Antigout effects and mechanisms of total flavonoids from prunus tomentosa.

BACKGROUND: In recent years, hyperuricemia and acute gouty arthritis have become increasingly common, posing a serious threat to public health. Current treatments primarily involve Western medicines with associated toxic side effects. OBJECTIVE: This study aims to investigate the therapeutic effects of total flavones from Prunus tomentosa (PTTF) on a rat model of gout and explore the mechanism of PTTF's anti-gout action through the TLR4/NF-κB signaling pathway. METHODS: We measured serum uric acid (UA), creatinine (Cr), blood urea nitrogen (BUN), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and interleukin-6 (IL-6) levels using an enzyme-linked immunosorbent assay (ELISA). Histopathological changes were observed using HE staining, and the expression levels of relevant proteins were detected through Western blotting. RESULTS: After PTTF treatment, all indicators improved significantly. PTTF reduced blood levels of UA, Cr, BUN, IL-1ß, IL-6, and TNF-α, and decreased ankle swelling. CONCLUSIONS: PTTF may have a therapeutic effect on animal models of hyperuricemia and acute gouty arthritis by reducing serum UA levels, improving ankle swelling, and inhibiting inflammation. The primary mechanism involves the regulation of the TLR4/NF-κB signaling pathway to alleviate inflammation. Further research is needed to explore deeper mechanisms.

Clinical effects of arthroscopic-assisted uni-portal spinal surgery and unilateral bi-portal endoscopy on unilateral laminotomy for bilateral decompression in patients with lumbar spinal stenosis: a retrospective cohort study.

OBJECTIVE: To investigate the clinical effectiveness of Arthroscopic-assisted Uni-portal Spinal Surgery (AUSS) in the treatment of lumbar spinal stenosis. METHODS: A total of 475 patients with lumbar spinal stenosis from January 2019 to January 2023 were included in this study. Among them, 240 patients were treated with AUSS (AUSS group); the other 235 patients were treated with unilateral bi-portal endoscopy treatment (UBE group). The differences in surgery-related clinical indicators, pain degree before and after surgery, Oswestry Disability Index (ODI), CT imaging parameters of spinal stenosis, and clinical efficacy were compared between the two groups. RESULTS: Patients in the AUSS group had a shorter operative time than those in the UBE group, and the length of incision and surgical bleeding were less than those in the UBE group, with statistically significant differences (P < 0.05). Before operation, there was no significant difference in the VAS score of low back pain and leg pain between the two groups (P > 0. 05). After operation, patients in both groups showed a significant reduction in low back and leg pain, and their VAS scores were significantly lower than before the operation (P < 0.05). Three months after surgery, the results of CT re-examination in both groups showed that the spinal stenosis of the patients was well improved, and the measurements of lumbar spinal interspace APDC, CAC, ICA, CAD and LAC were significantly higher than those before surgery (P < 0. 05). Besides, the lumbar function of patients improved significantly in both groups, and ODI measurements were significantly lower than those before surgery (P < 0.05). CONCLUSION: Both AUSS and UBE with unilateral laminotomy for bilateral decompression can achieve good clinical results in the treatment of lumbar spinal stenosis, but the former has the advantages of simpler operation, shorter operation time, shorter incision length, and less surgical blood loss.

Reporting of tumor lysis syndrome with targeted therapy for hepatic cancer in the FDA adverse events reporting system.

BACKGROUND: Hepatic cancer is a common cancer in clinical practice. Current drug therapies for this condition include targeted therapy, chemotherapy, and immunotherapy. Tumor lysis syndrome (TLS) is the most serious complication of oncology treatment. According to the literature, several cases reported TLS occurred with targeted therapies for hepatic cancer. METHODS: Reporting odds ratio and information component were used to measure the disproportionate signals for TLS associated with targeted therapies, using data from the FDA's Adverse Event Reporting System (FAERS). A stepwise sensitivity analysis was conducted to test the robustness of signals. Time-to-onset analysis was used to describe the latency of TLS events associated with targeted therapies. The Bradford Hill criteria were used to perform a global assessment of the evidence. RESULTS: Sorafenib, lenvatinib, cabozantinib, and bevacizumab showed higher disproportionate signals for TLS than chemotherapy. The median number of days to TLS occurrence after drug therapy was 5.5, 6.5, and 6.5 days for sorafenib, lenvatinib, and bevacizumab, respectively. CONCLUSIONS: There is a significant association between tumor lysis syndrome and targeted therapies for hepatic carcinoma, with particularly strong signals for sorafenib and lenvatinib. Clinicians should be aware of the potential for tumor lysis syndrome in targeted therapies for hepatic carcinoma.

Effects of Prunus Tomentosa Thumb Total Flavones on adjuvant arthritis in rats and regulation of autophagy.

BACKGROUND: Rheumatoid arthritis (RA) is a slow in taking effect systemic autoimmune disease. Prunus Tomentosa Thumb Total Flavones (PTTTF) has anti-inflammatory and antioxidant properties. OBJECTIVE: The purpose of this study is to the PTTTF on adjuvant arthritis (AA) in rats and to explore the mechanism of autophagy. METHODS: Adjuvant arthritis model was established in rats. The cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-17 (IL-17), tumor necrosis factor (TNF-α) of rat synovial tissue were determined by RT-PCR. The histopathological varieties of knee joints in AA rats were observed by HE staining. The expressions of autophagy-related proteins ATG5, ATG7, ATG12, Beclin1, Lc3II and Bcl-2 in rat synovial tissue were determined by Western Blotting. RESULTS: PTTTF (50, 100, 200 mg/kg) significantly inhibited inflammation in rats (P< 0.01). PTTTF significantly inhibited inflammatory factor COX in rat synovial tissue. COX-2, IL-1ß, IL-6, IL-17, TNF-α expression (P< 0.05); PTTTF can significantly improve the pathological damage of rat knee joint PTTTF and can significantly inhibited the expression of autophagy-related proteins in rat synovium (P< 0.05 ). CONCLUSION: PTTTF can inhibit adjuvant arthritis in rats and can inhibit the expression of autophagy-related proteins ATG5, ATG7, ATG12, Beclin1, Lc3II and Bcl-2.

Macrophage Extracellular Traps Exacerbate Secondary Spinal Cord Injury by Modulating Macrophage/Microglia Polarization via LL37/P2X7R/NF-κB Signaling Pathway.

Persistent inflammation in the secondary spinal cord injury (SCI) is an important reason for the failure of nerve repair, which is partly due to the continuous activation of local M1-like macrophage/microglia. It is reported that extracellular trap (ET) has been a new way of cell death, which can be released by macrophages and named macrophage extracellular trap (Met). Furthermore, it exists widely in the pathophysiological process of many diseases, but it has been rarely studied in the field of SCI. In this study, we constructed a spinal cord contusion model and assessed the function outcome of SCI rats. We used immunofluorescence, flow cytometry, and transmission electron microscope (TEM) to demonstrate the existence of Mets. Besides, some related experiments had also been employed to explore the relationship between Mets and M1 polarization of macrophage/microglia. We also performed Co-IP and Western blotting to reveal a new extracellular proinflammatory signal pathway. Finally, we made a linear regression analysis between the concentrations of specific markers of Mets in human serum and ASIA scores. Briefly, our results suggested that macrophages infiltrated in SCI area could induce macrophage/microglia to differentiate into M1-like cells by releasing Mets, which may be achieved partly through LL37-P2X37-NF-κB signal pathway. However, limiting Mets could effectively inhibit M1 polarization and promote function recovery. In addition, the concentrations of Met related proteins in human serum showed high correlation with ASIA scores and could be applied to reflect the severity of SCI. In conclusion, Mets may be a new target for SCI therapy and a promising index for SCI assessment.

miR-672-3p Promotes Functional Recovery in Rats with Contusive Spinal Cord Injury by Inhibiting Ferroptosis Suppressor Protein 1.

Aberrantly expressed microRNAs (miRNAs) after spinal cord injury (SCI) participate in diverse biological pathways and processes, including apoptosis, inflammation, oxidative stress responses, peroxidation, and ferroptosis. This study was aimed at exploring the mechanisms underlying miRNA-mediated ferroptosis in an SCI rat model. In the present study, a T10 weight-dropping SCI model was established and miRNA profiling was used to detect miRNA expression profiles post-SCI. Basso-Beattie-Bresnahan scores and inclined plane test, hematoxylin and eosin (HE) and Nissl staining, immunohistochemistry and immunofluorescence, western blotting, cell viability, and Annexin V/7-aminoactinomycin D (7-AAD) assays were used to evaluate locomotor activity, histological changes in the injured spinal cords, neuronal ferroptosis, ferroptosis suppressor protein 1 (FSP1) expression, and cell death, respectively. It was observed that many miRNAs were differentially expressed after SCI, and miR-672-3p, which increased significantly, was selected after cross-referencing with predicted target miRNAs. The luciferase reporter assay demonstrated that miR-672-3p downregulated FSP1, a glutathione-independent ferroptosis suppressor, by binding to its 3' untranslated region. Oxygen and glucose deprivation- (OGD-) treated PC12 and AGE1.HN cells were treated with miR-672-3p mimics or inhibitors in vitro. The effect of miR-672-3p mimics or inhibitor on OGD-PC12/AGE1.HN ferroptosis was evaluated by flow cytometry, immunohistochemistry, immunofluorescence, and western blotting. The miR-672-3p mimics promoted ferroptosis after SCI, whereas the miR-672-3p inhibitor inhibited this process. Rats with SCI treated with miR-672-3p mimics or inhibitor showed similar results in vivo. Furthermore, the ferroptosis-related changes caused by SCI or miR-672-3p were reversed by overexpression of FSP1 lentivirus in vivo and in vitro. These results indicated that sh-miR-672-3p exerted a neural restoration effect in vivo and in vitro by inhibiting ferroptosis via the FSP1 pathway.

Protective Effects of Anwulignan against HCl/Ethanol-Induced Acute Gastric Ulcer in Mice.

Gastric ulcer is one of the most common gastrointestinal diseases. Anwulignan (AN) is a major active component of Schisandra sphenanthera Rehd. This study was designed to evaluate the protective effect of AN against the acute gastric ulcer induced by HCl/ethanol in mice. The mice were given HCl/ethanol by gavage to establish an acute gastric ulcer model. Then, the serum and gastric tissue samples were taken for biochemical analyses. The results showed that the pretreatment with AN could significantly reduce the gastric ulcer index (GUI) and increase the ulcer inhibition rate, indicating that AN can protect against gastric ulcers. AN showed its antioxidant roles by decreasing the content of reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG) and increasing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and anti-inflammatory roles by decreasing the content of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and myeloperoxidase (MPO) and increasing the content of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-10 (IL-10), prostaglandin E2 (PGE2), and nitric oxide (NO) in both serum and gastric tissue. Furthermore, AN also activated the NRF2/ARE signaling pathway and inhibited the MAPK/NF-κB signaling pathway. AN improves the acute gastric ulcer induced by HCl/ethanol in mice, which may be mainly through its antioxidant capacity and anti-inflammatory effect.

The occurrence of myelin oligodendrocyte glycoprotein antibodies in aquaporin-4-antibody seronegative Neuromyelitis Optica Spectrum Disorder: A systematic review and meta-analysis.

BACKGROUND: Despite inclusion in neuromyelitis optica spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated diseases are increasingly recognized as an independent disease entity. In this study, we conducted a systematic review and meta-analysis to comprehensively update the rate of occurrence of MOG-Ab in Aquaporin4 (AQP4)-antibody seronegative NMOSD. METHODS: We searched PubMed, EMBASE, and Cochrane databases for studies reporting the rates of patients with MOG-Ab in NMOSD. Fixed or random-effects models were used to pool results across studies. RESULTS: Fourteen studies met the inclusion criteria. Overall, MOG-Abs positive patients comprised 9.3% of all NMO/NMOSD (95% confidence interval [CI] 7.9%-10.8%, I2 = 13.1%), 32.5% of all AQP4-Ab seronegative NMO/NMOSD (95% CI 25.7%-39.3%, I2 = 45.8%), and 41.6% of AQP4-Ab seronegative NMOSD cases diagnosed by IPND 2015 criteria (95% CI 35.1%-48.2%, I2 = 0.0%). The pooled prevalence of MOG-Ab was 31.0% among Asian AQP4-Ab seronegative NMO/NMOSD patients (95% CI 22.1%-39.9% I2=54.1%) and 34.3% in European seronegative NMO/NMOSD (95% CI 21.9%-46.7%, I2 = 51.9%). CONCLUSIONS: This study shows that MOG-Abs represent a substantial proportion of AQP4-Ab seronegative NMOSD patients despite different underlying mechanisms, clinical manifestations, and treatment response, suggesting MOG-Ab screening in AQP4-Ab seronegative NMOSD patients can facilitate accurate diagnoses and treatments.

Immunomodulatory effect of Schisandra polysaccharides in cyclophosphamide-induced immunocompromised mice.

As a strategy to prevent the well-known immunosuppressant effects of cyclophosphamide (Cyp), the immunomodulatory effects of the polysaccharide extract of the fruit of Schisandra chinensis (Turcz.) Baill. were investigated in the present study. The crude Schisandra polysaccharide (SCP) was obtained by water extraction and alcohol precipitation methods. The total carbohydrate, uronic acid and protein contents were determined using the phenol-sulfuric acid, m-hydroxydiphenyl and Bradford method, respectively. The monosaccharide composition of SCP was determined by high-performance liquid chromatography. ICR mice were randomly divided into control, model, low-dose SCP (0.4 mg/10 g), medium-dose SCP (0.8 mg/10 g) and high-dose SCP (1.6 mg/10 g) groups. The mice in the SCP groups were intragastrically administered SCP once a day for 21 days and those from the control and model groups were administered the same volume of distilled water. Subsequently, the mice in the model and SCP groups were intraperitoneally injected with Cyp (20 mg/kg) once a day for 5 days. The mouse leukocyte count in the peripheral blood as well as thymus and spleen indexes were determined, and the phagocytic function of macrophages was estimated using a carbon clearance test. The thymus and spleen were histomorphologically observed. The levels of tumor necrosis factor-α and interferon-γ were measured by ELISA. Furthermore, antibody formation and spleen lymphocyte proliferation were measured by the serum hemolysin and the MTT method, respectively. The apoptotic rate of splenic lymphocytes was determined by flow cytometric analysis. The results indicated that SCP prevents Cyp-induced impairment of the cellular, humoral and non-specific immunity, and may be an auxiliary immune enhancer for the prevention of immune hypofunction.

Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR.

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.

Comparing the equivalent particle number density distribution of gas and plasma flow fields.

In this paper, the equivalent particle number density distribution of gas and plasma flow fields is investigated. For the purpose of facilitating comparison, argon gas and argon arc plasma are chosen as practical examples for experiment. The equivalent particle number density distributions of the argon gas and argon arc plasma are reconstructed from the experimentally measured refractive index distributions obtained by moiré tomography, while five cross sections, which are 7, 8.5, 10, 11.5, and 13 mm away from the jet nozzle are chosen for practical calculation and comparison. In experiment, the probe wavelength and the export pressure of argon gas and argon arc plasma are the same. The experimental results manifest that (1) the equivalent particle number density decreases with the distance away from the jet nozzle of the gas flow field, while (2) the equivalent particle number density of the plasma flow field has a different variation. Finally, the experimental results are theoretically explained and analyzed.