RESUMO
Centrifugal partition chromatography in the pH-zone-refining mode was successfully applied to the separation of alkaloids from the crude extract of Corydalis decumbens. The experiment was performed with a two-phase solvent system composed of petroleum ether-ethyl acetate-ethanol-water (5:5:3:7, v/v/v/v) where triethylamine (10 mM) was added to the stationary phase and hydrochloric acid (10 mM) to the mobile phase. From 1.6 g of the crude extract, 43 mg protopine, 189 mg (+)-egenine, and 158 mg tetrahydropalmatine were obtained with a purity of 98.2%, 94.6%, and 96.7%, respectively. Tetrahydropalmatine showed an interesting anticomplement effect with CH50 0.11 and AP50 0.25 mg/mL, respectively. In a mechanistic study, tetrahydropalmatine interacted with C1, C3, C4, and C5 components in the complement activation cascade.
Assuntos
Alcaloides , Proteínas Inativadoras do Complemento , Corydalis , Corydalis/química , Distribuição Contracorrente/métodos , Alcaloides/farmacologia , Alcaloides/química , Solventes/química , Concentração de Íons de Hidrogênio , Misturas Complexas , Cromatografia Líquida de Alta PressãoRESUMO
BACKGROUND: Atypical haemolytic uremic syndrome (aHUS) is an uncommon form of thrombotic microangiopathy (TMA). However, it remains difficult to diagnose the disease early, given its non-specific and overlapping presentation to other conditions such as thrombotic thrombocytopenic purpura and typical HUS. It is also important to identify the underlying causes and to distinguish between primary (due to a genetic abnormality leading to a dysregulated alternative complement pathway) and secondary (often attributed by severe infection or inflammation) forms of the disease, as there is now effective treatment such as monoclonal antibodies against C5 for primary aHUS. However, primary aHUS with severe inflammation are often mistaken as a secondary HUS. We presented an unusual case of adult-onset Still's disease (AOSD) with macrophage activation syndrome (MAS), which is in fact associated with anti-complement factor H (anti-CFH) antibodies related aHUS. Although the aHUS may be triggered by the severe inflammation from the AOSD, the presence of anti-CFH antibodies suggests an underlying genetic defect in the alternative complement pathway, predisposing to primary aHUS. One should note that anti-CFH antibodies associated aHUS may not always associate with genetic predisposition to complement dysregulation and can be an autoimmune form of aHUS, highlighting the importance of genetic testing. CASE PRESENTATION: A 42 years old man was admitted with suspected adult-onset Still's disease. Intravenous methylprednisolone was started but patient was complicated with acute encephalopathy and low platelet. ADAMTS13 test returned to be normal and concurrent aHUS was eventually suspected, 26 days after the initial thrombocytopenia was presented. Plasma exchange was started and patient eventually had 2 doses of eculizumab after funding was approved. Concurrent tocilizumab was also used to treat the adult-onset Still's disease with MAS. The patient was eventually stabilised and long-term tocilizumab maintenance treatment was planned instead of eculizumab following haematology review. Although the aHUS may be a secondary event to MAS according to haematology opinion and the genetic test came back negative for the five major aHUS gene, high titre of anti-CFH antibodies was detected (1242 AU/ml). CONCLUSION: Our case highlighted the importance of prompt anti-CFH antibodies test and genetic testing for aHUS in patients with severe AOSD and features of TMA. Our case also emphasized testing for structural variants within the CFH and CFH-related proteins gene region, as part of the routine genetic analysis in patients with anti-CFH antibodies associated aHUS to improve diagnostic approaches.
Assuntos
Síndrome Hemolítico-Urêmica Atípica , Fator H do Complemento , Doença de Still de Início Tardio , Humanos , Doença de Still de Início Tardio/complicações , Doença de Still de Início Tardio/diagnóstico , Doença de Still de Início Tardio/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/complicações , Síndrome Hemolítico-Urêmica Atípica/imunologia , Fator H do Complemento/imunologia , Adulto , Masculino , Autoanticorpos/sangue , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/complicações , Síndrome de Ativação Macrofágica/imunologiaRESUMO
The pericarps of Trichosanthes kirilowii are often used to treat cough in traditional Chinese medicine, and its ethanol extract exhibited effective therapeutic effects on acute lung injury (ALI) in vivo caused by H1N1. An anticomplement activity-guided fractionation on the extract resulted in the isolation of ten new terpenoids, including seven monoterpenoids, trichosanates A-G (1-7), and three cucurbitane-type triterpenoids, cucurbitacins W-Y (8-10), as well as eleven known terpenoids (11-21). The new terpenoids' structures were determined by spectroscopic analysis, X-ray crystallographic analysis (1), electronic circular dichroism (ECD) analysis and calculations (2-10). Twelve monoterpenoids (1-7 and 11-15) and five cucurbitane-type triterpenoids (8-10, 18, and 20) exhibited anticomplement activity in vitro. For the monoterpenoids, the long aliphatic chain substituents might enhance their anticomplement activity. Additionally, two representative anticomplement terpenoids, 8 and 11, obviously attenuated H1N1-induced ALI in vivo by inhibiting complement overactivation and reducing inflammatory responses.
Assuntos
Vírus da Influenza A Subtipo H1N1 , Trichosanthes , Triterpenos , Cucurbitacinas , Trichosanthes/química , Monoterpenos/farmacologia , Triterpenos/farmacologia , Triterpenos/química , Extratos Vegetais/farmacologiaRESUMO
AIM: Glomerular microthrombosis (GMT) was a common vascular lesion in patients with lupus nephritis (LN). The objective of this study was to investigate the relationship between serum anti-beta2-glycoprotein I antibodies (a-ß2GP1) and anti-complement 1q antibodies (a-C1q) antibodies and to investigate the possible mechanism of GMT in children with LN. METHODS: The subjects were 191 children with LN diagnosed by renal biopsy in our hospital from January 2017 to January 2020. The patients were divided into GMT group and non-GMT group. The clinical manifestations, laboratory tests, renal pathology, prognosis of the two groups and the relationship between a-ß2GP1 and a-C1q antibodies were observed. RESULTS: In 191 children with LN, 52 cases (27.23%) presented with GMT. The value of C3, haemoglobin (Hb), estimate glomerular filtration rate (eGFR) and anticardiolipin antibody (ACA) in GMT group were lower than that of non-GMT group (p < .05, p < .01). The value of serum creatinine (Scr), 24 h proteinuria (PRO), urine red blood cells (RBC), N-acetyl-ß-d-glucosidase (NAG) and retinol-binding protein (RBP), a-C1q, a-ß2GP1, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and renal histopathological activity index (AI) score in GMT group were higher than that of non-GMT group (p < .05, p < .01). The positive proportions of serum a-C1q and a-ß2GP1 in GMT group were higher than those in non-GMT group (p < .05). According to Spearman correlation analysis, a-C1q was positively correlated with AI score, SLEDAI, a-ß2GP1, GMT, LN-III and LN-IV. Hb, eGFR and a-C1q Ab were associated with the formation of GMT in children with LN. The complete proteinuria remission and renal survival in GMT group were significantly lower than those in non-GMT group (p < .05, p < .01). CONCLUSION: LN children with GMT had more severe clinical manifestations and renal pathologic damages, and poor outcome. Serum a-C1q level was positively correlated with a-ß2GP1, and a-ß2GP1 may be involved in the formation of GMT in children with LN, which might involve in the activation of complement classical pathway.
Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Trombose , Humanos , Criança , Nefrite Lúpica/patologia , Glomérulos Renais/patologia , Autoanticorpos , Rim/patologia , Trombose/etiologia , Proteinúria/etiologia , Proteinúria/patologiaRESUMO
BACKGROUND: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a cluster of potentially life-threatening disorders, often involving the kidney with a necrotizing crescentic glomerulonephritis with scanty deposition of immunoglobulins and complement. Historically the role of complement has been considered ancillary. Recently, an anti-myeloperoxidase (MPO) AAV model in complement-deficient mice has shown an involvement for the complement cascade in the development of the renal injuries. Further animal studies showing that in contrast to mice deficient for factor B and C5 animals deficient for C4 were susceptible to AAV development by injection of anti-MPO antibodies emphasized the specific involvement of the alternative pathway. Consonantly, the C5a receptor (Cd88) blockade was found to protect mice from MPO-AAV. CCX168, i.e., avacopan, a powerful inhibitor of C5a receptor that can be administered orally, was shown to reduce the proinflammatory effects of C5a and abolish the activation of neutrophils, their migration and adherence to endothelium, and the vascular endothelial cell retraction that increases permeability. SUMMARY: Avacopan was found to be safe in healthy volunteers given a wide range of doses in a phase 1 clinical trial. The phase 2 trial CLEAR assessed the possibility to decrease dose or entirely replace glucocorticosteroids in the standard-of-care therapy of AAV. Avacopan, added to CYC or RTX either in combination with GCs or not, shortened the time to remission in patients with either newly diagnosed or relapsing AAV. The phase 3 ADVOCATE study compared the ability of an avacopan-associated regimen to induce and sustain remission in AAV patients versus a conventional GC-associated scheme. Remission at week 26 was observed in 72.3% of patients given avacopan and in 70.1% of those given prednisone. Sustained remission at week 52 (second primary endpoint) was obtained in 65.7% of patients given avacopan and in 54.9% receiving prednisone. The avacopan-associated regimen was noninferior at week 26 and superior at week 52 in sustaining remission as compared to the GC-based scheme. KEY MESSAGES: The results of the ADVOCATE trial opened new prospects for the treatment of AAV and also other immune-mediated diseases with renal involvement. The possible position of avacopan in a routine clinical setting and its possible indications in specific subsets of patients with AAV are extensively discussed.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Anticitoplasma de Neutrófilos/uso terapêutico , Ativação do Complemento , Humanos , Camundongos , Prednisona/uso terapêutico , Receptor da Anafilatoxina C5a/uso terapêuticoRESUMO
Autoantibodies against the complement component C1q (anti-C1q) are among the main biomarkers in lupus nephritis (LN) known to contribute to renal injury. C1q, the recognition subcomponent of the complement classical pathway, forms a heterotetrameric complex with C1r and C1s, and can also associate a central complement regulator and C1 Inhibitor (C1-Inh). However, the frequency and the pathogenic relevance of anti-C1r, anti-C1s and anti-C1-Inh autoantibodies remain poorly studied in LN. In this paper, we screened for anti-C1q, anti-C1r, anti-C1s and anti-C1-Inh autoantibodies and evaluated their association with disease activity and severity in 74 LN patients followed up for 5 years with a total of 266 plasma samples collected. The presence of anti-C1q, anti-C1r, anti-C1s and anti-C1-Inh was assessed by ELISA. IgG was purified by Protein G from antigen-positive plasma and their binding to purified C1q, C1r and C1s was examined by surface plasmon resonance (SPR). The abilities of anti-C1q, anti-C1r and anti-C1s binding IgG on C1 complex formation were analyzed by ELISA. The screening of LN patients' plasma revealed 14.9% anti-C1q positivity; only 4.2%, 6.9% and 0% were found to be positive for anti-C1r, anti-C1s and anti-C1-Inh, respectively. Significant correlations were found between anti-C1q and anti-dsDNA, and anti-nuclear antibodies, C3 and C4, respectively. High levels of anti-C1q antibodies were significantly associated with renal histologic lesions and correlated with histological activity index. Patients with the most severe disease (A class according to BILAG Renal score) had higher levels of anti-C1q antibodies. Anti-C1r and anti-C1s antibodies did not correlate with the clinical characteristics of the LN patients, did not interfere with the C1 complex formation, and were not measurable via SPR. In conclusion, the presence of anti-C1q, but not anti-C1s or anti-C1r, autoantibodies contribute to the autoimmune pathology and the severity of LN.
Assuntos
Complemento C1r , Nefrite Lúpica , Autoanticorpos , Ativação do Complemento , Complemento C1q/metabolismo , Complemento C1r/genética , Complemento C1s/metabolismo , Humanos , Imunoglobulina GRESUMO
Two novel natural flavonoid substituted polysaccharides (MBAP-1 and MBAP-2) were obtained from Tamarix chinensis Lour. and characterized by HPGPC, methylation, ultra-high-performance liquid chromatography-ion trap tandem mass spectrometry (UPLC-IT-MSn), and NMR analysis. The results showed that MBAP-1 was a homogenous heteropolysaccharide with a backbone of 4)-ß-d-Glcp-(1â and â3,4,6)-ß-d-Glcp-(1â. MBAP-2 was also a homogenous polysaccharide which possessed a backbone of â3)-α-d-Glcp-(1â, â4)-ß-d-Glcp-(1â and â3,4)-ß-d-Glcp-2-OMe-(1â. Both the two polysaccharides were substituted by quercetin and exhibited anticomplement activities in vitro. However, MBAP-1 (CH50: 0.075 ± 0.004 mg/mL) was more potent than MBAP-2 (CH50: 0.249 ± 0.006 mg/mL) and its reduced product, MBAP-1R (CH50: 0.207 ± 0.008 mg/mL), indicating that multiple monosaccharides and uronic acids might contribute to the anticomplement activity of the flavonoid substituted polysaccharides of T. chinensis. Furthermore, the antioxidant activity of MBAP-1 was also more potent than that of MBAP-2. In conclusion, these two flavonoid substituted polysaccharides from T. chinensis were found to be potential oxidant and complement inhibitors.
Assuntos
Flavonoides , Tamaricaceae , Proteínas Inativadoras do Complemento , Flavonoides/farmacologia , Peso Molecular , Polissacarídeos/química , Polissacarídeos/farmacologiaRESUMO
Catastrophic Antiphospholipid Syndrome (CAPS) is a life-threatening complication of APS requiring complex management to optimize patient outcome. We describe a 54-year-old man with APS with history of splanchnic vein thrombosis, a Factor II G20210A heterozygote, autoimmune hemolytic anemia and thrombocytopenia. He developed sudden onset of severe flank pain due to spontaneous bilateral adrenal hemorrhage while on warfarin with a therapeutic INR. Despite unfractionated heparin and initial clinical improvement, severe thrombocytopenia developed requiring dexamethasone, rituximab, and romiplostim. Hospitalization was complicated further by thrombosis of the inferior vena cava, pulmonary embolism, and painful violaceous patches on his neck and ear cartilages. Punch biopsy of lesions revealed C5b-C9 deposition of small vessel thromboses. Although the inciting event for his thrombotic storm remains uncertain, anti-complement therapy with eculizumab provided rapid and durable lesion resolution. Eculizumab was discontinued after 6 months and patient remains in remission without recurrent thrombosis. This case provides insight on the management of CAPS, including the use of eculizumab.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Antifosfolipídica , Trombocitopenia , Trombose , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/tratamento farmacológico , Heparina , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Three polysaccharides (SH-1, SH-2 and SH-3) were purified from a brown macroalgea, Sargassum hemiphyllum. The autohydrolysis products from each polysaccharide were separated to three fractions (S fractions as oligomers, L fractions as low molecular weight polysaccharides and H fractions as high molecular weight polysaccharides). Mass spectroscopy of S fractions (SH-1-S, SH-2-S and SH-3-S) showed that these three polymers all contained short stretches of sulfated fucose. The structures of L fractions (SH-1-L, SH-2-L and SH-3-L) were determined by nuclear magnetic resonance (NMR). SH-1-L was composed of two units, unit A (sulfated galactofucan) and unit B (sulfated xylo-glucuronomannan). Unit A contained a backbone of (1, 6-linked ß-D-Gal) n1, (1, 3-linked 4-sulfated α-L-Fuc) n2, (1, 3-linked 2, 4-di-sulfated α-L-Fuc) n3, (1, 4-linked α-L-Fuc) n4 and (1, 3-linked ß-D-Gal) n5, accompanied by some branches, such as sulfated fuco-oligomers, sulfated galacto-oligomers or sulfated galacto-fuco-oligomers. And unit B consisted of alternating 1, 4-linked ß-D-glucuronic acid (GlcA) and 1, 2-linked α-D-mannose (Man) with the Man residues randomly sulfated at C6 or branched with xylose (Xyl) at C3. Both SH-2-L and SH-3-L were composed of unit A and their difference was attributed to the ratio of n1: n2: n3: n4: n5. Based on monosaccharide analysis, we hypothesize that both SH-1-H and SH-2-H contained unit A and unit B while SH-3-H had a structure similar to SH-3-L. An assessment of anti-complement activities showed that the sulfated galactofucan had higher activities than sulfated galacto-fuco-xylo-glucuronomannan. These results suggest that the sulfated galactofucans might be a good candidate for anti-complement drugs.
Assuntos
Fucose/química , Galactose/química , Ácido Glucurônico/química , Polissacarídeos/química , Sargassum/química , Fucose/isolamento & purificação , Galactose/isolamento & purificação , Hidrólise , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Polissacarídeos/isolamento & purificação , Polissacarídeos/ultraestruturaRESUMO
Atypical haemolytic uraemic syndrome is an ultra-rare, life-threatening disease. Causative variants in genes that encode complement factors can be identified in 40-70% of cases. We performed genetic analysis of 21 Czech children with atypical haemolytic uraemic syndrome. Genetic or acquired predisposition to the disease was identified in the majority of our patients: CFHR1 and CFHR3 deletions in 14/21 (67%; 13 of them were positive for anti-complement factor H antibodies), variants in complement genes or DGKE in 13/21 (62%). Multiple genetic findings were identified in eight patients (38%). The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population was estimated to be 0.092 (CI 0.053-0.131) cases per million inhabitants and 0.92 (CI 0.53-1.32) cases per 100,000 births for the entire reporting period. Ten patients were initially treated with plasma exchange and eight with eculizumab or with a combination of eculizumab and plasma exchange. At the last follow-up, 20 patients were alive and one patient had end-stage renal disease.Conclusion: The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population corresponds to the reported incidence in Europe. We detected the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies in Czech paediatric patients. Treatment by eculizumab led to superior outcomes and prevention of the disease relapses compared with plasma exchange therapy. Our results may help to understand the polygenic nature of atypical haemolytic uraemic syndrome as a disease that results from a combination of various risk factors. What is Known: ⢠Atypical haemolytic uraemic syndrome (aHUS) is considered a polygenic and multifactorial disease. Genetic predisposition to aHUS is identified in 40-70% of children. ⢠Anti-complement factor H antibodies are usually found in 6-25% of affected children. What is New: ⢠Potentially causative genetic or acquired factors were confirmed in the majority of patients. The prevailing finding was the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies (62% of patients). ⢠The incidence of aHUS in Czech children is 0.092 (CI 0.053-0.131) cases per million inhabitants and 0.92 (CI 0.53-1.32) cases per 100,000 births for the entire reporting period.
Assuntos
Síndrome Hemolítico-Urêmica Atípica , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/terapia , Criança , República Tcheca/epidemiologia , Europa (Continente) , Humanos , Troca Plasmática , Fatores de RiscoRESUMO
Kalimeris indica (L) Sch-Bip is a medicinal plant used by the Miao ethnic group in the Guizhou province of China. It is widely used as a fresh vegetable to treat colds, diarrhea and gastric ulcers. However, few studies have been conducted on the mechanism of its effect on colds, and its quality control. The anticomplement and antitussive activities of different polar extracts of K. indica were evaluated. Fifty-nine compounds, mainly including phenols and flavonoids, were identified in K. indica extract by ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry. A method was established through ultra-high-performance liquid chromatography with a photodiode array to simultaneously determine the anticomplement and antitussive activity of five compounds in K. indica combining chemical identification with chemometrics for discrimination and quality assessment. Also, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid exhibited significantly higher anticomplementary activity than the other three compounds. The quantitative data were further analyzed by principal component analysis and orthogonal partial least-squares discriminant analysis. Heatmap visualization was conducted to clarify the distribution of the major compounds in different geographical origins. Screening pharmacological activities by a combination of chemometrics and chemical identification might be an effective method for the quality control of K. indica.
Assuntos
Asteraceae/química , Extratos Vegetais/análise , Extratos Vegetais/química , Animais , Anti-Inflamatórios/análise , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antitussígenos/análise , Antitussígenos/química , Antitussígenos/farmacologia , China , Cromatografia Líquida de Alta Pressão , Tosse/fisiopatologia , Medicamentos de Ervas Chinesas , Eritrócitos/metabolismo , Flavonoides/análise , Flavonoides/química , Flavonoides/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fenóis/análise , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Espectrometria de Massas em TandemRESUMO
Chimonanthus nitens Oliv. leaf (CNOL), as a traditional Chinese medicine, has been widely used for the treatment of influenza and colds over a long history. However, the mechanism of colds related to the effects of CNOL have been little studied. In this study, the anticomplement and antitussive activities of different polarity extracts of CNOL were evaluated. Ethyl acetate extract (EAE) among different extracts not only significantly decreased cough times by 21-58% (P < 0.01), but also had anticomplement effects demonstrated by the CH50 values of 0.100 mg/ml. A total of 28 constituents (10 coumarins, 13 flavonoids and five phenolics) were identified in EAE based on the ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry technique. Eight compounds in EAE were evaluated by an ammonia-induced cough model to reveal the antitussive mechanisms and classical anticomplement pathway. The results indicated that the antitussive effects of scopoletin, kaempferol-3-O-rutinoside and kaempferol may depend on central mechanisms and that flavonoids such as compounds of kaempferol-3-O-rutinoside and kaempferol have better anticomplementary activity than coumarins like compounds of scopolin, scopoletin and isofraxidin. Taken together, kaempferol-3-O-rutinoside and kaempferol could be important chemical markers in the present study that might be used to evaluate the quality and biological activity of CNOL.
Assuntos
Antitussígenos , Calycanthaceae/química , Proteínas Inativadoras do Complemento , Extratos Vegetais , Animais , Antitussígenos/química , Antitussígenos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Proteínas Inativadoras do Complemento/química , Proteínas Inativadoras do Complemento/farmacologia , Tosse/induzido quimicamente , Tosse/fisiopatologia , Modelos Animais de Doenças , Cobaias , Quempferóis , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Espectrometria de Massas em Tandem/métodosRESUMO
Glechomae Herba (GH) is derived from the dried aerial part of Glechoma longituba (Nakai) Kupr., which is harvested from spring to autumn. It has the effects of clearing heat and detoxification. The aim of this paper was to study the chemical composition and the anti-complement activity of GH collected in different months. Ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry based on predicted compounds screening and diagnostic ion filter strategy was developed for identifying the chemical composition of GH collected in different months. A total of 102 compounds-40 chlorogenic acids (CGAs), 32 phenolic acids, and 30 flavonoids-were reasonably identified in GH. Thirty-four CGAs were discovered in GH for the first time. The correlations between chemical compositions and anti-complement activities of GH collected in different months were analyzed. Phenolic acids and flavonoids were found to be negatively correlated with anti-complement activity, and CGAs were positively correlated with anti-complement activity. At the same time, six CGA standards had obvious anti-complement activity. It was demonstrated that different harvest months had a significant impact on the difference in chemical composition and anti-complement activity of GH. And CGAs might play an important role in the anti-complement activity of GH.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inativadores do Complemento , Lamiaceae/química , Extratos Vegetais , Espectrometria de Massas em Tandem/métodos , China , Ácido Clorogênico/análise , Ácido Clorogênico/farmacologia , Inativadores do Complemento/análise , Inativadores do Complemento/farmacologia , Flavonoides/análise , Flavonoides/farmacologia , Hidroxibenzoatos/análise , Hidroxibenzoatos/farmacologia , Medicina Tradicional Chinesa , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Estações do AnoRESUMO
Age-related macular degeneration (AMD) is the leading cause of blindness affecting the elderly in the Western world. The most severe form of AMD, wet AMD (wAMD), is characterized by choroidal neovascularization (CNV) and acute vision loss. The current treatment for these patients comprises monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) antibodies, but this treatment is expensive, uncomfortable for the patient, and only effective in some individuals. AMD is a complex disease that has strong associations with the complement system. All three initiating complement pathways may be relevant in CNV formation, but most evidence indicates a major role for the alternative pathway (AP) and for the terminal complement complex, as well as certain complement peptides generated upon complement activation. Since the complement system is associated with AMD and CNV, a complement inhibitor may be a therapeutic option for patients with wAMD. The aim of this review is to (i) reflect on the possible complement targets in the context of wAMD pathology, (ii) investigate the results of prior clinical trials with complement inhibitors for wAMD patients, and (iii) outline important considerations when developing a future strategy for the treatment of wAMD.
Assuntos
Neovascularização de Coroide/fisiopatologia , Ativação do Complemento/imunologia , Degeneração Macular Exsudativa/patologia , Animais , Humanos , Degeneração Macular Exsudativa/imunologiaRESUMO
Blossoms of Inula nervosa Wall. (BINW) are traditionally used as an analgesic and antitussive in China. In this study, in vitro anticomplementary activities of crude extract from BINW in 21 batches and of extracts of four monomeric compounds were evaluated by the classical pathway. The effect of the region of origin on the quality of BINW was evaluated by fingerprint analysis for the first time. Furthermore, chemometric methods including similarity analysis and principal component analysis were employed to evaluate the quality of BINW. The nine major monomeric compounds were quantitated by ultra-high-performance liquid chromatography. All nine analytes demonstrated excellent linearity with recoveries ranging from 97.25% to 102.76%. The limits of detection and quantification were 0.07-12.20 µg/mL and 0.22-40.27 µg/mL, respectively. Results indicate that different regions of origin have a significant effect on the quality of BINW. Fingerprint analysis in combination with chemometrics and multi-ingredient determination is an efficient and reliable approach for quality evaluation. The BINW samples from Yunnan had the highest ratio of 1,5-dicaffeoylquinic acid and thymol; they also exhibited significantly higher anticomplementary activity than those from three other areas. This study successfully established a rapid and efficient method to evaluate the quality and biological activity of BINW.
Assuntos
Inativadores do Complemento/farmacologia , Flores/química , Inula/química , Extratos Vegetais/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Eritrócitos/efeitos dos fármacos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , OvinosRESUMO
Two new lignans named neourticol A (1) and neourticol B (2), together with seven known compounds (3-9), were isolated from Urticae Fissae Herba, a folk medicine for rheumatism arthritis in China. The active evaluation results showed that 1 and 2 possessed the potent anti-complement and anti-inflammatory activities.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Lignanas/química , Lignanas/farmacologia , Urticaceae/química , Animais , China , Medicina Tradicional Chinesa , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Five new compounds including two phenyldilactones (1, 2), two coumarins (3, 4) and a dimer of N-E-feruloyl tyramine (5) together with twenty-three known compounds (6-28) were isolated from a medicinal plant Polygonum chinense. The structures of the new compounds were established by detailed spectral analysis. The absolute configurations of 1 and 5 were elucidated by Mosher's method, Mo2(OAc)4-induced electronic circular dichroism (ECD) data, and ECD calculation. All the compounds were found to show potent anticomplement activity with CH50 and AP50 values ranging from 0.18 to 1.45â¯mM, and 0.26 to 2.80â¯mM, respectively. Phenyldilactones and phenylpropionic tyramines were firstly reported as anticomplement agents. The targets of compounds 1, 3, 5 and 10 in complement activation cascade were identified as well.
Assuntos
Proteínas Inativadoras do Complemento/farmacologia , Cumarínicos/farmacologia , Hemólise/efeitos dos fármacos , Lactonas/farmacologia , Polygonum/química , Tiramina/farmacologia , Proteínas Inativadoras do Complemento/química , Proteínas Inativadoras do Complemento/isolamento & purificação , Cumarínicos/química , Cumarínicos/isolamento & purificação , Relação Dose-Resposta a Droga , Lactonas/química , Lactonas/isolamento & purificação , Estrutura Molecular , Plantas Medicinais , Relação Estrutura-Atividade , Tiramina/análogos & derivados , Tiramina/químicaRESUMO
Given the complex etiology of age-related macular degeneration (AMD), treatments are developed to target intermediate/late stages of the disease. Unfortunately, the design of therapies for early stages of the disease is limited by our understanding of the mechanisms involved in the formation of basal deposits and drusen, the first clinical signs of AMD. During the last decade, the identification of common and rare alleles in complement genes as risk AMD variants in addition to the presence of active complement components in basal deposits and drusen has provided compelling evidence that the complement system plays a key role in the pathobiology of AMD. However, the mechanisms for complement activation in AMD are unknown. Here we propose that the activation of the complement system is a consequence of alterations in the aged extracellular matrix (ECM) of the retinal pigment epithelium (RPE)/Bruch's membrane (BrM), which favors the anchoring of complement C3b generated by convertase-independent cleavage of C3 via tick-over and produces a chronic activation of the alternative complement pathway.
Assuntos
Lâmina Basilar da Corioide/imunologia , Via Alternativa do Complemento , Matriz Extracelular/imunologia , Degeneração Macular/imunologia , Epitélio Pigmentado da Retina/imunologia , Animais , Lâmina Basilar da Corioide/metabolismo , Lâmina Basilar da Corioide/patologia , Ensaios Clínicos como Assunto , Complemento C3/metabolismo , Complemento C3b/imunologia , Complemento C3b/metabolismo , Via Alternativa do Complemento/efeitos dos fármacos , Via Alternativa do Complemento/genética , Desenho de Fármacos , Matriz Extracelular/metabolismo , Oftalmopatias Hereditárias/imunologia , Oftalmopatias Hereditárias/metabolismo , Humanos , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Degeneração Macular/tratamento farmacológico , Degeneração Macular/genética , Degeneração Macular/metabolismo , Camundongos , Modelos Imunológicos , Terapia de Alvo Molecular , Peptídeos Cíclicos/uso terapêutico , Drusas Retinianas/imunologia , Drusas Retinianas/metabolismo , Epitélio Pigmentado da Retina/metabolismoRESUMO
In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.
Assuntos
Síndrome Hemolítico-Urêmica Atípica/imunologia , Ativação do Complemento , Complemento C3/imunologia , Glomerulonefrite/imunologia , Rim/imunologia , Animais , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/patologia , Ativação do Complemento/efeitos dos fármacos , Complemento C3/genética , Inativadores do Complemento/uso terapêutico , Predisposição Genética para Doença , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/genética , Glomerulonefrite/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Fenótipo , Fatores de Risco , Resultado do TratamentoRESUMO
Complement-mediated inflammation and tissue damage is an important drive to pathology in autoimmune diseases, targeting inhibit the complement activation is promising treatment strategy for these diseases. We performed anticomplement activity-guided fractionation of the water extract of Eclipta prostrata by ion-exchange and size-exclusion chromatography, yielding two bioactive polysaccharides EAP20-1 and EAP20-2. The molecular weights of EAP20-1 and EAP20-2 were respectively calculated to be 5.2 kDa and 6.3 kDa by HPGPC, both polysaccharides was composed by d-Gal, l-Glc, and Ara at different ratios of 7.3:2.7:1 and 7.6:3.1:1. In addition, the main linkage types of EAP20-1 and EAP20-2 were ß-1,4-Gal, ß-1,6-Gal and α-1,4,6-Glc according to methylation analyses. EAP20-1 and EAP20-2 exhibited significant inhibitory effect on the complement activation through both classical and alternative pathways and with no influence on the coagulation system. Preliminary mechanism study indicated that both EAP20-1 and EAP20-2 inhibited the activation of the complement system by interacting with C1q, C1r, C1s, C2, C4, C5, C7, and C9 components.