Croton stipulaceus Kunth, a native Mexican medicinal plant with antioxidant and anti-inflammatory activities / Croton stipulaceus Kunth, planta medicinal mexicana con actividad antioxidante y antiinflamatoria

Leaves of Croton stipulaceuswere extracted (EHex, ECHCl3and EEtOH extracts) to assesstheir antioxidant potential, anti-inflammatory activity in murine models and acute toxicity. EEtOH showed the highest effect in DPPH (37.80% inhibition), FRAP (1065.00 ± 55.30 µmolFe2+) and total polyphenols (231.24 ± 9.05 meq AG/gM). EHex was the most active, ~ 50% inhibition of TPA-induced ear edema; while EEtOH (dose of 2 mg/ear) showed the highest inhibition in the chronic model (97% inhibition), and inhibited MPO activity (48%). In carrageenan-induced edema, ECHCl3(dose 500 mg/kg) was the most active. None of the extracts showed acute toxicity (LD50) at 2 g/kg (p.o.). This work is the first report that supports the traditional use of C. stipulaceusas an anti-inflammatory.

De las hojas de Croton stipulaceusse obtuvieron diferentes extractos (EHex, ECHCl3y EEtOH) evaluando el potencial antioxidante y la actividad antiinflamatoria en modelos murinos y la toxicidad aguda. El EEtOH mostró mayor efecto en DPPH (37.80% inhibición), FRAP (1065.00 ± 55.30 µmolFe2+) y polifenolestotales (231.24 ± 9.05 meq AG/gM). El EHex fue el más activo, cercano al 50% de inhibición del edema auricular inducido con TPA; mientras que el EEtOH (dosis de 2 mg/oreja) mostró la mayor inhibición en el modelo crónico (97% inhibición), e inhibió la actividad de la MPO (48%). En el edema inducido con carragenina, el ECHCl3(dosis 500 mg/kg) fue el más activo. Ninguno de los extractos mostró una toxicidad aguda (DL50) mayor a 2 g/kg (p.o). Este trabajo es el primer reporte que sustenta el uso tradicional de C. stipulaceuscomo antiinflamatorio.

Dopamine Dynamics in the Amygdala Influence Emotional Changes in the Early Stage of Systemic Inflammatory Response Syndrome in Rats

SUMMARY: Systemic inflammatory response syndrome (SIRS) is a potentially fatal reaction to various forms of tissue damage and infections that cause damage to various organs. Furthermore, the brain is damaged earlier than other organs, resulting in diffuse brain dysfunction. The central clinical symptom of SIRS is delirium and emotional changes are involved in disease development. Although the amygdala is known to play a major role, the mechanisms underlying emotional changes in the early stages of SIRS have not been elucidated. Therefore, changes to dopamine levels in the amygdala were observed using an in vivo model of lipopolysaccharide (LPS)- induced SIRS to clarify the biochemical mechanisms activated in the early stages of SIRS. Extracellular dopamine was collected from the amygdala of free moving rats via microdialysis and then analyzed by high-performance liquid chromatography. In addition, emotional changes were assessed with the open field and sucrose preference tests. In the LPS group, dopamine release in the amygdala increased remarkably immediately after LPS administration, peaking at 120 min. Thereafter, dopamine release temporarily decreased, but then significantly increased again after 180 min. The present results suggest that diffuse brain dysfunction in the early stages of SIRS may involve altered dopamine levels in the amygdala.

El síndrome de respuesta inflamatoria sistémica (SRIS) es una reacción potencialmente fatal a diversas formas de daño tisular e infecciones que causan injuria a varios órganos. Además, el cerebro se daña antes que otros órganos, lo que provoca una disfunción cerebral difusa. El síntoma clínico central del SIRS es el delirio y los cambios emocionales están involucrados en el desarrollo de la enfermedad. Aunque se sabe que la amígdala desempeña un papel importante, no se han dilucidado los mecanismos que subyacen a los cambios emocionales en las primeras etapas del SRIS. Por lo tanto, en el estudio se provocaron cambios en los niveles de dopamina en la amígdala utilizando un modelo in vivo de SRIS inducido por lipopolisacáridos (LPS) para dilucidar los mecanismos bioquímicos activados en las primeras etapas del SRIS. La dopamina extracelular se recogió de la amígdala de ratas en movimiento libre mediante microdiálisis y luego se analizó mediante cromatografía líquida de alta resolución. Además, se evaluaron los cambios emocionales con las pruebas de campo abierto y de preferencia de sacarosa. En el grupo de LPS, la liberación de dopamina en la amígdala aumentó de manera notable inmediatamente después de la administración de LPS, alcanzando un máximo a los 120 minutos. A partir de entonces, la liberación de dopamina disminuyó temporalmente, pero luego volvió a aumentar significativamente después de 180 min. Los resultadosactuales sugieren que la disfunción cerebral difusa en las primeras etapas del SIRS puede implicar niveles alterados de dopamina en la amígdala.

Diagnostic utility, disease activity, and disease phenotype correlation of serum ASCA, pANCA, and PR3-ANCA in pediatric inflammatory bowel disease

Abstract Objective: This study aimed to evaluate the diagnostic utility, disease activity, and phenotypic association of serum anti-Saccharomyces cerevisiae antibody (ASCA), perinuclear anti-neutrophil cytoplasmic antibody (pANCA), PR3-ANCA, and MPO-ANCA in pediatric patients with inflammatory bowel disease (IBD). Methods: Pediatric patients diagnosed with IBD were recruited and classified as Crohn's disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U) through full investigation. The Paris classification was used to evaluate disease phenotypes of pediatric CD and UC. Results: In all, 229 pediatric patients with IBD (CD 147, UC 53, IBD-U 29) were included. The ASCA IgG seropositivity significantly differed among the three groups (CD 75.4%, UC 17.5%, and IBD-U 60.0%; p < 0.001). PR3-ANCA positive rates were the highest in UC (24.0%), followed by IBD-U (17.6%), and none in CD (p = 0.002); pANCA-positive rates were higher in IBD-U (33.6%), followed by UC (28.0%) than in CD (1.4%) (p < 0.001). Regarding disease phenotype, perianal disease revealed higher serum ASCA IgG titers (median 36.7 U/mL in P1 vs. 25.2 U/mL in P0, p = 0.019). Serum ASCA IgG and IgA cutoff values to distinguish CD were 32.7 (U/mL) and 11.9 (U/mL), respectively, with a specificity of 80.0%. Conclusion: Serological biomarkers of ASCA IgG and IgA were effective for differentiating CD in pediatric IBD patients, and serum pANCA and PR3-ANCA, but not MPO-ANCA, were effective in distinguishing UC and IBD-U. Furthermore, measuring serological titers of ASCA IgG and IgA may help differentiate CD and evaluate the disease activity and phenotype of pediatric IBD in practice.

Drugs and natural products for the treatment of COVID-19 during 2020, the first year of the pandemic / Fármacos y productos naturales para el tratamiento de la COVID-19 durante 2020, el primer año de la pandemia

Abstract This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.

Resumen El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.

Caso probable de síndrome de reconstitución inmune por mpox en una persona con inmunosupresión avanzada por VIH / Probable case of mpox immune reconstitution inflammatory syndrome (IRIS) in a person with HIV disease

Se presenta el caso clínico de persona viviendo con VIH, con mala adherencia a tratamiento, sin vacunación previa para mpox, que evolucionó con un cuadro clínico probable de síndrome de reconstitución inmune posterior a reinicio de TAR, debido a la progresión de las lesiones cutáneas. Recibió tratamiento con tecovirimat por siete días, con evolución clínica favorable. Corresponde al primer caso reportado que recibió terapia con tecovirimat en Chile.

We report a clinical case of a person living with HIV with poor adherence to treatment, no previous mpox vaccination, who had a probable mpox syndrome immune reconstitution after restarting ART, due to worsening of skin lesions. He received treatment with tecovirimat for 7 days, clinically improved and was discharged in good condition. We reported this first clinical case that received tecovirimat in Chile.

Analysis of the metabolic profile and comorbidities in women with endometriosis before and after surgical treatment / Análise do perfil metabólico e comorbidades em mulheres com endometriose antes e depois do tratamento cirúrgico

Aim: this study aimed to evaluate the effects of surgical treatment for endometriosis on the metabolic profile of women diagnosed with deep endometriosis. Methods: we conducted a prospective observational study with a sample of 30 women in the menacme diagnosed with deep endometriosis who underwent videolaparoscopic surgery in a reference center in Brazil between October 2020 and December 2021. A total of 30 women performed clinical and laboratory tests regarding their metabolic profile on two occasions, during preoperative tests and six months after video-laparoscopy. Results: patients had lower average levels of Total Cholesterol (TC), Low-Density Cholesterol (LDL-c), Triglycerides (TGC), and Fasting Glycemia (FG) after the surgical procedure. The average TC level was 8.2% lower after surgery, LDL-c was 12.8% lower, TGC was 10.9% lower, and FG was 7.3% lower. The results showed a statistically significant difference for all these parameters (p < 0.001). Conclusions: video-laparoscopy was associated with a favorable lipid profile compared to the preoperative lipid profile, with a significant improvement in the average levels of LDL-c, HDL-c, TC, TGC, and FG. Long-term follow-up studies are needed to determine whether surgical treatment for endometriosis can improve the metabolic parameters of women with endometriosis and favor a lower predisposition to atherogenesis.

Objetivo: Aeste estudo teve como objetivo avaliar os efeitos do tratamento cirúrgico da endometriose no perfil metabólico de mulheres com diagnóstico de endometriose profunda. Métodos: foi realizado um estudo observacional prospectivo com uma amostra de 30 mulheres na menacme, com diagnóstico de endometriose profunda, que foram submetidas à videolaparoscopia em um centro de referência no Brasil, entre outubro de 2020 e dezembro de 2021. As mulheres realizaram exames clínicos e laboratoriais quanto ao seu perfil metabólico em duas ocasiões, durante exames pré-operatórios e seis meses após a videolaparoscopia. Resultados: as pacientes apresentaram níveis médios mais baixos de Colesterol Total (CT), Colesterol de Baixa Densidade (LDL-c), Triglicerídeos (TGC) e Glicemia de Jejum (GJ) após o procedimento cirúrgico. O nível médio de CT foi 8,2% menor após a cirurgia, o LDL-c foi 12,8% menor, o TGC foi 10,9% menor e a GJ foi 7,3% menor. Os resultados mostraram diferença estatisticamente significativa para todos esses parâmetros (p < 0,001). Conclusões: a videolaparoscopia foi associada a um perfil lipídico favorável em comparação ao perfil lipídico pré-operatório, com melhora significativa nos níveis médios de LDL-c, HDL-c, CT, TGC e GJ. Estudos de acompanhamento a longo prazo são necessários para determinar se o tratamento cirúrgico da endometriose pode melhorar os parâmetros metabólicos de mulheres com endometriose e favorecer uma menor predisposição à aterogênese.

Fenotipificación y genotipificación en pacientes con enfermedad inflamatoria intestinal en un centro de referencia de Colombia / Phenotyping and genotyping in patients with inflammatory bowel disease in a reference center in Colombia

RESUMEN Introducción: Se ha tratado de identificar los factores genéticos relacionados con susceptibilidad para enfermedad inflamatoria intestinal (EII), y los hallazgos actuales se inclinan por un modelo de patología complejo, sin un patrón hereditario claro. Objetivo: Realizar caracterización fenotípica y genotípica de pacientes con EII en población colombiana y describir su posible asociación con predisposición. Materiales y métodos: Serie de casos, 16 pacientes con EII por criterios clínicos y anatomopatológicos, inicio de síntomas gastrointestinales después de los 18 años. Todos tuvieron asesoramiento genético pre-test y se realizaron árboles genealógicos de mínimo tres generaciones. También, genotipificación, por medio de un panel de genes múltiples que incluía genes relacionados con EII y algunos trastornos autoinmunitarios. Finalmente, se realizó análisis genómico de variantes. Resultados: 9 mujeres y 7 hombres, con edad media de diagnóstico de EII 35 años, y 32 años para aparición de síntomas gastrointestinales. 11/16(68,75%) requirieron terapia biológica. 10/16 (62,5%) presentaron refractariedad a terapia estándar. 3/16 (18,75%) tenían antecedentes familiares positivos de EII. 100% casos presentaron al menos un single nucleotide polymorphism relacionado con riesgo de EII en más de un gen. Los genes más relacionados con colitis ulcerosa (CU), fueron CD48, CD6, y TYK2 para CU, y CD6 e ITGAM para la enfermedad de Crohn. El gen más frecuente fue CD6. Se observó en 3/16 (18,75%) presencia de hasta 5 genes, 4 en 3/16 (18,75%), y tres en 5/16 (31,25%). Conclusión: En EII hay presencia de variantes genéticas con predisposición asociada, pero sin patogenicidad confirmada, y cuya sumatoria parece contribuir en su fisiopatología.

ABSTRACT Introduction: Attempts have been made to identify the genetic factors related to susceptibility to inflammatory bowel disease (IBD), and the current conclusions are in favor of a complex pathology model, without a clear hereditary pattern. Objective: To perform phenotypic and genotypic characterization of patients with IBD in Colombian population and to describe its possible association with predisposition. Materials and methods: case series, 16 patients with IBD according to clinical and pathological criteria, onset of gastrointestinal symptoms after 18 years of age. All had pre-test genetic counseling and family trees of at least three generations were made. Also, genotyping, using a multigene panel that included genes related to IBD and some autoimmune disorders. Finally, a genomic analysis of variants was performed. Results: 9 women and 7 men, with mean age of diagnosis of IBD of 35 years, and gastrointestinal symptoms appearance of 32 years. 11/16 (68.75%) required biological therapy. 10/16 (62.5%) were refractory to standard therapy. 3/16 (18.75%) had positive family history of IBD. 100% cases presented at least one single nucleotide polymorphism related to IBD risk in more than one gene. The genes most related to ulcerative colitis (UC) were CD48, CD6, and TYK2 for UC, and CD6 and ITGAM for Crohn's disease. The most frequent gene was CD6. It was found presence of up to 5 genes in 3/16 (18.75%), 4 in 3/16 (18.75%), and three in 5/16 (31.25%). Conclusion: In IBD there is the presence of genetic variants with associated predisposition, but without confirmed pathogenicity, and whose sum seems to contribute to its pathophysiology.

The role of glucose metabolism reprogramming and its targeted therapeutic agents in inflammation-related diseases / 药学学报

Cells undergo glucose metabolism reprogramming under the influence of the inflammatory microenvironment, changing their primary mode of energy supply from oxidative phosphorylation to aerobic glycolysis. This process is involved in all stages of inflammation-related diseases development. Glucose metabolism reprogramming not only changes the metabolic pattern of individual cells, but also disrupts the metabolic homeostasis of the body microenvironment, which further promotes aerobic glycolysis and provides favourable conditions for the malignant progression of inflammation-related diseases. The metabolic enzymes, transporter proteins, and metabolites of aerobic glycolysis are all key signalling molecules, and drugs can inhibit aerobic glycolysis by targeting these specific key molecules to exert therapeutic effects. This paper reviews the impact of glucose metabolism reprogramming on the development of inflammation-related diseases such as inflammation-related tumours, rheumatoid arthritis and Alzheimer's disease, and the therapeutic effects of drugs targeting glucose metabolism reprogramming on these diseases.

Role of Flavonoids in Traditional Chinese Medicine to Improve Cerebral Ischaemia-reperfusion Injury and Its Mechanism： A Review / 中国实验方剂学杂志

Cerebral ischemia-reperfusion injury （CIRI） has a very high incidence， disability， and mortality rates， which seriously affects human life and health. In recent years， modern medicine has made some progress in the diagnosis and treatment of CIRI， but there are still problems such as difficulties in postoperative rehabilitation and adverse drug reactions， and new therapeutic drugs for CIRI are urgently needed. As an important class of active ingredients in traditional Chinese medicine， flavonoids can play antioxidant， apoptosis inhibition， anti-inflammatory， and other pharmacological effects to improve brain tissue damage， which is important for improving the quality of life of CIRI patients and slowing down the aging of the social population. Numerous studies have found that flavonoids in traditional Chinese medicine can regulate cell surface receptors Toll-like receptor 4/nuclear factor-kappaB （TLR4/NF-κB）， phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt）， adenylate-activated protein kinase/mammalian target of rapamycin protein （AMPK/mTOR）， Ras homologous gene family member A/Rho-associated coiled-coil protein kinase （RhoA/ROCK）， nuclear factor E2-associated factor 2/Kelch-like epoxychloropropane-associated protein-1/haemoglobin oxygenase 1 （Nrf2/Keap1/ HO-1）， Notch， and other signaling pathways， so as to regulate the transcription and expression of related proteins after CIRI， alleviate brain tissue injury， and improve CIRI. This paper analyzed the relevant literature in China and abroad in recent years， reviewed the mechanism of action and related pathways of flavonoids in traditional Chinese medicine to improve CIRI， and explored the new therapeutic direction of CIRI at the metabolic level， with a view to providing a basis for the further development and application of flavonoids in traditional Chinese medicine.

Effect of Osteoking on Inflammatory Injury and NF-κB/NFATc1 Signaling Pathway in Model Mice with Postmenopausal Osteoporosis / 中国实验方剂学杂志

ObjectiveTo explore the possible mechanism of Osteoking （OK） on postmenopausal osteoporosis （PMOP）. MethodForty adult female mice were randomly divided into a sham operation （Sham） group， osteoporosis model （OVX） group， estradiol intervention （E2） group， and OK group， with 10 mice in each group. The modeling was completed by conventional back double incision ovariectomy， and the corresponding drugs were given one week later. After 12 weeks， the body mass and uterine index of mice were measured， and the pathological changes of bone tissue and the number of osteoclasts （OCs） were determined by hematoxylin-eosin （HE） and tartrate-resistant acid phosphatase （TRAP） staining， respectively. Bone mineral density （BMD）， trabecular number （Tb.N）， trabecular separation （Tb.Sp）， and bone volume fraction （BV/TV） were measured by microcomputed tomography （Micro-CT）. The maximum load of the femur was detected by a three-point bending test. The contents of tumor necrosis factor-α （TNF-α） and bone resorption marker C-terminal telopeptide of type Ⅰ collagen （CTX-1） were measured by enzyme linked immunosorbent assay （ELISA）. The protein expression levels of nuclear factor-kappa B p65 （NF-κB p65）， phosphorylated nuclear factor-kappa B p65 （p-NF-κB p65）， nuclear factor kappa B inhibitor alpha （IκBα）， phosphorylated nuclear factor kappa B alpha （p-IκBα）， nuclear factor of activated T cells 1 （NFATc1）， and proto-oncogene （c-Fos） were detected by Western blot. The mRNA expressions of OCs-related specific genes matrix metalloproteinase-9 （MMP-9）， NFATc1， TRAP， cathepsin K （CTSK）， and c-Fos were detected by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultCompared with the Sham group， the uterine index decreased significantly in the OVX group， and the body mass （BMI） increased significantly. The structure of bone trabeculae was completely damaged， and the number of OCs increased. BMD， Tb.N， BV/TV， and maximum load decreased， while Tb.Sp was up-regulated. The levels of TNF-α and CTX-1 in serum were up-regulated. The protein expressions of c-Fos， p-NF-κB p65/NF-κB p65， NFATc1， and p-IκBα/IκBα were increased. The mRNA expressions of NFATc1， c-Fos， CTSK， TRAP， and MMP-9 were up-regulated （P<0.05， P<0.01）. Compared with the OVX group， the body mass of the OK and E2 groups decreased， and the uterine index increased. The bone trabeculae increased， and the number of OCs decreased. BMD， Tb.N， BV/TV， and maximum load increased， while Tb.Sp decreased. The levels of TNF-α and CTX-1 in serum were decreased. The protein expressions of c-Fos， p-NF-κB p65/NF-κB p65， NFATc1， and p-IκBα/IκBα were decreased， and the mRNA expressions of NFATc1， c-Fos， CTSK， TRAP， and MMP-9 were decreased （P<0.05， P<0.01）. ConclusionOK can inhibit the NF-κB/NFATc1 signaling pathway and reduce bone mass loss by reducing the level of inflammatory injury factors in PMOP mice， which is one of the mechanisms for treating PMOP.

Blumea balsamifera （L.） DC Oil Alleviates LPS-Induced Inflammatory Response in Macrophages by Affecting Arachidonic Acid Metabolism Via NF-κB Nonclassical Pathway / 中山大学学报(医学科学版)

ObjectiveTo study the anti-inflammatory effects of Blumea balsamifera （L.） DC oil （BBO） based on nuclear factor kappa-B （NF-κB） nonclassical and arachidonic acid （AA） pathway. MethodsEffects of BBO on the production of slow reacting substance of anaphylaxis （SRS-A） were detected by the ileal smooth muscle method. The contents of prostaglandin E2 （PGE2） and leukotriene B4 （LTB4） in lipopolysaccharides （LPS） -induced macrophages were detected by ELISA kit. The expression of COX-2， 5-LOX， FLAP and RelB were detected by qRT-PCR. Western blot was performed to detect the effects of BBO on the level of NF-κB nonclassical pathway proteins TNF receptor associated factor 3 （TRAF3）， TNF receptor associated factor 2 （TRAF2）， NF-κB-inducing kinase （NIK）， p100 and RelB. ResultsThe contractile tension of guinea pig ileum was reduced （P<0.001）， and the SRS-A production inhibition rate reached 65.34% at 1mg·mL-1 BBO concentration. Compared with LPS group， BBO reduced the concentrations of PGE2 （P<0.05） and LTB4 （P<0.05）， and decreased the expressions of COX-2 （P<0.05）， 5-LOX （P<0.05） and FLAP （P<0.05） in AA pathway at concentrations of 40-80 μg·mL-1. Moreover， 40-80 μg·mL-1 BBO decreased the concentrations of TRAF3 （P<0.05）， TRAF2 （P<0.05）， and NIK （P<0.05）， and further inhibited the phosphorylation of p100 （P<0.05）， as well as the level of the transcription factor RelB in genes （P<0.05） and proteins （P<0.05） in nonclassical NF-κB pathway， whereas BBO did not cause such changes. ConclusionBBO may potentially exert its anti-inflammatory effects by suppressing the regulatory proteins TRAF3 and TRAF2 and the transcription factor RelB in NF-κB nonclassical pathway. The inhibitory action extending to the induction kinase function of NIK， further hindering the phosphorylation of p100 and its binding with the transcription factor RelB. Consequently， downstream elements in the AA pathway， including the pivotal rate-limiting enzymes COX-2， 5-LOX and FLAP， were altered. This modulation influences the levels of inflammatory mediators such as PGE2 and LTB4.

Panax notoginseng saponin relieving the inflammatory pain caused by complete Freund’s adjuvant by inhibiting the activation of astrocytes in mice / 解剖学报

Objective To analyse the analgesic effect and possible mechanism of panax notoginseng saponin (PNS) on mouse models of chronic inflammatory pain caused by complete Freund’s adjuvant (CFA). Methods A total of 48 male C57BL/ 6J mice were divided randomly into four groups: normal saline control group (Ctrl), CFA group (CFA), CFA + PNS group (CFA+PNS), CFA + dexamethasone (DEX) group (CFA+DEX). Von Frey filaments were used to detect mechanical pain in mice. Immunohistochemistry was used to detect the number and morphological changes of glial fibrillary acidic protein (GFAP) positive astrocytes. Western blotting was used to detect the expressions of GFAP, nucleotide-binding and oligomerization domain(NOD)-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, interleukin (IL)-1β, and IL-18 in mice’s spinal cord segments in each group. Results Compared with the Ctrl group, mice in the CFA group showed a significant decrease in mechanical pain thresholds at day 1, day 3, day 5, day 7, and day 14. Additionally, there was a significant decrease in NLRP3, ASC, Caspase-1, IL-1β and IL-18 in the spinal cord of the mice. PNS intervention could relieve mechanical pain and down-regulate the expressions of NLRP3, ASC, Caspase-1, IL-1β and IL-18 in the spinal cord of mice, with no significant difference compared with the CFA+DEX group. CFA group mice had significantly more GFAP positive cells in their posterior horns than Ctrl group mice, as measured by immunohistochemistry; PNS intervention decreased the number of GFAP positive cells in the posterior horn of the spinal cord in model mice;DEX had no effect on the number of GFAP positive cells in the dorsal horn of spinal cord. According to Western blotting results, GFAP expression in the spinal cord of the CFA group was significantly more than that of the Ctrl group; PNS intervention significantly reduced GFAP expression in the spinal cord of CFA group mice;DEX had no effect on the expression of GFAP in the posterior horn of spinal cord. Conclusion PNS has a good alleviating effect on inflammatory pain, and its mechanism may be related to inhibition of astrocyte activation and NLRP3 inflammasome activation.

Efficacy and safety of paclitaxel albumin assisted platinum chemotherapy in the treatment of recurrent and metastatic cervical cancer based on tumor factors and inflammatory status / 中国临床药理学与治疗学

AIM: To investigate the efficacy and safety of paclitaxel albumin assisted platinum chemotherapy in the treatment of recurrent and metastatic cervical cancer based on tumor factors and inflammatory status. METHODS: A total of 100 patients with recurrent and metastatic cervical cancer in our hospital from January 2020 to January 2023 were randomly divided into two groups: 50 patients in the control group were treated with paclitaxel-assisted nedaplatin regimen, and 50 patients in the study group were treated with paclitaxel-assisted nedaplatin regimen. The short-term efficacy, tumor factors, inflammatory factors, relapse-metastasis related indexes, quality of life, functional status and adverse reactions were compared between the two groups. RESULTS: The total remission rate of the study group (72.00%) was higher than that of the control group (48.00%) (P0.05), but the total incidence of adverse reactions (12.00%) was lower than that of the control group (32.00%) (P<0.05). CONCLUSION: Paclitaxel albumin-assisted nedaplatin has a reliable effect in the treatment of recurrent and metastatic cervical cancer, which can further reduce the level of tumor factors, relieve inflammation, and has high safety.

Dimethyl fumarate inhibits NLRP3/AIM2 inflammasomes to prevent spleen radiation injury ZHANG / 中国药理学通报

Aim To investigate the protective effect of dimethyl fumarate on spleen injury induced by gamma radiation in mice and the related mechanism. Methods C57BL/6 mice were randomly divided into the blank control group, radiation model group and DMF administration group, which were administered once at 12 h before irradiation and once at 0. 5 h, 12 h, 24 h and 48 h after irradiation. The 30-day survival rate, body weight and pathological injury of spleen were measured after a one-time total body irradiation of Co 7 rays (8 Gy). TUNEL staining was used to detect apoptosis of spleen cells. Enzyme-linked immunoassay ( ELISA) was applied to detect the contents of TNF-a, IL-1 p, IL-6, IL-18, NLRP3 and AIM2 in spleen. Western blot test and immunofluorescence staining test was employed to verify the changes of NLRP3 and AIM2 contents in spleen tissue after irradiation. Results DMF could obviously improve the survival rate of irradiated mice, improve the weight loss of irradiated mice, re-duce the pathological injury of spleen, and inhibit the apoptosis of spleen cells after irradiation. ELISA results showed that DMF could significantly inhibit the increase of spleen inflammatory cytokines TNF-a, IL-lp, IL-6, IL-18 and inflammasome components NL-RP3 and AIM2 induced by irradiation. Western blot and tissue immunofluorescence staining also confirmed that DMF could inhibit the increase of NLRP3 and AIM2 inflammasome protein levels caused by irradiation. Meanwhile, NLRP3 agonist and AIM2 agonist could antagonize the radiation protection effect of DMF on spleen cells. Conclusion DMF can ameliorate spleen injury of Co 7-ray injured mice, and its mechanism is closely related to NLRP3/AIM2 inflamma-somes, which can be used as a potential protective drug for radiation injury.

Histamine 1 receptor agonist inhibits LPS-induced immune responses in astrocytes via Akt/NF-KB signaling pathway / 中国药理学通报

Aim To investigate the effect of histamine H, receptor (HjR) on the immune responses in astrocytes induced by lipopolysaccharide (LPS) and the regulatory mechanism of its signaling pathway. Methods LPS was used to establish an in vitro astrocyte inflammation model. Rat primary astrocytes were divided into the control group, LPS group, LPS + Hj R agonist group (2-pyridylethlamine, Pyri), and HjR agonist group. Astrocytes were treated with Pyri 100 p,mol • L~ for 1 h, then stimulated with LPS at 100 p,g • L~ for 24 h. Cell viability was measured using the CCK-8 assay. The expression of GFAP and HjR was detected by immunofluorescence. Glial morphological changes were observed under a microscope. The levels of proinflammatory mediators (TNF-a and IL-6) were detected by ELISA. The protein expressions of p-Akt, Akt, p-NF-KB p65, and NF-KB p65 were detected by Western blot. Results Compared with the control group, more activated astrocytes with fewer cell processes and branches were observed in the LPS group. Besides, LPS enhanced the GFAP expression level, reduced the H,R expression level and stimulated the production of TNF-a and IL-6 from astrocytes. Pre treatment with Pyri for 1 h ameliorated the glial morphological changes stimulated by LPS, inhibited LPS-induced upregulation of GFAP level and the inflammatory factors secretion. In addition, LPS stimulated astrocytes showed a higher phosphorylation of Akt and NF-KB p65, which was also ameliorated by Pyri. Conclusions H, R agonist can inhibit LPS-induced astrocyte activation and inflammatory factor secretion, and the Akt/NF-KB signaling pathway may be an important pathway for the involvement of H,R in immune regulation.

Preparation of tripterygium glycoside nanoparticles and therapeutic effect on arthritis rats / 中国药理学通报

Aim To prepare tripterygium glycoside nanoparticles and probe into their therapeutic effect on collagen-induced arthritis ( CIA) rats. Methods Tripterygium glycosides polyglycoside nanoparticles were prepared by thin film dispersion method and their quality was assessed. The CIA model was established and drug intervention performed. The body weight, toe swelling degree and arthritis index were measured. The pathological changes of the organs, knee and ankle synovium were observed. The serum levels of kidney function and inflammatory cytokine expression were detected in rats. Results The prepared tripterygium wil-fordii polyglycoside nanoparticles were round particles with uniform distribution and stable properties under electron microscope. Compared with the model group, the swelling of the left and right toes of medication group significantly decreased (P < 0. 01), and the ar-thritis index markedly decreased ( P < 0. 01). Among them, the efficacy of the TG-NPs group was better than that of the TG group. Compared with the normal group, the indexes of heart, spleen, kidney and testis all significantly decreased (P <0. 05, P<0.01). TG-NPs group had a significantly reduced pathological ankle-joint injury in knee cartilage and increased apoptotic synovial cells. Compared with the model group, the serum levels of ALT and BUN and CRE in TG-NPs group were significantly lower (P < 0. 05 ), and IL-1β, TNF-α and IL-6 levels decreased significantly (P <0. 05). Conclusions TG-NPs have good therapeutic effect on CIA through induction of synovial cell apoptosis and decrease of the expression of inflammatory cytokines. By intravenous injection of blood circula-tion, slow and controlled release of drugs can be achieved, the first pass effect caused by oral drug can be avoided, the viscera toxicity can be reduced, which provides an experimental basis for the development of new nanoagents for the treatment of rheumatoid arthritis.

Effect of safflower yellow on learning and memory ability of APP/PS1 at different months based on TLR4/NF-KB signaling pathway / 中国药理学通报

Aim To investigate the effect of safflower yellow (SY) on learning and memory ability of APP/ PS1 mice at different disease stages, and to explore the mechanism of SY anti- Alzheimer's disease by using 3-,6- and 9-month-old APP/PS 1 transgenic mice as experimental animal models. Methods Behavioral experiments were conducted to observe the effects of SY on learning and memory of APP/PS1 mice of different months. ELISA was used to detect the effect of SY on the expression of inflammatory factors in cortex of mice of different months. Western blot was used to detect the microglia activation marker protein, and its mechanism of action was further analyzed. Results SY could enhance the learning and memory ability of mice aged 3, 6 and 9 months, reduce the content of IL-6 and increase the content of TGF-β1 in brain tissue, up-regulate the expression levels of arginase-1 (arg-1) and triggering receptor expressed on myeloid cells 2 (tREM2) in brain tissue of mice of different months, and down-regulate the expression levels of inducible nitric oxide synthase (iNOS), Toll-like receptors 4 (tlr4) and nuclear factor-kappa B (nf-KB). Conclusions Compared with 3- and 9-month-old mice, SY is the most effective in improving learning memory in 6-month-old APP/PS1 mice. SY inhibits TLR4/NF-KB pathway activation by inducing TREM2 expression in brain tissue of APP/PS 1 transgenic mice, promotes microglia phenotype shift to anti-inflammatory phenotype, reduces chronic neuroinflammatory response, and improves learning memory in APP/PS1 mice at all months of age.

Expression of neutrophil extracellular traps and phagocytic functions among patients with hepatic alveolar echinococcosis / 中国血吸虫病防治杂志

Objective To investigate the expression of neutrophil extracellular traps (NETs) and phagocytic function in the peripheral blood of patients with hepatic alveolar echinococcosis (HAE), and to examine their correlations with clinical inflamma tory indicators and liver functions. Methods A total of 50 patients with HAE admitted to Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qinghai University from August 2022 to June 2023 were enrolled, while 50 age- and gender-matched healthy individuals from the Centre for Healthy Examinations of the hospital during the same period served as controls. The levels of NETs markers neutrophil myeloperoxidase (MPO) and neutrophil elastase (NE) were measured using enzyme-linked immunosorbent assay (ELISA). Peripheral blood neutrophils were isolated using density gradient centrifugation, stimulated in vitro using phorbol 12-myristate 13 acetate (PMA), and the levels of MPO and citrullination histone H3 (CitH3) released by neutrophils were quantified using flow cytometry. The phagocytic functions of neutrophils were examined using flow cytometry. In addition, the correlations of MPO and NE levels with clinical inflammatory indicators and liver biochemical indicators were examined using Spearman correlation analysis among HAE patients. Results The peripheral blood plasma MPO［(417.15 ± 76.08) ng/mL vs. (255.70 ± 80.84) ng/mL; t = 10.28, P < 0.05］, NE［(23.16 ± 6.75) ng/mL vs. (11.92 ± 3.17) ng/mL; t = 10.65, P < 0.05］and CitH3 levels［(33.93 ± 18.93) ng/mL vs. (19.52 ± 13.89) ng/mL; t = 4.34, P < 0.05］were all significantly higher among HAE patients than among healthy controls, and a lower phagocytosis rate of neutrophils was detected among HAE patients than among healthy controls［(70.85 ± 7.32)% vs. (94.04 ± 3.90)%; t = 20.18, P < 0.05］, and the ability to produce NETs by neutrophils was higher among HAE patients than among healthy controls following in vitro PMA stimulation. Pearson correlation analysis showed that the phagocytosis rate of neutrophils correlated negatively with platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), interleukin-6 (IL-6) level and C-reactive protein (CRP) level (rs = −0.515 to −0.392, all P values < 0.05), and the MPO and NE levels positively correlated with inflammatory markers NLR, PLR, CRP and IL-6 (rs = 0.333 to 0.445, all P values < 0.05) and clinical liver biochemical indicators aspartic transaminase, alanine aminotransferase, direct bilirubin and total bilirubin among HAE patients (rs = 0.290 to 0.628, all P values < 0.001). Conclusions Excessive formation of NETs is found among HAE patients, which affects the phagocytic ability of neutrophils and results in elevated levels of inflammatory indicators. NETs markers may be promising novel biomarkers for early diagnosis, monitoring, and severity assessment of liver disease.

Protective effect and mechanism of Longshengzhi capsules on cerebral ischemia-reperfusion injury in rats / 中国药房

OBJECTIVE To explore the protective effect and mechanism of Longshengzhi capsules on cerebral ischemia- reperfusion injury in rats. METHODS The model of middle cerebral artery occlusion （MCAO） was established by using the improved thread occlusion method. The experiment was divided into six groups： sham surgery group （only separating blood vessels without inserting thread plugs， given the same volume of normal saline）， model group （modeling， given the same volume of normal saline）， nimodipine group （positive control， modeling， dose of 20 mg/kg）， and low-dose， medium-dose， and high-dose groups of Longshengzhi capsules （modeling， doses of 0.72， 1.44 and 2.88 g/kg， respectively）， with 10 mice in each group. Each group was given corresponding medication solution/normal saline by gavage， once a day， for 7 consecutive days. One hour after the last administration， the Zea Longa scoring method was used to score the neurological deficits in each group of rats， and the ABC enzyme-linked immunosorbent assay was used to detect the serum levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in rats； TTC staining was used to observe the volume of cerebral infarction in rats and calculate the cerebral infarction volume ratio. Hematoxylin eosin staining was used to observe the pathological changes in the brain tissue of rats. Immunohistochemical staining was used to detect the positive expression of NLRP3 protein in the brain tissue of rats. Real-time fluorescence quantitative PCR was used to detect mRNA relative expressions of Toll-like receptor 4 （TLR4） and nuclear factor-κB （NF-κB） in the brain tissue of rats. Western blot assay was adopted to detect the relative expressions of TLR4， NLRP3 and phosphorylated NF-κB （p-NF-κB） protein in the brain tissue of rats and its intracellular NF-κB protein. RESULTS Compared with the sham surgery group， the neural dysfunction score， serum levels of TNF-α and IL-6， cerebral infarction volume ratio， relative expression levels of NF-κB and TLR4 mRNA， as well as protein relative expressions of TLR4， NLRP3 and p-NF-κB in the brain tissue， and relative protein expression of intracellular NF-κB were increased significantly in the model group （P＜0.01）； the enlarged gap and significant edema were observed in cortical nerve cells of brain tissue in rats， with a large amount of inflammatory cell infiltration； the positive expression of NLRP3 protein in brain tissue of rats obviously increased. Compared with the model group， the levels of the above indicators in the medium-dose and high-dose groups of Longshengzhi capsules， as well as the Nimodipine group， were reversed to varying degrees， and most differences were statistically significant （P＜0.05 or P＜0.01）； the pathological morphology observation showed a significant improvement， and the positive expression of NLRP3 protein in the brain tissue of rats was obviously reduced. CONCLUSIONS Longshengzhi capsules may inhibit TLR4/NF-κB/NLRP3 signaling pathway and neuroinflammatory response， thereby achieving a protective effect against cerebral ischemia-reperfusion injury in rats.

Toxic effects of permethrin on HMC3 microglia and its associated mechanism / 环境与职业医学

Background Permethrin is a commonly used pyrethroid insecticide and has been found to be potentially neurotoxic. Microglia are innate immune cells in the central nervous system and are involved in the development of a range of neurodegenerative diseases. Objective To observe possible toxic effects of permethrin on human microglia clone 3 (HMC3) in vitro and explore associated mechanism. Methods HMC3 were treated with 0, 10, 25, and 55 μmol·L−1 permethrin for 72 h. Cell cycle and apoptosis were measured using flow cytometry. Cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin B2 (CCNB2), cellular tumor antigen p53 (p53), factor-related apoptosis (FAS), caspase 3 (CASP3), and H2A histone family member X (H2AX) were detected by quantitative real-time PCR (qPCR). The differential genes and enrichment pathways of HMC3 after 0 and 25 μmol·L−1 permethrin treatment was analyzed by RNA sequencing. HMC3 was treated by 0, 10, 25, and 55 μmol· L−1 permethrin for 72 h. The content of nitric oxide (NO) in the supernatant was detected using Griess reagent. The secretion level of interleukin-6 (IL-6) was detected by enzyme linked immunosorbent assay (ELISA). The mRNA expression levels of mitogen-activated protein kinase (MAPK) pathway (including MAPK1, MAPK8, and MAPK14), interleukin-1β (IL-1β), IL-6, and matrix metalloproteinase (MMP) families (including MMP1, MMP2, MMP3, and MMP9) were detected by qPCR. The protein expressions of phosphorylated p38 mitogen-activated protein kinase (p-p38), phosphorylated extracellular signal-regulated kinase (p-ERK), IL-1β, IL-6, and MMP1 were detected by Western blot. Results HMC3 was arrested in G2/M phase after 0, 10, 25, and 55 μmol·L−1 permethrin treatment for 72 h, of which there was a statistically significant difference between the 55 μmol·L−1 permethrin treatment group and the control group (P<0.01), and the mRNA expression of CDKN1A was up-regulated according to the qPCR (P<0.05). There was no statistically significant difference in the proportions of apoptosis between the groups (P＞0.05). The RNA sequencing showed that the differential genes were enriched in the MAPK pathway, and the mRNA expressions of MAPK1, MAPK8, and MAPK14 were up-regulated after the permethrin treatment at 55 μmol·L−1 compared to the control group by qPCR (P<0.05). The Western blot revealed that, compared to the control group, the levels of p-p38 and p-ERK were increased after the 10 μmol·L−1 permetrin treatment (P<0.05), the p-ERK level was increased after the 25 μmol·L−1 permetrin treatment (P<0.05), and the p-p38 level was up-regulated after the 55 μmol·L−1 permetrin treatment (P<0.05). The secretion of NO in the supernatant of HMC3 increased after permetrin treatment compared to the control group (P<0.05), the mRNA and protein expressions and the secretion of IL-6 showed an upward trend, the mRNA and protein expressions of IL-1β were up-regulated (P<0.05), and the mRNA and protein expressions of MMP1 were up-regulated in the 25 and 55 μmol·L−1 permethrin groups (P<0.05). Conclusion Permethrin inhibits HMC3 cell proliferation in vitro, induces cell cycle arrest, activates MAPK pathway, and promotes the expression of inflammatory factors IL-1β and MMP1, which may be one of the mechanism of neurotoxicity induced by permethrin.