Mechanism of baixiangdan capsules on anti-neuroinflammation: combining dry and wet experiments.

Neuroinflammation plays an important role in the pathogenesis of neurological disorders, and despite intensive research, treatment of neuroinflammation remains limited. BaiXiangDan capsule (BXD) is widely used in clinical practice. However, systematic studies on the direct role and mechanisms of BXD in neuroinflammation are still lacking. We systematically evaluated the potential pharmacological mechanisms of BXD on neuroinflammation using network pharmacological analysis combined with experimental validation. Multiple databases are used to mine potential targets for bioactive ingredients, drug targets and neuroinflammation. GO and KEGG pathway analysis was also performed. Interactions between active ingredients and pivotal targets were confirmed by molecular docking. An experimental model of neuroinflammation was used to evaluate possible therapeutic mechanisms for BXD. Network pharmacological analysis revealed that Chrysoeriol, Kaempferol and Luteolin in BXD exerted their anti-neuroinflammatory effects mainly by acting on targets such as NCOA2, PIK3CA and PTGS2. Molecular docking results showed that their average affinity was less than -5 kcal/mol, with an average affinity of -8.286 kcal/mol. Pathways in cancer was found to be a potentially important pathway, with involvement of PI3K/AKT signaling pathways. In addition, in vivo experiments showed that BXD treatment ameliorated neural damage and reduced neuronal cell death. Western blotting, RT-qPCR and ELISA analysis showed that BXD inhibited not only the expression of IL-1ß, TNF-α and NO, but also NF-κB, MMP9 and PI3K/AKT signaling pathways. This study applied network pharmacology and in vivo experiments to explore the possible mechanisms of BXD against neuroinflammation, providing insight into the treatment of neuroinflammation.

Predicting the Safety and Effectiveness of Inferior Vena Cava Filters (PRESERVE): Outcomes at 12 months.

OBJECTIVE: To determine the safety and effectiveness of vena cava filters (VCFs). METHODS: A total of 1429 participants (62.7 ± 14.7 years old; 762 [53.3% male]) consented to enroll in this prospective, nonrandomized study at 54 sites in the United States between October 10, 2015, and March 31, 2019. They were evaluated at baseline and at 3, 6, 12, 18, and 24 months following VCF implantation. Participants whose VCFs were removed were followed for 1 month after retrieval. Follow-up was performed at 3, 12, and 24 months. Predetermined composite primary safety (freedom from perioperative serious adverse events [AEs] and from clinically significant perforation, VCF embolization, caval thrombotic occlusion, and/or new deep vein thrombosis [DVT] within 12-months) and effectiveness (composite comprising procedural and technical success and freedom from new symptomatic pulmonary embolism [PE] confirmed by imaging at 12-months in situ or 1 month postretrieval) end points were assessed. RESULTS: VCFs were implanted in 1421 patients. Of these, 1019 (71.7%) had current DVT and/or PE. Anticoagulation therapy was contraindicated or had failed in 1159 (81.6%). One hundred twenty-six (8.9%) VCFs were prophylactic. Mean and median follow-up for the entire population and for those whose VCFs were not removed was 243.5 ± 243.3 days and 138 days and 332.6 ± 290 days and 235 days, respectively. VCFs were removed from 632 (44.5%) patients at a mean of 101.5 ± 72.2 days and median 86.3 days following implantation. The primary safety end point and primary effectiveness end point were both achieved. Procedural AEs were uncommon and usually minor, but one patient died during attempted VCF removal. Excluding strut perforation greater than 5 mm, which was demonstrated on 31 of 201 (15.4%) patients' computed tomography scans available to the core laboratory, and of which only 3 (0.2%) were deemed clinically significant by the site investigators, VCF-related AEs were rare (7 of 1421, 0.5%). Postfilter, venous thromboembolic events (none fatal) occurred in 93 patients (6.5%), including DVT (80 events in 74 patients [5.2%]), PE (23 events in 23 patients [1.6%]), and/or caval thrombotic occlusions (15 events in 15 patients [1.1%]). No PE occurred in patients following prophylactic placement. CONCLUSIONS: Implantation of VCFs in patients with venous thromboembolism was associated with few AEs and with a low incidence of clinically significant PEs.

The NLRP3 inflammasome is involved in resident intruder paradigm-induced aggressive behaviors in mice.

Background: Aggressive behaviors are one of the most important negative behaviors that seriously endangers human health. Also, the central para-inflammation of microglia triggered by stress can affect neurological function, plasticity, and behavior. NLRP3 integrates stress-related signals and is a key driver of this neural para-inflammation. However, it is unclear whether the NLRP3 inflammasome is implicated in the development of aggressive behaviors. Methods: First, aggressive behavior model mice were established using the resident intruder paradigm. Then, aggressive behaviors were determined with open-field tests (OFT), elevated plus-maze (EPM), and aggressive behavior tests (AT). Moreover, the expression of P2X7R and NLRP3 inflammasome complexes were assessed by immunofluorescence and Western blot. The levels of NLRP3 and inflammatory cytokines were evaluated using enzyme-linked immunosorbent assay (ELISA) kits. Finally, nerve plasticity damage was observed by immunofluorescence, transmission electron microscope, and BrdU staining. Results: Overall, the resident intruder paradigm induced aggressive behaviors, activated the hippocampal P2X7R and NLRP3 inflammasome, and promoted the release of proinflammatory cytokines IL-1ß in mice. Moreover, NLRP3 knockdown, administration of P2X7R antagonist (A804598), and IL-1ß blocker (IL-1Ra) prevented NLRP3 inflammasome-driven inflammatory responses and ameliorated resident intruder paradigm-induced aggressive behaviors. Also, the resident intruder paradigm promoted the activation of mouse microglia, damaging synapses in the hippocampus, and suppressing hippocampal regeneration in mice. Besides, NLRP3 knockdown, administration of A804598, and IL-1Ra inhibited the activation of microglia, improved synaptic damage, and restored hippocampal regeneration. Conclusion: The NLRP3 inflammasome-driven inflammatory response contributed to resident intruder paradigm-induced aggressive behavior, which might be related to neuroplasticity. Therefore, the NLRP3 inflammasome can be a potential target to treat aggressive behavior-related mental illnesses.

Predicting the Safety and Effectiveness of Inferior Vena Cava Filters (PRESERVE): Outcomes at 12 months.

OBJECTIVE: To determine the safety and effectiveness of vena cava filters (VCFs). METHODS: A total of 1429 participants (62.7 ± 14.7 years old; 762 [53.3% male]) consented to enroll in this prospective, nonrandomized study at 54 sites in the United States between October 10, 2015, and March 31, 2019. They were evaluated at baseline and at 3, 6, 12, 18, and 24 months following VCF implantation. Participants whose VCFs were removed were followed for 1 month after retrieval. Follow-up was performed at 3, 12, and 24 months. Predetermined composite primary safety (freedom from perioperative serious adverse events [AEs] and from clinically significant perforation, VCF embolization, caval thrombotic occlusion, and/or new deep vein thrombosis [DVT] within 12-months) and effectiveness (composite comprising procedural and technical success and freedom from new symptomatic pulmonary embolism [PE] confirmed by imaging at 12-months in situ or 1 month postretrieval) end points were assessed. RESULTS: VCFs were implanted in 1421 patients. Of these, 1019 (71.7%) had current DVT and/or PE. Anticoagulation therapy was contraindicated or had failed in 1159 (81.6%). One hundred twenty-six (8.9%) VCFs were prophylactic. Mean and median follow-up for the entire population and for those whose VCFs were not removed was 243.5 ± 243.3 days and 138 days and 332.6 ± 290 days and 235 days, respectively. VCFs were removed from 632 (44.5%) patients at a mean of 101.5 ± 72.2 days and median 86.3 days following implantation. The primary safety end point and primary effectiveness end point were both achieved. Procedural AEs were uncommon and usually minor, but one patient died during attempted VCF removal. Excluding strut perforation greater than 5 mm, which was demonstrated on 31 of 201 (15.4%) patients' computed tomography scans available to the core laboratory, and of which only 3 (0.2%) were deemed clinically significant by the site investigators, VCF-related AEs were rare (7 of 1421, 0.5%). Postfilter, venous thromboembolic events (none fatal) occurred in 93 patients (6.5%), including DVT (80 events in 74 patients [5.2%]), PE (23 events in 23 patients [1.6%]), and/or caval thrombotic occlusions (15 events in 15 patients [1.1%]). No PE occurred in patients following prophylactic placement. CONCLUSIONS: Implantation of VCFs in patients with venous thromboembolism was associated with few AEs and with a low incidence of clinically significant PEs.

piR-36249 and DHX36 together inhibit testicular cancer cells progression by upregulating OAS2.

Background: PIWI-interacting RNAs (piRNAs) are a class of noncoding RNAs originally reported in the reproductive system of mammals and later found to be aberrantly expressed in tumors. However, the function and mechanism of piRNAs in testicular cancer are not very clear. Methods: The expression level and distribution of piR-36249 were detected by RT-qPCR and immunofluorescence staining assay. Testicular cancer cell (NT2) progression was measured by CCK8 assay, colony formation assay and wound healing assay. Cell apoptosis was assessed by flow cytometry and western blot. RNA sequencing and dual-luciferase reporter assay were conducted to identify the potential targets of piR-36249. The relationship between piR-36249 and OAS2 or DHX36 was confirmed using overexpression assay, knockdown assay, pull-down assay and RIP assay. Results: piR-36249 is significantly downregulated in testicular cancer tissues compared to tumor-adjacent tissues. Functional studies demonstrate that piR-36249 inhibits testicular cancer cell proliferation, migration and activates the cell apoptosis pathway. Mechanically, we identify that piR-36249 binds to the 3'UTR of 2'-5'-oligoadenylate synthetase 2 (OAS2) mRNA. OAS2 has been shown in the literature to be a tumor suppressor modulating the occurrence and development of some tumors. Here, we show that OAS2 knockdown also promotes testicular cancer cell proliferation and migration. Furthermore, piR-36249 interacts with DHX36, which has been reported to promote translation. DHX36 can also bind to OAS2 mRNA, and knockdown of DHX36 increases OAS2 mRNA but downregulates its protein, indicating the enhancing effect of DHX36 on OAS2 protein expression. Conclusion: All these data suggest that piR-36249, together with DHX36, functions in inhibiting the malignant phenotype of testicular cancer cells by upregulating OAS2 protein and that piR-36249 may be used as a suppressor factor to regulate the development of testicular cancer.

Ephedrae herba: A comprehensive review of its traditional uses, phytochemistry, pharmacology, and toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Ephedrae herba (called Mahuang in China) is the dried herbaceous stem of Ephedra sinica Stapf, Ephedra intermedia Schrenk et C. A. Mey., and Ephedra equisetina Bge. Ephedrae herba has a long history of use as an herb, and it was originally recorded in Sheng Nong's herbal classic. Ephedrae herba has also been widely used as both medicine and food. In the clinic, Ephedrae herba is commonly used for treating colds, bronchial asthma, nasal congestion, and other diseases. AIM OF REVIEW: This review aims to provide a systematic summary on the traditional use, chemical constituents, pharmacological effects, clinical applications, quality control, toxicology, and pharmacokinetics of Ephedrae herba to provide a theoretical basis for further reasonable development of Ephedrae herba in clinical practice and creation of new drugs. MATERIALS AND METHODS: Information on Ephedrae herba was gathered from various sources, including the scientific databases including CNKI, PubMed, SciFinder and ScienceDirect, classical books on traditional Chinese herbal medicine, Ph.D. and M.Sc. dissertations; Baidu Scholar; and from different professional websites. RESULTS: Ephedrae herba is distributed in regions of China and other areas. Ephedra and its compound preparations can be used for colds, bronchial asthma, nasal congestion and other diseases. Approximately 281 chemical constituents have been isolated from Ephedrae herba, including alkaloids, flavonoids, tannins, polysaccharides, volatile oils, organic acids, and other compounds. Among these constituents, alkaloids and volatile oils are the most abundant and represent the major bioactive constituents. Ephedrae herba possesses multiple pharmacological activities, including diuretic effect, anti-allergic effect, blood pressure regulatory, anti-inflammatory effect, anti-oxidation effect and anti-viral effects. Ephedrine hydrochloride and pseudoephedrine hydrochloride are generally selected as indicators for the quantitative determination of Ephedrae herba. The maximum dosage of Ephedrae herba should not exceed 10 g. If overused, adverse reactions such as palpitations, sweating, irritability and insomnia will occur. CONCLUSIONS: Ephedrae herba is an ancient herbal medicine with a broad spectrum of pharmacological activities that has been used for thousands of years in China. It is one of the most commonly used herbal components of the TCM formulas. Hydrochloride and pseudoephedrine are the major bioactive constituents. However, there is a need to further understand the mechanisms of active components of Ephedrae herba. Future studies should perform an in-depth analyses of the pharmacokinetics and mechanisms of toxicity of Ephedrae herba. Quality standards should be developed to correspond to the various application methods to ensure the efficacy of drugs in actual treatment.

Examination of Adverse Reactions After COVID-19 Vaccination Among Patients With a History of Multisystem Inflammatory Syndrome in Children.

Importance: Data are limited regarding adverse reactions after COVID-19 vaccination in patients with a history of multisystem inflammatory syndrome in children (MIS-C). The lack of vaccine safety data in this unique population may cause hesitancy and concern for many families and health care professionals. Objective: To describe adverse reactions following COVID-19 vaccination in patients with a history of MIS-C. Design, Setting, and Participants: In this multicenter cross-sectional study including 22 North American centers participating in a National Heart, Lung, and Blood Institute, National Institutes of Health-sponsored study, Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC), patients with a prior diagnosis of MIS-C who were eligible for COVID-19 vaccination (age ≥5 years; ≥90 days after MIS-C diagnosis) were surveyed between December 13, 2021, and February 18, 2022, regarding COVID-19 vaccination status and adverse reactions. Exposures: COVID-19 vaccination after MIS-C diagnosis. Main Outcomes and Measures: The main outcome was adverse reactions following COVID-19 vaccination. Comparisons were made using the Wilcoxon rank sum test for continuous variables and the χ2 or Fisher exact test for categorical variables. Results: Of 385 vaccine-eligible patients who were surveyed, 185 (48.1%) received at least 1 vaccine dose; 136 of the vaccinated patients (73.5%) were male, and the median age was 12.2 years (IQR, 9.5-14.7 years). Among vaccinated patients, 1 (0.5%) identified as American Indian/Alaska Native, non-Hispanic; 9 (4.9%) as Asian, non-Hispanic; 45 (24.3%) as Black, non-Hispanic; 59 (31.9%) as Hispanic or Latino; 53 (28.6%) as White, non-Hispanic; 2 (1.1%) as multiracial, non-Hispanic; and 2 (1.1%) as other, non-Hispanic; 14 (7.6%) had unknown or undeclared race and ethnicity. The median time from MIS-C diagnosis to first vaccine dose was 9.0 months (IQR, 5.1-11.9 months); 31 patients (16.8%) received 1 dose, 142 (76.8%) received 2 doses, and 12 (6.5%) received 3 doses. Almost all patients received the BNT162b2 vaccine (347 of 351 vaccine doses [98.9%]). Minor adverse reactions were observed in 90 patients (48.6%) and were most often arm soreness (62 patients [33.5%]) and/or fatigue (32 [17.3%]). In 32 patients (17.3%), adverse reactions were treated with medications, most commonly acetaminophen (21 patients [11.4%]) or ibuprofen (11 [5.9%]). Four patients (2.2%) sought medical evaluation, but none required testing or hospitalization. There were no patients with any serious adverse events, including myocarditis or recurrence of MIS-C. Conclusions and Relevance: In this cross-sectional study of patients with a history of MIS-C, no serious adverse events were reported after COVID-19 vaccination. These findings suggest that the safety profile of COVID-19 vaccination administered at least 90 days following MIS-C diagnosis appears to be similar to that in the general population.

Xiangshao Granules reduce the aggressive behavior and hippocampal injury of premenstrual irritability in rats by regulating JIK/JNK/p38 signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: As a typical prescription for soothing the liver, Xiangshao granule has a good effect on the symptoms of irritability and anxiety. Clinical evidence suggests that it has significant efficacy in the treatment of Premenstrual dysphoria disorder (PMDD). However, the underlying mechanism remains unclear. AIM OF THE STUDY: PMDD is a common disease in women of childbearing age, seriously affecting their family, society, and daily work life. The registered herbal medicine, Xiangshao granules, is used for relieving PMDD dysphoria and irritability symptoms with excellent efficacy in China. This study was focused on the deep intervention mechanism of Xiangshao granules in treating PMDD. MATERIALS AND METHODS: The vaginal smear and open field test were used to screen rats in nonreception phase of estrus cycle with similar macroscopic behaviors and regular estrus cycle. The rat model of PMDD irritability was established through social isolation and residential invasion, with which, the irritability symptoms of PMDD patients with menstrual cycle dependence was also well simulated. Elevated plus Maze Test and Social interaction activities were used to measure the anxiety-like behavior of rats. TUNEL Staining and Hematoxylin-Eosin staining were used to measure apoptosis of hippocampal neurons. RT-PCR, Western blot and immunofluorescence were used to measure the expression of GR, JIK, p-JIK, p38, P-P38, JNK, caspase 3, and caspase 12. RESULTS: In this study, Xiangshao granules showed consistent therapeutic effects similar with those in clinic, significantly reducing aggressive and anxiety-like behaviors with improved social skills in PMDD rats. In mechanism, Xiangshao granules lowered the apoptosis of hippocampal neurons and weakened the morphological damage of the hippocampal brain evidenced by the decreased mRNA and protein expression of glucocorticoid receptor, caspase-3, and caspase-12. In addition, administration of Xiangshao granules led to the decreased expression of JIK in the PMDD irritability rat model which agreed well with the previous studies. The JNK/p38 mitogen-activated protein kinases (MAPKs) signaling pathway is abnormally activated in the hippocampal brain region of PMDD rats, while treated with Xiangshao granules could increase JIK expression and inhibit the abnormal activation of the JNK/p38 MAPK signaling pathway, effectively reducing the stress damage in the hippocampus. CONCLUSIONS: Xiangshao Granules Reduce the Aggressive Behavior and Hippocampal Injury of Premenstrual Irritability in Rats by Regulating JIK/JNK/p38 Signal Pathway.

Mechanism Study on Chinese Medicine in Treatment of Nodular Goiter.

Nodular goiter has become increasingly prevalent in recent years. Clinically, there has been a burgeoning interest in nodular goiter due to the risk of progression to thyroid cancer. This review aims to provide a comprehensive summary of the mechanisms underlying the therapeutic effect of Chinese medicine (CM) in nodular goiter. Articles were systematically retrieved from databases, including PubMed, Web of Science and China National Knowledge Infrastructure. New evidence showed that CM exhibited multi-pathway and multi-target characteristics in the treatment of nodular goiter, involving hypothalamus-pituitary-thyroid axis, oxidative stress, blood rheology, cell proliferation, apoptosis, and autophagy, especially inhibition of cell proliferation and promotion of cell apoptosis, involving multiple signal pathways and a variety of cytokines. This review provides a scientific basis for the therapeutic use of CM against nodular goiter. Nonetheless, future studies are warranted to identify more regulatory genes and pathways to provide new approaches for the treatment of nodular goiter.

LncRNA-MALAT1 Regulates Cancer Glucose Metabolism in Prostate Cancer via MYBL2/mTOR Axis.

It is known that the long noncoding RNAs (lncRNA) MALAT1 is associated with tumorigenesis and progression in various cancers; however, its functions and mechanisms in prostate cancer (PCa) initiation and progression are still unknown. In the present study, our findings revealed that MALAT1 plays a critical part in regulating PCa proliferation and glucose metabolism. Knockdown of MALAT1 affects the protein and mRNA levels of MYBL2. In addition, MALAT1 enhances the phosphorylation level of mTOR pathway by upregulating MYBL2. Knockdown of MALAT1 or MYBL2 in PCa cell lines significantly inhibits their proliferation capacity. Silencing MALAT1/MYBL2/mTOR axis in PCa cell lines affects their glycolysis and lactate levels, and we verified these findings in mice. Furthermore, we explored the underlying tumorigenesis functions of MYBL2 in PCa and found that high expression of MYBL2 was positively associated with TNM stage, Gleason score, PSA level, and poor survival rate in PCa patients. Taken together, our research suggests that MALAT1 controls cancer glucose metabolism and progression by upregulating MYBL2-mTOR axis.

Radix Ranunculi ternati: review of its chemical constituents, pharmacology, quality control and clinical applications.

OBJECTIVES: Radix ranunculi ternati (RRT) is widely used as traditional and folk medicine distributed in China, as well as in Kyushu and Shikoku in Japan. Although RRT has a short history of use as medicine, it has a high medicinal value. This study summarizes the research progress on the chemical constituents, pharmacological activity, quality control measures and clinical applications to provide a valuable and exhaustive reference for the development and application of RRT. KEY FINDINGS: Phytochemical studies showed that this plant mainly contains glycosides, organic acids, esters, sterols, flavonoids, alkaloids and volatile oils. The pharmacological activity of RRT includes immune regulation, anti-tumour, anti-tuberculosis, antioxidant, antibacterial, hepatoprotective and anti-inflammatory effects. This plant is especially effective in the treatment of cancer, tuberculosis, thyroid and nasopharynges disorders.

LncRNA NEAT1-associated aerobic glycolysis blunts tumor immunosurveillance by T cells in prostate cancer.

Long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) is nuclear-located and transcribed from chromatin 11. To date, little is known about the cellular functions and regulatory mechanisms of NEAT1 in prostate cancer (PCa). In this study, whole-genome RNA sequencing data were downloaded from TCGA and GEO databases. Biological information was used to analyze the different expressions of NEAT1. In situ hybridization (ISH) was performed to detect the expression of NEAT1 in PCa and paracarcinoma clinical samples. Then, NEAT1 was knocked down in PC3 cells through lentiviral infection with a plasmid construct. Bioinformatics and integrative analytical approaches were utilized to identify the relationships of NEAT1 with specific cancer-related gene sets. Cell proliferation assay and colony formation assay were performed to evaluate the cell proliferative ability. Glycolysis stress test, metabolism assay, and infiltrating T-cell function analysis were implemented to assess the changes in metabolism and immune microenvironment of PCa. We found that the expression of NEAT1 was higher in PCa than in non-neoplastic tissues. The cell proliferative capability of PCa cells was significantly reduced in the NEAT1 knockdown group. PCR array and bioinformatics analysis revealed that the enrichment of acidic substance-related gene sets was associated with NEAT1 expression. NEAT1 depletion inhibited PCa cell aerobic glycolysis accompanied by the reduction of lactate levels in the medium. Further, we found that lactate dehydrogenase A (LDHA) expression was positively regulated by NEAT1. At last, co-culture systems indicated that NEAT1 or LDHA knockdown promoted the secretion of CD8+ T-lymphocyte factors, including TNF-α, IFN-γ, and Granzyme B, and enhanced the antitumor effects.

Targeting NLRP3 Inflammasome in Translational Treatment of Nervous System Diseases: An Update.

Neuroinflammatory response is the immune response mechanism of the innate immune system of the central nervous system. Both primary and secondary injury can activate neuroinflammatory response. Among them, the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome plays a key role in the inflammatory response of the central system. Inflammasome is a type of pattern recognition receptor, a cytoplasmic polyprotein complex composed of members of the Nod-like receptor (NLR) family and members of the pyrin and HIN domain (PYHIN) family, which can be affected by a variety of pathogen-related molecular patterns or damage-related molecular patterns are activated. As one of the research hotspots in the field of medical research in recent years, there are increasing researches on immune function abnormalities in the onset of neurological diseases such as depression, AD, ischemic brain injury and cerebral infarction, the NLRP3 inflammasome causes the activated caspase-1 to cleave pre-interleukin-1ß and pre-interleukin-18 into mature interleukin-1ß and interleukin-18, in turn, a large number of inflammatory factors are produced, which participate in the occurrence and development of the above-mentioned diseases. Targeted inhibition of the activation of inflammasomes can reduce the inflammatory response, promote the survival of nerve cells, and achieve neuroprotective effects. This article reviews NLRP3 inflammasome's role in neurological diseases and related regulatory mechanisms, which providing references for future research in this field.