Jolkinolide B attenuates allergic airway inflammation and airway remodeling in asthmatic mice.

Asthma is a widely prevalent chronic disease that brings great suffering to patients and may result in death if it turns severe. Jolkinolide B (JB) is one diterpenoid component separated from the dried roots of Euphorbia fischeriana Steud (Euphorbiaceae), and has anti--inflammatory, antioxidative, and antitumor properties. However, the detailed regulatory role and associated regulatory mechanism in the progression of asthma remain elusive. In this work, it was demonstrated that the extensive infiltration of bronchial inflammatory cells and the thickening of airway wall were observed in ovalbumin (OVA)-induced mice, but these impacts were reversed by JB (10 mg/kg) treatment, indicating that JB relieved the provocative symptoms in OVA-induced asthma mice. In addition, JB can control OVA-triggered lung function and pulmonary resistance. Moreover, JB attenuated OVA-evoked inflammation by lowering the levels of interleukin (IL)-4, IL-5, and IL-13. Besides, the activated nuclear factor kappa B (NF-κB) and transforming growth factor-beta-mothers against decapentaplegic homolog 3 (TGFß/smad3) pathways in OVA-induced mice are rescued by JB treatment. In conclusion, it was disclosed that JB reduced allergic airway inflammation and airway remodeling in asthmatic mice by modulating the NF-κB and TGFß/smad3 pathways. This work could offer new opinions on JB for lessening progression of asthma.

Effects of weight-bearing dance aerobics on lower limb muscle morphology, strength and functional fitness in older women.

Objective: To investigate the effects of 12-week weight-bearing dance aerobics (WBDA) on muscle morphology, strength and functional fitness in older women. Methods: This controlled study recruited 37 female participants (66.31y ± 3.83) and divided them into intervention and control groups according to willingness. The intervention group received 90-min WBDA thrice a week for 12 weeks, while the control group maintained normal activities. The groups were then compared by measuring muscle thickness, fiber length and pennation angle by ultrasound, muscle strength using an isokinetic multi-joint module and functional fitness, such as 2-min step test, 30-s chair stand, chair sit-and-reach, TUG and single-legged closed-eyed standing test. The morphology, strength, and functional fitness were compared using ANCOVA or Mann-Whitney U test to study the effects of 12 weeks WBDA. Results: Among all recruited participants, 33 completed all tests. After 12 weeks, the thickness of the vastus intermedius (F = 17.85, P < 0.01) and quadriceps (F = 15.62, P < 0.01) was significantly increased in the intervention group compared to the control group, along with a significant increase in the torque/weight of the knee flexor muscles (F = 4.47, P = 0.04). Similarly, the intervention group revealed a significant improvement in the single-legged closed-eyed standing test (z = -2.16, P = 0.03) compared to the control group. Conclusion: The study concluded that compared to the non-exercising control group, 12-week WBDA was shown to thicken vastus intermedius, increase muscle strength, and improve physical function in older women. In addition, this study provides a reference exercise program for older women.

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Lomitapide repurposing for treatment of malignancies: A promising direction.

The development of novel drugs from basic science to clinical practice requires several years, much effort, and cost. Drug repurposing can promote the utilization of clinical drugs in cancer therapy. Recent studies have shown the potential effects of lomitapide on treating malignancies, which is currently used for the treatment of familial hypercholesterolemia. We systematically review possible functions and mechanisms of lomitapide as an anti-tumor compound, regarding the aspects of apoptosis, autophagy, and metabolism of tumor cells, to support repurposing lomitapide for the clinical treatment of tumors.

No evidence for enhanced disease with human polyclonal SARS-CoV-2 antibody in the ferret model.

Since SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-dependent enhancement (ADE) of disease as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral/ocular) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7-10 days post-infection. To evaluate the potential for ADE, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2.

Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade.

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.

Enhanced Detection of Early Pulmonary Fibrosis Disease Using 68Ga-FAPI-LM3 PET.

Early detection of pulmonary fibrosis is a critical yet insufficiently met clinical necessity. This study evaluated the effectiveness of FAPI-LM3, a 68Ga-radiolabeled heterobivalent molecular probe that targets fibroblast activating protein (FAP) and somatostatin receptor 2 (SSTR2), in the early detection of pulmonary fibrosis, leveraging its potential for early disease identification. A bleomycin-induced early pulmonary fibrosis model was established in C57BL/6 mice for 7 days. FAP and SSTR2 expression levels were quantitatively assessed in human idiopathic pulmonary fibrosis lung tissue samples and bleomycin-treated mouse lung tissues by using western blotting, real-time quantitative PCR (RT-qPCR), and immunofluorescence techniques. The diagnostic performance of FAPI-LM3 was investigated by synthesizing monomeric radiotracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3 alongside the heterobivalent probe 68Ga-FAPI-LM3. These imaging radiopharmaceuticals were used in small-animal PET to compare their uptake in fibrotic and normal lung tissues. Results indicated significant upregulation of FAP and SSTR2 at both RNA and protein levels in fibrotic lung tissues compared with that in normal controls. PET imaging demonstrated significantly enhanced uptake of the 68Ga-FAPI-LM3 probe in fibrotic lung tissues, with superior visual effects compared to monomeric tracers. At 60 min postinjection, early stage fibrotic tissues (day 7) demonstrated low-to-medium uptake of monomeric probes, including 68Ga-DOTA-LM3 (0.45 ± 0.04% ID/g) and 68Ga-FAPI-46 (0.78 ± 0.09% ID/g), whereas the uptake of the heterobivalent probe 68Ga-FAPI-LM3 (1.90 ± 0.10% ID/g) was significantly higher in fibrotic lesions than in normal lung tissue. Blockade experiments confirmed the specificity of 68Ga-FAPI-LM3 uptake, which was attributed to synergistic targeting of FAP and SSTR2. This study demonstrates the potential of 68Ga-FAPI-LM3 for early pulmonary fibrosis detection via molecular imaging, offering significant benefits over monomeric tracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3. This strategy offers new possibilities for noninvasive and precise early detection of pulmonary fibrosis.

Predicting the Pro-Inflammatory Effects of Oxidized Methyl Oleate Based on the Volatile Compounds.

The negative impact of lipid peroxidation on health is intimately tied to its oxidation products. In this study, methyl oleate was oxidized at 180℃ for 0, 2, 4, 8 and 12 h respectively. The free radicals and volatile components generated during the oxidation process were determined using electron spin resonance and headspace solid-phase microextraction (HS-SPME)-GC-MS. The pro-inflammatory effects of oxidized methyl oleate were evaluated in RAW264.7 cells. Then partial least-squares regression (PLSR) models were established for predicting the 3 pro-inflammatory genes expression based on the volatile components. The results revealed that the alkoxy radical content increased rapidly during oxidation from 4 h to 8 h, and the rate of oxidation of methyl oleate dropped after 8 h. A total of 27 volatile oxidation compounds were detected by HS-SPME-GC-MS. The content of most compounds, including aldehydes, esters, and acids, exhibited a pattern of initial increase and then decrease as the oxidation time increased. Similarly, the proinflammatory effects of oxidized methyl oleate peaked after 8 h of oxidation. The PLSR quantitative prediction models showed that the coefficient of determination (R2P) between the predicted and measured values of the 3 inflammatory gene expressions were 0.915, 0.946 and 0.951 respectively. The established PLSR model predicts the pro-inflammatory effects of oxidized methyl oleate well and provides a theoretical foundation for quick evaluation of the pro-inflammatory effects of oxidized lipids.

Intratumoral microbiome is associated with gastric cancer prognosis and therapy efficacy.

The role of the intratumoral microbiome in gastric cancer (GC) has not been comprehensively assessed. Here, we explored the relationship between the microbial community and GC prognosis and therapy efficacy. Several cancer-associated microbial characteristics were identified, including increased α-diversity, differential ß-diversity, and decreased Helicobacter pylori abundance. After adjusting for clinical features, prognostic analysis revealed 2 phyla, 14 genera, and 5 species associated with the overall survival of patients with GC. Additionally, 2 phyla, 14 genera, and 6 species were associated with adjuvant chemotherapy (ACT) efficacy in patients with stage II - III GC. Furthermore, we classified GC microbiome structures into three microbial subtypes (MS1, MS2 and MS3) with distinguishing features. The MS1 subtype exhibited high immune activity and enrichment of microbiota related to immunotherapy and butyric acid-producing, as well as potential benefits in immunotherapy. MS2 featured the highest α-diversity and activation of the TFF pathway, MS3 was characterized by epithelial-mesenchymal transition and was associated with poor prognosis and reduced ACT efficacy. Collectively, the results of this study provide valuable insights into the microbial characteristics associated with GC prognosis and therapy efficacy.

[Determination of 12 prohibited veterinary drug residues in pig urine by ultra high performance liquid chromatography-tandem mass spectrometry].

A method was established for the simultaneous detection of 12 prohibited veterinary drugs, including ß2-receptor agonists, nitrofuran metabolites, nitroimidazoles, chlorpromazine, and chloramphenicol, in pig urine. The sample was pretreated by enzymolysis, acid hydrolysis/derivatization, and liquid-liquid extraction combined with solid-phase extraction. Detection was performed using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Ammonium acetate solution (0.2 mol/L, 4.5 mL) and ß-glucuronidase/aryl sulfatase (40 µL) were added to the sample, which was subsequently enzymolized at 37 ℃ for 2 h. Then, 1.5 mL of 1.0 mol/L hydrochloric acid solution and 100 µL of 0.1 mol/L o-nitrobenzaldehyde solution were added to the sample. The mixture was incubated at 37 ℃ for 16 h, and the analytes were extracted with 8 mL of ethyl acetate by liquid-liquid extraction. The lower aqueous phase obtained after extraction was extracted and purified using a mixed cation-exchange solid-phase extraction column. The extracts were combined, the extraction solution was blow-dried with nitrogen, and the residue was redissolved for determination. The samples were analyzed under multiple-reaction monitoring mode with both positive and negative electrospray ionization, and quantified using an isotope internal standard method. The correlation coefficients (r) of the 12 compounds were >0.99. The limits of detection (LODs) and quantification (LOQs) of chloramphenicol were 0.05 and 0.1 µg/L, respectively, and the LODs and LOQs of the other compounds were 0.25 and 0.5 µg/L, respectively. The mean recoveries and RSDs at 1, 2, and 10 times the LOQ were 83.6%-115.3% and 2.20%-12.34%, respectively. The proposed method has the advantages of high sensitivity, good stability, and accurate quantification; thus, it is suitable for the simultaneous determination of the 12 prohibited veterinary drug residues in pig urine.

Fractured vertebra antedisplacement reconstruction technique: a feasible treatment choice for posttraumatic thoracolumbar kyphosis.

OBJECTIVE: The goal of this study was to evaluate the feasibility of the fractured vertebra antedisplacement reconstruction technique for the treatment of posttraumatic thoracolumbar kyphosis (PTK). METHODS: A total of 22 patients with PTK who were treated with the fractured vertebra antedisplacement reconstruction technique were retrospectively analyzed. The radiological evaluation included global kyphosis, thoracolumbar angle, and sagittal vertical axis. The clinical evaluation included visual analog scale pain score, Oswestry Disability Index score, SF-12 Health Survey score, and American Spinal Injury Association grade. The complications were recorded. RESULTS: The mean global kyphosis was 55.0° ± 12.6° preoperatively, 8.5° ± 5.0° postoperatively, and 10.3° ± 4.8° at the latest follow-up (p < 0.001). The average total kyphosis correction achieved was 44.7° ± 14.2°, with a range of 23.4°-79.4°, indicating a mean final correction of 80.1%. The mean thoracolumbar angle was 46.2° ± 13.2° preoperatively, 6.6° ± 4.5° postoperatively, and 7.6° ± 4.2° at the latest follow-up (p < 0.001). The mean sagittal vertical axis was improved significantly, from 51.1 ± 24.2 mm preoperatively to 28.5 ± 17.4 mm at the latest follow-up (p = 0.001). One patient (4.5%) experienced single intervertebral fusion nonunion, and 1 patient (4.5%) experienced distal screw loosening. No patients experienced any neurological deterioration. The visual analog scale pain score, Oswestry Disability Index score, SF-12 Health Survey score, and American Spinal Injury Association grade achieved significant improvement at the latest follow-up. CONCLUSIONS: Fractured vertebra antedisplacement reconstruction technique can effectively correct kyphosis, reconstruct spinal stability, and improve the patient's symptoms and neurological function. This technique is safer, minimally traumatic, and less technically demanding to avoid osteotomy-related complications. It is a feasible treatment choice for PTK.

Association between gut microbiota and spinal stenosis: a two-sample mendelian randomization study.

Introduction: Considerable evidence has unveiled a potential correlation between gut microbiota and spinal degenerative diseases. However, only limited studies have reported the direct association between gut microbiota and spinal stenosis. Hence, in this study, we aimed to clarify this relationship using a two-sample mendelian randomization (MR) approach. Materials and Methods: Data for two-sample MR studies was collected and summarized from genome-wide association studies (GWAS) of gut microbiota (MiBioGen, n = 13, 266) and spinal stenosis (FinnGen Biobank, 9, 169 cases and 164, 682 controls). The inverse variance-weighted meta-analysis (IVW), complemented with weighted median, MR-Egger, weighted mode, and simple mode, was used to elucidate the causality between gut microbiota and spinal stenosis. In addition, we employed mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and the MR-Egger intercept test to assess horizontal multiplicity. Cochran's Q test to evaluate heterogeneity, and "leave-one-out" sensitivity analysis to determine the reliability of causality. Finally, an inverse MR analysis was performed to assess the reverse causality. Results: The IVW results indicated that two gut microbial taxa, the genus Eubacterium fissicatena group and the genus Oxalobacter, have a potential causal relationship with spinal stenosis. Moreover, eight potential associations between genetic liability of the gut microbiota and spinal stenosis were implied. No significant heterogeneity of instrumental variables or horizontal pleiotropy were detected. In addition, "leave-one-out" sensitivity analysis confirmed the reliability of causality. Finally, the reverse MR analysis revealed that no proof to substantiate the discernible causative relationship between spinal stenosis and gut microbiota. Conclusion: This analysis demonstrated a possible causal relationship between certain particular gut microbiota and the occurrence of spinal stenosis. Further studies focused on the mechanism of gut microbiota-mediated spinal stenosis can lay the groundwork for targeted prevention, monitoring, and treatment of spinal stenosis.

Fibroblast Activation Protein Inhibitor Tracers and Their Preclinical, Translational, and Clinical Status in China.

Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors.

Isolation of anthraquinone derivatives from Rubia cordifolia (Rubiaceae) and their bioactivities against plant pathogenic microorganisms.

BACKGROUND: The discovery of antimicrobial ingredients from natural products could be an effective way to create novel fungicides. Rubia cordifolia L., a traditional Chinese herb, may have antimicrobial effects on plant pathogens according to our previous screening study. RESULTS: Rubia cordifolia L. extracts had moderate inhibitory effects on apple Valsa canker (Valsa mali) and tomato grey mould (Botrytis cinerea) at a concentration of 10 mg mL-1. With the use of bioguided isolation methods, eight compounds (1-8) were obtained, including the new compound 2,2,6-trimethyl-6-(4-methylphenyl)-tetrahydropyrano- 3-ol (7), and seven quinone derivatives. Two compounds, mollugin (1) and 1,3,6-trihydroxy-2-methylanthraquinone (6), were found to exhibit outstanding antifungal activities against V. mali and Phytophthora capsici Leon. The half maximal effective concentration (EC50) of compound 1 and compound 6 against V. mali were 79.08 and 81.78 µg mL-1, respectively, and the EC50 of compound 6 against P. capsici was 4.86 µg mL-1. Compound 1 also showed excellent activity against tobacco mosaic virus (TMV). The inactive, inductive, protective and curative activities against TMV were 84.29%, 83.38%, 86.81%, and 60.02%, respectively, at a concentration of 500 µg mL-1, which were all close to or greater than that of the positive control (100 µg mL-1 chitosan oligosaccharide, COS). CONCLUSION: Mollugin and 1,3,6-trihydroxy-2-methylanthraquinone are potentially valuable active compounds that lay a foundation for research on botanical fungicide products derived from R. cordifolia L. and provide lead structures for quinone derivative synthesis and structural modification. © 2024 Society of Chemical Industry.

Using a golf specific functional movement screen to predict golf performance in collegiate golfers.

Background: This study aims to examine the relationship between functional movements and golf performance using the Golf Specific Functional Movement Screen (GSFMS). Methods: This cross-sectional study included a total of 56 collegiate golfers (aged 20.89 ± 0.99 years, height of 174.55 ± 7.76 cm, and weight 68.48 ± 9.30 kg) who met the criteria, and were recruited from Hainan Normal University in June 2022. The participants' golf motor skills (1-yard putt, 10-yard putt, 25-yard chip, 130/100-yard set shot, driver, and 9-hole stroke play) were tested and the GSFMS (e.g., pelvic tilt, pelvic rotation, and torso rotation) was used. Results: There were significant weak or moderate correlations between the variables. Furthermore, a multiple linear regression analysis found that pelvic rotation and lower-body rotation abilities can significantly predict golf skill levels, which collectively explain 31.2% of the variance in golf skill levels among collegiate golfers (Adjusted R2 = 0.312, F = 2.663, p < 0.05). Standardised ß values indicate that pelvic rotation (ß = 0.398) has a more substantial impact on golf skill levels than lower-body rotation (ß = 0.315). Conclusions: This study found the weak to moderate correlations between the GSFMS and golf performance, and pelvic rotation and lower-body rotation abilities, thus predicting golf skills. Our findings provide novel insights into the relationship between functional abilities and comprehensive skill performance within the context of the Gray Cook's Movement Pyramid model, and provide theoretical support and practical reference for collegiate golf motor-skill learning and sports injury prevention.

Polystyrene microplastics disturb maternal glucose homeostasis and induce adverse pregnancy outcomes.

Pregnant women are a special group that is sensitive to adverse external stimuli, causing metabolic abnormalities and adverse pregnancy outcomes. Microplastics (MPs), an environmental pollutant widely used in various fields, can induce a variety of toxic responses in mammals. Recent studies verified an association between MPs and metabolic disorders. Our research built a gestational mouse model in which polystyrene microplastics (PS-MPs) of 1 µm size were consumed at concentrations of 0.1, 1, and 10 mg/L during pregnancy. Results indicated that PS-MPs induced placental malfunction and fetal growth retardation. Significant glucose disorders, decreased liver function, hepatic inflammation, and oxidative stress were also observed after PS-MPs exposure. The hepatic SIRT1/IRS1/PI3K pathway was inhibited in the 10 mg/L PS-MPs exposure group. Our study found that PS-MPs activated inflammatory response and oxidative stress by increasing hepatic lipopolysaccharide (LPS) that inhibited the hepatic SIRT1/IRS1/PI3K pathway, ultimately leading to insulin resistance, glucose metabolism disorders, and adverse pregnancy outcomes. This study provides a basis for preventing environment-related gestational diabetes and concomitant adverse pregnancy outcomes.

Deselenylative Acylation and Nitration of Monoselenides.

A deselenylative protocol that enables the construction of the C-C and C-N bonds has been disclosed. By using acyl chloride/AgOTf as an efficient acylation reagent, diarylselenides smoothly undergo deselenylative acylation to produce a series of aroyl compounds. In addition, deselenylative nitration can be enabled by a mild nitration reagent consisting of TsCl and AgNO3, furnishing a diverse array of nitroaromatic compounds.

Scutellarein Ameliorated Chondrocyte Inflammation and Osteoarthritis in Rats.

OBJECTIVE: Osteoarthritis (OA) is a degenerative joint disorder characterized by the gradual degradation of joint cartilage and local inflammation. This study aimed to investigate the anti-OA effect of scutellarein (SCU), a single-unit flavonoid compound obtained from Scutellaria barbata D. Don, in rats. METHODS: The extracted rat chondrocytes were treated with SCU and IL-1ß. The chondrocytes were divided into control group, IL-1ß group, IL-1ß+SCU 50 µmol/L group, and IL-1ß+SCU 100 µmol/L group. Morphology of rat chondrocytes was observed by toluidine blue and safranin O staining. CCK-8 method was used to detect the cytotoxicity of SCU. ELISA, qRT-PCR, Western blotting, immunofluorescence, SAß-gal staining, flow cytometry, and bioinformatics analysis were applied to evaluate the effect of SCU on rat chondrocytes under IL-1ß intervention. Additionally, anterior cruciate ligament transection (ACL-T) was used to establish a rat OA model. Histological changes were detected by safranin O/fast green, hematoxylin-eosin (HE) staining, and immunohistochemistry. RESULTS: SCU protected cartilage and exhibited anti-inflammatory effects via multiple mechanisms. Specifically, it could enhance the synthesis of extracellular matrix in cartilage cells and inhibit its degradation. In addition, SCU partially inhibited the nuclear factor kappa-B/mitogen-activated protein kinase (NF-κB/MAPK) pathway, thereby reducing inflammatory cytokine production in the joint cartilage. Furthermore, SCU significantly reduced IL-1ß-induced apoptosis and senescence in rat chondrocytes, further highlighting its potential role in OA treatment. In vivo experiments revealed that SCU (at a dose of 50 mg/kg) administered for 2 months could significantly delay the progression of cartilage damage, which was reflected in a lower Osteoarthritis Research Society International (OARSI) score, and reduced expression of matrix metalloproteinase 13 (MMP13) in cartilage. CONCLUSION: SCU is effective in the therapeutic management of OA and could serve as a potential candidate for future clinical drug therapy for OA.

Voacangine mitigates oxidative stress and neuroinflammation in middle cerebral artery occlusion-induced cerebral ischemia/reperfusion injury by averting the NF-κBp65/MAPK signaling pathways in rats.

Ischemic stroke is a leading cause of human mortality. Cerebral ischemia-reperfusion injury (CI/RI) is a primary cause of stroke. Ischemia-reperfusion (I/R) resulting in oxidative stress and inflammatory events may lead to severe neuronal impairments. Thus, anti-oxidative and anti-inflammatory mediators that can alleviate post-I/R neuronal injuries are required for the treatment of CI/RI. An alkaloid, voacangine (VCG) is a recognized antioxidant, anti-inflammatory, and anticancer agent. Hence, the current study intended to explore the neuroprotective potential and the principal mechanisms of VCG in CI/RI. The experimental rats were divided into four sets: control, I/R-induced, I/R + VCG (2.5 mg/kg), I/R + VCG (5 mg/kg). CI/RI was induced by implanting a thread into the middle cerebral artery occlusion (MCAO) model. Brain damages were assessed on the basis of brain edema, brain infarct volume, neurological deficit score, histopathology, oxidative stress, and neuroinflammation. Results revealed that VCG inhibited the triggering of NLRP3 inflammasome, pro-inflammatory cytokines, lipid peroxidation, but enhanced the antioxidant status in MCAO rats. Furthermore, VCG treatment averted brain damage by I/R, neuroinflammation, and oxidative stress by suppressing NF-κBp65/MAPK pathways. The results of the study provide pertinent insights pertaining to the role of VCG as a potential neuroprotective agent against ischemic stroke.