenoid and anthocyanin contents in P. vulgaris. UV solar exclusion significantly increased the catalase (CAT) and peroxidase (POD) activities, increased superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities and slightly decreased the glutathione (GSH) content. UV solar exclusion significantly increased the soluble sugar and H2O2 contents and increased the soluble protein content but significantly decreased the proline content and slightly decreased the MDA content. The secondary metabolite contents (total phenolics, rosmarinic acid, caffeic acid, hyperoside, ursolic acid and oleanolic acid) and in vitro antioxidative properties (DPPH· and ABTS·+scavenging activities) were significantly increased in P. vulgaris spicas under UV solar exclusion. Additionally, the total polysaccharide and total flavonoids contents were slightly increased by UV solar exclusion. The salviaflaside content was significantly reduced by UV solar exclusion. CONCLUSION: Our study demonstrated that P. vulgaris activates several antioxidant defence systems against oxidative damage caused by UV solar exclusion.

Pharmacokinetic/Pharmacodynamic Evaluation of a Novel Aminomethylcycline Antibiotic, KBP-7072, in the Neutropenic Murine Pneumonia Model against Staphylococcus aureus and Streptococcus pneumoniae.

KBP-7072 is a novel aminomethylcycline antibiotic in clinical development for community-acquired pneumonia. The goal of present studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter magnitude correlated with efficacy in the murine pneumonia infection model against Staphylococcus aureus and Streptococcus pneumoniae KBP-7072 pharmacokinetic measurements were performed in plasma and epithelial lining fluid (ELF) at 4-fold-increasing doses from 1 to 256 mg/kg of body weight subcutaneously. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 82% to 238% comparing ELF drug concentrations to plasma free drug concentrations. Twenty-four-hour dose-ranging efficacy studies were then performed in the neutropenic murine pneumonia model against 5 S. aureus (3 methicillin-resistant and 2 methicillin-susceptible) and 6 S. pneumoniae (2 Tetr and 2 Penr) strains. KBP-7072 demonstrated potent in vivo activity resulting in a 3- to 5-log10 kill in CFU burden compared to the start of therapy for all strains. The PK/PD index area under the concentration-time curve (AUC)/MIC corelated well with efficacy (R2, 0.80 to 0.89). Net stasis was achieved at plasma 24-h free drug AUC/MIC values of 1.13 and 1.41 (24-h ELF AUC/MIC values of 2.01 and 2.50) for S. aureus and S. pneumoniae, respectively. A 1-log10 kill was achieved at 24-h plasma AUC/MIC values of 2.59 and 5.67 (24-h ELF AUC/MIC values of 4.22 and 10.08) for S. aureus and S. pneumoniae, respectively. A 2-log10 kill was achieved at 24-h plasma AUC/MIC values of 7.16 and 31.14 (24-h ELF AUC/MIC values of 8.37 and 42.92) for S. aureus and S. pneumoniae, respectively. The results of these experiments will aid in the rational design of dose-finding studies for KBP-7072 in patients with community-acquired bacterial pneumonia (CAP).

Plant morphology, physiological characteristics, accumulation of secondary metabolites and antioxidant activities of Prunella vulgaris L. under UV solar exclusion

BACKGROUND: Prunella vulgaris L. has been an important medicinal plant for the treatment of thyroid gland malfunction and mastitis in China for over 2000 years. There is an urgent need to select effective wavelengths for greenhouse cultivation of P. vulgaris as light is a very important factor in P. vulgaris growth. Here, we described the effects of natural light (control) and UV solar exclusion on the morphological and physiological traits, secondary metabolites contents and antioxidant activities of P. vulgaris. RESULTS: The results showed that UV solar exclusion resulted in remarkable alterations to morphological and biomass traits; significantly reduced the chlorophyll a, chlorophyll b and total chlorophyll contents; significantly enhanced the ratio of chlorophyll a to b; and significantly increased the carotenoid and anthocyanin contents in P. vulgaris. UV solar exclusion significantly increased the catalase (CAT) and peroxidase (POD) activities, increased superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities and slightly decreased the glutathione (GSH) content. UV solar exclusion significantly increased the soluble sugar and H2O2 contents and increased the soluble protein content but significantly decreased the proline content and slightly decreased the MDA content. The secondary metabolite contents (total phenolics, rosmarinic acid, caffeic acid, hyperoside, ursolic acid and oleanolic acid) and in vitro antioxidative properties (DPPH· and ABTS·+scavenging activities) were significantly increased in P. vulgaris spicas under UV solar exclusion. Additionally, the total polysaccharide and total flavonoids contents were slightly increased by UV solar exclusion. The salviaflaside content was significantly reduced by UV solar exclusion. CONCLUSION: Our study demonstrated that P. vulgaris activates several antioxidant defence systems against oxidative damage caused by UV solar exclusion.

Effects of UV-B Radiation on the Content of Bioactive Components and the Antioxidant Activity of Prunella vulgaris L. Spica during Development.

The effects of UV-B radiation on the content of bioactive components and the antioxidant activity of Prunella vulgaris L. spica during development were studied. The experimental design involved two levels of UV-B radiation intensity (0 and 120 µW cm-2 nm-1). The results showed that the contents of total flavonoids, rosmarinic acid, caffeic acid and hyperoside, as well as the antioxidant capacities (DPPH● and ABTS•+ scavenging activities), in the spicas significantly decreased during spica development. The content of salviaflaside in the spicas significantly increased during development. The highest contents of total flavonoids, rosmarinic acid, and caffeic acid and the highest antioxidant activities were found in spicas in the full-flowering stage, while the highest content of hyperoside was found in spicas in the bud stage. In addition, the highest content of salviaflaside was found in spicas in the mature-fruiting stage. UV-B radiation significantly promoted the synthesis of secondary metabolites, increased the contents of the main bioactive components in the three developmental stages of isolated dried spicas, and significantly increased the DPPH● and ABTS•+ scavenging activities of P. vulgaris spicas in the mature-fruiting stage. Moreover, the total flavonoids content was positively correlated with the DPPH● and ABTS•+ scavenging activities, and the correlation with the DPPH● scavenging activity was very strong. This result shows that the highest contents of the main bioactive components in the spicas were not all found in the same developmental stages of P. vulgaris. Our research revealed that the best stage for harvesting P. vulgaris spica was between the bud stage and the full-flowering stage since harvesting at this point provides a higher content of bioactive components and a higher antioxidant capacity, which is relevant for medicinal applications.

Overexpression of TaNHX3, a vacuolar Na⁺/H⁺ antiporter gene in wheat, enhances salt stress tolerance in tobacco by improving related physiological processes.

Salt stress is one of the major abiotic stresses affecting plant growth, development, and productivity. In this study, we functionally characterized a wheat vacuolar Na(+)/H(+) antiporter gene (TaNHX3). TaNHX3 is 78.9% identical with TaNHX2 in nucleic acid level, encoding a polypeptide of 522 amino acids (aa). TaNHX3 is targeted onto tonoplast after ER sorting and can complement the growth under salt stress in a yeast mutant with a defective vacuolar Na(+)/H(+) antiporter exchange. TaNHX3 transcripts were induced by applying salt stress in wheat cultivars. More TaNHX3 were detected in the salt-stress-resistant cultivar Ji 7369 compared with the salt-stress-sensitive cultivar Shimai 12 and Ji-Shi-3, an isogenic line derived from aforementioned cultivars with Shimai 12 genetic background. The ectopic TaNHX3 expression in tobacco significantly enhanced the plant tolerance to salt stress. Compared with control plants, the TaNHX3 overexpressing plants displayed no varied Na(+) contents and accumulated more Na(+) amount in plants. However, they exhibited higher fresh and dry weights, more accumulative nitrogen, phosphorus, and potassium, higher contents of chlorophyll, carotenoid, soluble protein, higher activities of the antioxidant enzymes including superoxide dismutase, catalase, and peroxidase, and lower malondialdehyde and H2O2 amount. Our results indicated that TaNHX3 plays an important role in regulating the cytosolic Na(+) transportation within vacuoles under high salinity, alleviating the Na(+) damage effects. The improved salt stress tolerance in TaNHX3 overexpressing tobacco plants is closely associated with the improvement of the aforementioned physiological processes. TaNHX3 can be used as a candidate gene for molecular breeding of salt-tolerant plants.

[Ligustrazine and Salvia miltiorrhiza injection solution in complementary therapy of pregnancy-induced hypertension: clinical analysis of 60 cases].

OBJECTIVE: To compare the clinical effects of ligustrazine and Salvia miltiorrhiza injection solutions in the complementary therapy of pregnancy-induced hypertension (PIH). METHODS: Sixty patients with PIH were equally divided into 2 groups to receive intravenous infusion of 80 mg ligustrazine and 16 ml Salvia miltiorrhiza injection solution respectively, in addition to the conventional therapies. The effects of the two complementary treatments were compared. RESULTS: After a treatment course of 10 days, ligustrazine produced obvious effect in inhibiting fibrinolysis and promoting microcirculation of the patients. Salvia miltiorrhiza injection resulted in obvious reduction of blood viscosity, cholesterol and lipoprotein. CONCLUSION: Ligustrazine and Salvia miltiorrhiza injections produce obvious therapeutic effects on PIH, but they are used for different clinical purposes as their in pharmacological action difference.