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ORIGINAL ARTICLE
Huangkui Capsule in Combination with Leflunomide Improves Immunoglobulin A Nephropathy by Inhibiting the TGF-β1/Smad3 Signaling Pathway
Shuwen PeiI,
Corresponding author
pswlois@163.com

Corresponding author.
, Yan LiII
I Department of Nephrology, Harbin First Hospital, Harbin, Heilongjiang 15000, China
II Intensive Care Unit, Harbin First Hospital, Harbin, Heilongjiang 15000, China
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    "titulo" => "Huangkui Capsule in Combination with Leflunomide Improves Immunoglobulin A Nephropathy by Inhibiting the TGF-&#946;1&#47;Smad3 Signaling Pathway"
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">HKL inhibits the expression of the TGF-&#946;1&#47;Smad3 signaling pathway in IgAN rats&#46; &#40;A-D&#41; Expression of TGF-&#946;1 &#40;A&#41;&#44; Smad2 &#40;B&#41;&#44; Smad3&#44; &#40;C&#41;&#44; and Smad4 &#40;D&#41; in rats of all groups&#59; &#40;E&#41; HKL upregulates the expression of Smad7 in IgAN rats&#46; HKC&#58; Huangkui capsule&#44; LEF&#58; leflunomide&#44; HKL&#58; HKC in combination with LEF&#44; IgAN&#58; Immunoglobulin A nephropathy&#44; &#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; Kruskal-Wallis test followed by Dunn&#39;s multiple comparisons test&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Primary immunoglobulin A nephropathy &#40;IgAN&#41; is one of the most common glomerular diseases in children and teenagers and is mainly characterized by proteinuria&#44; filtration membrane injury&#44; and glomerulonephritis &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46; In China&#44; the development of IgAN is the major cause of end-stage kidney diseases &#40;<a class="elsevierStyleCrossRefs" href="#bib3">3-5</a>&#41;&#46; Delayed or inappropriate treatment of patients with IgAN in the early stage resulted in permanent disability in approximately 30&#37; of these patients &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">Currently&#44; there is insufficient evidence regarding the pathogenesis of IgAN&#44; which prevents the development of efficient strategies for the treatment of IgAN&#46; However&#44; according to current research&#44; immunological factors and signaling pathways are related to the development of IgAN &#40;<a class="elsevierStyleCrossRefs" href="#bib7">7-9</a>&#41;&#46; For example&#44; the level of transforming growth factor &#946;1 &#40;TGF-&#946;1&#41; in glomeruli is positively correlated to matrix accumulation &#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41;&#46; TGF-&#946;1 is a key regulatory factor in liver fibrosis and inflammation&#44; as well as in the growth&#44; apoptosis&#44; and differentiation of cells &#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#41;&#46; Its downstream signal transduction is mediated by Smad2 and Smad3&#44; which are phosphorylated by the heteromultimer of the TGF-&#946;1 receptor at the SSXS of the C-terminal &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#44; which binds to Smad4 and translocates into the nucleus for transcriptional regulation &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">The Huangkui capsule &#40;HKC&#41; and leflunomide &#40;LEF&#41; are drugs that are frequently used for the treatment of chronic inflammation&#46; HKC is a capsule comprising the effective constituents extracted from <span class="elsevierStyleItalic">Abelmoschus manihot</span> &#40;L&#46;&#41; medic&#46; It has been approved by the National Medical Products Administration of the People&#39;s Republic of China &#40;Z19990040&#41; for the treatment of chronic nephritis &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; Existing evidence has revealed that the major constituents of HKC are isoquercitrin &#40;C<span class="elsevierStyleInf">21</span>N<span class="elsevierStyleInf">20</span>O<span class="elsevierStyleInf">12</span>&#41;&#44; myricetin &#40;C<span class="elsevierStyleInf">15</span>N<span class="elsevierStyleInf">10</span>O<span class="elsevierStyleInf">8</span>&#41;&#44; quercetin-3-O-D-glucoside &#40;C<span class="elsevierStyleInf">21</span>N<span class="elsevierStyleInf">20</span>O<span class="elsevierStyleInf">12</span>&#41;&#44; quercetin &#40;C<span class="elsevierStyleInf">15</span>N<span class="elsevierStyleInf">10</span>O<span class="elsevierStyleInf">7</span>&#41;&#44; hyperoside &#40;C<span class="elsevierStyleInf">21</span>N<span class="elsevierStyleInf">20</span>O<span class="elsevierStyleInf">12</span>&#41;&#44; and gossypetin &#40;C<span class="elsevierStyleInf">15</span>N<span class="elsevierStyleInf">10</span>O<span class="elsevierStyleInf">8</span>&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46; HKC can ameliorate nephritis&#44; nephrotic syndrome&#44; anaphylactoid purpura nephritis&#44; IgAN&#44; membranous nephropathy&#44; and diabetic nephropathy &#40;<a class="elsevierStyleCrossRefs" href="#bib14">14-16</a>&#41;&#46; LEF&#44; an immunosuppressant&#44; exhibits promising efficacy in some immune-related diseases and has frequently been used in the clinical treatment of IgAN&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">Therefore&#44; the present study aimed to investigate the efficacy and pathogenesis of HKC in combination with LEF &#40;HKL&#41; for the treatment of IgAN and to determine its effects on the TGF-&#946;1&#47;Smad3 signaling pathway&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">MATERIALS AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Ethical approval</span><p id="para50" class="elsevierStylePara elsevierViewall">The procedures of this study were approved by the Ethical Board of Harbin First Hospital&#44; and all participants provided written informed consent prior to enrollment&#46; The study protocols involving animal experiments were reviewed and approved by the Animal Care and Ethics Committee&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Participants</span><p id="para60" class="elsevierStylePara elsevierViewall">We recruited a total of 33 participants&#58; 15 healthy participants &#40;control group&#41; and 18 patients with IgAN &#40;IgAN group&#41;&#46; The criteria for inclusion of patients with IgAN were as follows&#58; &#40;1&#41; age &#62;16 years&#44; &#40;2&#41; diagnosis of IgAN via kidney biopsy&#44; and &#40;3&#41; absence of any other immune-related diseases or complications&#46; The criteria for inclusion of healthy participants were as follows&#58; &#40;1&#41; absence of kidney disease and &#40;2&#41; presence of other immune diseases or known infections&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Quantitative reverse transcription polymerase chain reaction &#40;qRT-PCR&#41;</span><p id="para70" class="elsevierStylePara elsevierViewall">The expression levels of TGF-&#946;1&#44; Smad2&#44; Smad3&#44; Smad4&#44; and Smad7 in the TGF-&#946;1&#47;Smad3 signaling pathway were measured using qRT-PCR&#46; The TRIzol reagent &#40;Invitrogen&#44; Carlsbad&#44; CA&#44; USA&#41; was used to isolate total RNA from the cells according to the manufacturer&#39;s instruction&#44; and RNA concentration and purity were evaluated using a NanoDrop spectrophotometer &#40;NanoDrop Technologies&#44; Wilmington&#44; DE&#44; USA&#41;&#46; Complimentary DNA was prepared via reverse transcription using the iScript kit &#40;Bio-Rad&#44; Hercules&#44; CA&#44; USA&#41;&#46; qRT-PCR was performed using the Power SYBR Green qRT-PCR kit &#40;Life Technologies&#44; Shanghai&#44; China&#41; with fluorescent bases for amplification using the TaqMan Master Mix &#40;Applied Biosystems&#44; CA&#44; USA&#41;&#46; Quantitative analysis data were collected using the ABI 7500 Fast System &#40;Applied Biosystems&#41; and 2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span> method&#46; The results were normalized to glyceraldehyde-3-phosphate dehydrogenase level&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Construction of IgAN rat models</span><p id="para80" class="elsevierStylePara elsevierViewall">A total of 32 healthy&#44; male&#44; specific pathogen-free Sprague Dawley rats aged between 6 and 7 weeks and weighing 200&#177;20g were provided by the Laboratory Animal Center of Guangdong and were fed in a specific pathogen-free environment&#46; Tests for the presence of urinary proteins showed negative results&#46; In addition to the eight rats in the control group&#44; the remaining rats were treated with bovine serum albumin &#40;BSA&#41;&#44; lipopolysaccharide &#40;LPS&#41;&#44; and tetrachloromethane &#40;CCL<span class="elsevierStyleInf">4</span>&#41; to construct IgAN rat models according to previously described methods &#40;<a class="elsevierStyleCrossRefs" href="#bib17">17-20</a>&#41;&#46; After 1 week of adaptation&#44; BSA &#40;600 mg&#47;kg&#41; was administered orally every other day&#46; All rats were injected with 0&#46;05 mg of LPS via the caudal veins in the sixth and eighth weeks&#44; followed by injection with 0&#46;1 mL of CCl<span class="elsevierStyleInf">4</span> every week for 12 weeks&#46; We randomly grouped the IgAN rat models into four groups&#58; the model group &#40;IgAN group&#41;&#44; HKC group &#40;2 g&#47;kg&#47;day&#41;&#44; LEF group &#40;5 mg&#47;kg&#47;day&#41;&#44; and HKL group&#46; The control and model groups were orally administered normal saline &#40;10 mL&#47;kg&#47;day&#41; once daily for 4 weeks&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Measurement of protein levels and red blood cell counts in urine</span><p id="para90" class="elsevierStylePara elsevierViewall">At the end of the 1<span class="elsevierStyleSup">st</span>&#44; 6<span class="elsevierStyleSup">th</span>&#44; 9<span class="elsevierStyleSup">th</span>&#44; 12<span class="elsevierStyleSup">th</span>&#44; 13<span class="elsevierStyleSup">th</span>&#44; 14<span class="elsevierStyleSup">th</span>&#44; 15<span class="elsevierStyleSup">th</span>&#44; and 16<span class="elsevierStyleSup">th</span> weeks&#44; a specially designed metabolimeter was used to collect 24-h urine samples&#44; during which time rats had limited access to food but had unlimited access to water&#46; The levels of urinary proteins were determined via colorimetry using Coomassie Brilliant Blue&#46; Thereafter&#44; hematuresis was observed using a light microscope&#44; and the count of red blood cells was averaged&#46; Samples with &#8805;3 red blood cells in each field under the microscope were considered positive for hematuresis&#46;</p></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Hematoxylin &#38; eosin &#40;HE&#41; staining and pathological criteria</span><p id="para100" class="elsevierStylePara elsevierViewall">The kidney and liver tissues of rats were collected simultaneously after IgAN induction and the corresponding treatment&#46; The kidney tissues of rats were fixed in 4&#37; paraformaldehyde&#44; embedded in paraffin&#44; and cut into 5-&#956;m-thick sections&#44; which were then stained with HE for histological and collagen analyses &#40;<a class="elsevierStyleCrossRef" href="#bib21">21</a>&#41;&#46; Semiquantitative evaluation of HE-stained sections was performed&#44; and kidney injury was graded from 0 to 4 as follows&#58; 0&#61;normal tissue&#59; 1&#61;changes affecting <span class="elsevierStyleItalic">&#60;</span>25&#37; of the sample&#59; 2&#61;changes affecting 25&#37;-50&#37; of the sample&#59; 3&#61;changes affecting 50&#37;-75&#37; of the sample&#59; and 4&#61;changes affecting &#62;75&#37; of the sample &#40;<a class="elsevierStyleCrossRef" href="#bib22">22</a>&#41;&#46; The updated Oxford Classification &#40;MEST-C&#41; was used to score and judge the experimental results&#44; which were independently diagnosed and scored by two pathologists &#40;<a class="elsevierStyleCrossRef" href="#bib23">23</a>&#41;&#46;</p></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">Immunohistochemical &#40;IHC&#41; analysis</span><p id="para110" class="elsevierStylePara elsevierViewall">The kidney sections &#40;4 mm thickness&#41; were fixed with paraformaldehyde&#44; mounted on slides&#44; dewaxed&#44; and hydrated&#46; The slides were placed in 10 mM sodium citrate buffer &#40;pH 6&#41; for 2 min and then cooled for 30 min&#46; After incubation in 3&#37; hydrogen peroxide for 15 min&#44; the sections were blocked with goat serum for 30 min and then incubated overnight with primary antibodies at 4&#176;C&#46; After washing with PBST buffer solution&#44; the cells were incubated with HRP combined with anti-rabbit and anti-mouse IgG for 30 min&#46; A diaminobenzidine tetrahydrochloride solution was used as a chromogenic agent&#44; and hematoxylin was used for redyeing to determine the location of the peroxidase complex&#46;</p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">Evaluation of the chemotaxis of Th22 cells</span><p id="para120" class="elsevierStylePara elsevierViewall">CD4&#43; T cells were isolated and purified from patients with IgAN and healthy participants using a CD4&#43; T cell isolation kit &#40;Miltenyi Biotec&#44; Bergisch Gladbach&#44; Germany&#41;&#46; CD4&#43; T cells isolated from patients with IgAN were divided into four groups&#58; IgAN group&#44; HKC group &#40;0&#46;5 g&#47;mL of HKC&#41;&#44; LEF group &#40;1 mg&#47;mL&#41;&#44; and HKL group&#46; Those isolated from healthy participants were considered the control group&#46; These cells were added to the upper chambers of 24-well plates supplemented with RPMI-1640 medium containing 0&#46;5&#37; fetal bovine serum in a final volume of 100 &#956;L&#44; whereas in the lower chamber&#44; 600 &#956;L of the supernatant of HMC &#40;provided by the Advanced Research Center of Central South University&#41; was added&#46; Then&#44; Transwell plates were preserved at 37&#176;C in 5&#37; CO<span class="elsevierStyleInf">2</span> for 5h&#46; Next&#44; Th22 cells in the lower chambers were analyzed using flow cytometry and classified by their chemotactic index &#40;chemotactic index&#61;quantity of migrated Th22 cells in each group&#47;quantity of migrated Th22 cells in the control group&#41;&#46; Migrated cells were fixed with 95&#37; ethanol and stained with 0&#46;1&#37; crystal violet&#44; followed by cell counting using a microscope &#40;Olympus&#44; Tokyo&#44; Japan&#41;&#46; The levels of CCL20&#44; CCL22&#44; and CCL27 were determined using ELISA kits &#40;R&#38;D&#44; Minneapolis&#44; MN&#44; USA&#41;&#46;</p></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">MTT and WST-1 assays</span><p id="para130" class="elsevierStylePara elsevierViewall">According to the standard protocol&#44; Th22 cells were seeded into a 96-well plate at a density of 5000 cells&#47;well and cell proliferation was measured using the CCK8 Kit &#40;7Sea Biotech&#44; Shanghai&#44; China&#41; according to the manufacturer&#39;s instructions&#46; Cell viability was evaluated using the WST-1 assay &#40;Roche Diagnostics GmbH&#44; Mannheim&#44; Germany&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib24">24</a>&#41;&#46;</p></span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle170">Statistical analysis</span><p id="para140" class="elsevierStylePara elsevierViewall">Statistical analysis was performed using GraphPad Prism 8&#46;0 &#40;GraphPad&#44; La Jolla&#44; CA&#44; USA&#41;&#46; All data are expressed as mean&#177;SD&#46; Differences were considered statistically significant at <span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#46;</p></span></span><span id="cesec130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle180">RESULTS</span><span id="cesec140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle190">Key components of the TGF-&#946;1&#47;Smad3 signaling pathway are upregulated in patients with IgAN</span><p id="para150" class="elsevierStylePara elsevierViewall">We performed qRT-PCR to determine the expression levels of the key components of the TGF-&#946;1&#47;Smad3 signaling pathway in patients with IgAN&#46; We observed that the expression levels of TGF-&#946;1&#44; Smad2&#44; Smad3&#44; and Smad4 were upregulated&#44; whereas those of Smad7&#44; which inhibits the phosphorylation of Smad2 and Smad3&#44; were downregulated &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1A-E</a>&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001 and &#42;&#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;00001&#41;&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia></span><span id="cesec150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle200">HKL reduces levels of urinary proteins and ameliorates glomerular injury in rats with IgAN</span><p id="para160" class="elsevierStylePara elsevierViewall">To validate the efficacy of HKL on IgAN&#44; we constructed an IgAN rat model that was later treated with HKL for 4 weeks&#44; followed by measurement of urinary protein levels&#46; First&#44; eight rats that received continuous injections of 0&#46;1 mL CCl<span class="elsevierStyleInf">4</span> for 12 weeks were randomly selected&#44; and alanine aminotransferase &#40;ALT&#41; level&#44; aspartate aminotransferase &#40;AST&#41; level&#44; albumin &#40;ALB&#41; level&#44; and prothrombin time &#40;PT&#41; were detected&#46; The results showed that IgAN rats constructed by the CCl<span class="elsevierStyleInf">4</span> method showed no obvious abnormalities in ALT&#44; AST&#44; ALB&#44; and PT indicators &#40;<a class="elsevierStyleCrossRef" href="#fig8">Figure S1A-D</a>&#41;&#46; To further verify that the livers of IgAN rats were not damaged&#44; the kidney structure of IgAN rats was anatomically examined&#44; and the liver status of IgAN rats was observed by HE staining&#46; The results of HE staining showed that the liver lobules of IgAN rats were intact&#44; the morphology of liver cells was intact&#44; the normal nucleus was not enlarged&#44; the boundary of hepatic cords was clear&#44; and no obvious abnormality was found in the sinusoidal system &#40;<a class="elsevierStyleCrossRef" href="#fig8">Figure S1E</a>&#41;&#46; These results indicate that our construction method was specific to kidney injury and had no significant impact on the liver&#46; IgAN rats showed increased urinary protein levels and red blood cell counts&#44; which were higher than those in the control group &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2A-B</a>&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001 and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#41;&#46; However&#44; after 1 week of HKL treatment&#44; a significant decrease was observed in these indicators in IgAN rats &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2A-B</a>&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001 and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#41;&#46; Although decreases were detected in IgAN rats after a single administration of HKC or LEF for 2 weeks&#44; these decreases were significantly different from those in the HKL group &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2A-B</a>&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001 and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#41;&#46; To further validate the efficacy of HKL in IgAN rats&#44; we evaluated pathological kidney injury in IgAN rats using HE staining&#46; As indicated in <a class="elsevierStyleCrossRef" href="#fig2">Figure 2C-F</a>&#44; the control group had no significant anomalies and presented with closely organized intercapillary cells and renal tubules &#40;kidney injury grade&#61;0&#41;&#46; IgAN rats had obvious pathological kidney injuries and exhibited proliferation of glomerular mesangial cells&#44; increased mesangial matrices&#44; significant tubule dilation&#44; vacuolization of tubular epithelial cells&#44; and infiltration of the tubulointerstitial area by inflammatory cells &#40;kidney injury grade&#61;4&#41;&#46; However&#44; after HKL treatment&#44; the proliferation of mesangial cells decreased&#44; the mesangial matrices returned to normal&#44; vacuolization of renal tubular epithelial cells decreased&#44; and level of inflammatory cells in the tubulointerstitial area decreased &#40;kidney injury grade&#61;0&#41;&#46; Single treatment with HKC or LEF for 2 weeks can somehow improve kidney injury&#44; but it still lacks the efficacy of HKL &#40;kidney injury grade&#61;1&#41;&#46; Subsequently&#44; IHC was used to observe the IgA deposition in the glomeruli&#46; The results showed that there was no IgA deposition in the control group&#44; whereas there was more IgA deposition in the IgAN group&#46; Single treatment with HKC or LEF reduced IgA deposition&#44; whereas there was no IgA deposition in the glomeruli of the HKL group &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2H-L</a>&#41;&#46; The histopathology of IgNA rats before and after drug treatment was scored according to the updated IgAN MEST-C scoring index&#46; It was found that HKC or LEF could improve the kidney pathology of IgNA rats to a certain extent&#44; and the effect seen in the HKL group was more obvious than that in the HKC or LEF group &#40;<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#41;&#46; These results suggest that the use of HKL in the treatment of IgAN rats had a positive effect on the improvement of renal pathology&#46;</p><elsevierMultimedia ident="fig8"></elsevierMultimedia><elsevierMultimedia ident="fig2"></elsevierMultimedia><elsevierMultimedia ident="tbl1"></elsevierMultimedia></span><span id="cesec160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle210">HKL inhibits the expression of the TGF-&#946;1&#47;Smad3 signaling pathway in IgAN rats</span><p id="para170" class="elsevierStylePara elsevierViewall">To determine the molecular mechanism of HKL in improving the pathogenesis of IgAN&#44; we performed qRT-PCR and found that HKL downregulated the expression levels of TGF-&#946;1&#44; Smad2&#44; Smad3&#44; and Smad4 in IgAN rats and upregulated the expression levels of Smad7 &#40;<a class="elsevierStyleCrossRef" href="#fig3">Figure 3A-E</a>&#44; &#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#41;&#46; Therefore&#44; we conclude that the TGF-&#946;1&#47;Smad3 signaling pathway may be involved in the ability of HKL to improve the health of IgAN rats&#46;</p><elsevierMultimedia ident="fig3"></elsevierMultimedia></span><span id="cesec170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle220">HKL inhibits the chemotaxis of Th22 cells</span><p id="para180" class="elsevierStylePara elsevierViewall">An increased number of Th22 cells correlates with IgAN deterioration &#40;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#41;&#44; which may be attributed to the infiltration and proliferation of lymphocytes &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#44; whereas lymphocyte migration in response to chemokine activities is the key to Th22 cell infiltration&#46; The evaluation of the chemotaxis of Th22 cells in each group suggested that compared with the control group&#44; Th22 cells in the IgAN group had a sharp increase in the chemotactic index&#46; However&#44; HKL treatment reversed the decrease in the chemotactic index of Th22 cells &#40;<a class="elsevierStyleCrossRef" href="#fig4">Figure 4A</a>&#44; &#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#41;&#46; Meanwhile&#44; staining of the migrated cells demonstrated that HKL treatment could curb the migration ability of Th22 cells &#40;<a class="elsevierStyleCrossRef" href="#fig4">Figure 4B-F</a>&#41;&#46; Existing data have shown that the chemotaxis of Th22 cells is regulated by chemotactic factors such as CCL20&#44; CCL22&#44; and CCL27 &#40;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#41;&#46; To further validate the effect of HKL on CCL20&#44; CCL22&#44; and CCL27&#44; we detected the levels of these indicators and found that they were overexpressed in the IgAN group&#44; whereas HKL treatment reduced the secretion of CCL20&#44; CCL22&#44; and CCL27 &#40;<a class="elsevierStyleCrossRef" href="#fig4">Figure 4G-I</a>&#44; &#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#41;&#46;</p><elsevierMultimedia ident="fig4"></elsevierMultimedia></span><span id="cesec180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle230">HKL inhibits the proliferation and activity of Th22 cells</span><p id="para190" class="elsevierStylePara elsevierViewall">The differentiation and proliferation of Th22 cells are conducive to the accumulation of Th22 cells&#46; In this study&#44; compared with the IgAN group&#44; Th22 cells in the HKL group showed a sharp decrease in proliferation &#40;<a class="elsevierStyleCrossRef" href="#fig5">Figure 5A</a>&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001 and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#41; and activity &#40;<a class="elsevierStyleCrossRef" href="#fig5">Figure 5B</a>&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001 and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#41;&#46; With respect to the progression of IgAN&#44; the migration of Th22 cells can further exacerbate the disease&#46;</p><elsevierMultimedia ident="fig5"></elsevierMultimedia></span><span id="cesec190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle240">Molecular mechanism underlying HKL-induced inhibition of the activity of Th22 cells</span><p id="para200" class="elsevierStylePara elsevierViewall">TGF-&#946;1 regulates proliferation and differentiation of Th22 cells &#40;<a class="elsevierStyleCrossRef" href="#bib27">27</a>&#41;&#46; To further explore the <span class="elsevierStyleItalic">in vitro</span> molecular mechanism of HKL&#44; we detected the <span class="elsevierStyleItalic">in vitro</span> expression of the key components of the TGF-&#946;1&#47;Smad3 signaling pathway in Th22 cells&#46; Compared with the cells in the IgAN group&#44; the expression levels of TGF-&#946;1&#44; Smad2&#44; Smad3&#44; and Smad4 were significantly inhibited&#44; whereas those of Smad7 were upregulated in the cells of the HKL group &#40;<a class="elsevierStyleCrossRef" href="#fig6">Figure 6A-E</a>&#44; &#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#41;&#46; Furthermore&#44; the number of Th22 cells was positively correlated with the level of TGF-&#946;1 &#40;<a class="elsevierStyleCrossRef" href="#fig6">Figure 6F</a>&#41;&#46;</p><elsevierMultimedia ident="fig6"></elsevierMultimedia></span></span><span id="cesec200" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle250">DISCUSSION</span><p id="para210" class="elsevierStylePara elsevierViewall">HKC and LEF are the most common drugs used for the treatment of inflammation&#44; and existing data have revealed the molecular mechanisms of HKC and LEF for the treatment of lupus nephritis&#44; chronic nephritis&#44; and other immune diseases &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#44;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#44;<a class="elsevierStyleCrossRef" href="#bib28">28</a>&#44;<a class="elsevierStyleCrossRef" href="#bib29">29</a>&#41;&#46; However&#44; there are insufficient data regarding the efficacy and molecular mechanism of HKL in the treatment of IgAN&#46; In this study&#44; we used IgAN rats and Th22 cells extracted from them to perform <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span> experiments with the aim of uncovering evidence for deeper understanding of the efficacy and molecular mechanism of HKL in the treatment of IgAN&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">Clinically&#44; patients with IgAN mainly present with symptoms of microscopic or visible blood in the urine&#44; proteinuria&#44; hypertension&#44; or kidney dysfunction &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41;&#46; In this study&#44; we found that the expression levels of the key components of the TGF-&#946;1&#47;Smad3 signaling pathway were upregulated in patients with IgAN and that IgAN rats after HKL treatment showed significant improvements in proteinuria and hematuria&#59; the levels of protein and red blood cells in these rats were significantly lower than those in rats treated with a single drug&#46; HE staining results also showed that HKL treatment significantly improved the glomerular pathological status of IgAN rats&#46; Similarly&#44; IHC staining demonstrated the effectiveness of HKL in IgAN rats&#46; Therefore&#44; HKL shows promise for the treatment of IgAN&#46;</p><p id="para230" class="elsevierStylePara elsevierViewall">To identify the potential mechanism of HKL in the treatment of IgAN&#44; we determined the expression profiles of some genes and found that HKL suppressed the activity of the TGF-&#946;1&#47;Smad3 signaling pathway in IgAN rats&#46; Therefore&#44; the mechanism of HKL in the treatment of IgAN may rely on the regulation of the TGF-&#946;1&#47;Smad3 signaling pathway&#46;</p><p id="para240" class="elsevierStylePara elsevierViewall">Chronic inflammation is a common hallmark of IgAN &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#44;<a class="elsevierStyleCrossRef" href="#bib30">30</a>&#41;&#46; Therefore&#44; we investigated the effect of HKL on IgAN in Th22 cells and demonstrated that HKL curbed the generation of TGF-&#946;1 in Th22 cells&#46; Interestingly&#44; existing data have revealed a correlation between TGF-&#946;1 and Th22 cells&#44; similar to our findings &#40;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#44;<a class="elsevierStyleCrossRef" href="#bib27">27</a>&#41;&#46; Th22 cells&#44; a type of T helper cell&#44; can activate other immune cells to regulate immunocompetence &#40;<a class="elsevierStyleCrossRef" href="#bib31">31</a>&#44;<a class="elsevierStyleCrossRef" href="#bib32">32</a>&#41;&#46; Excessive proliferation of Th22 cells contributes to severe inflammation &#40;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&#46; Th22 cells can further exacerbate IgAN&#44; particularly in patients with IgAN &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#46; CCL20&#44; CCL22&#44; and CCL27 are important for the functions of Th22 cells &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#46; The interaction between these chemotactic factors and Th22 cells can further induce lymphocyte anomalies in patients with IgAN &#40;<a class="elsevierStyleCrossRef" href="#bib33">33</a>&#44;<a class="elsevierStyleCrossRef" href="#bib34">34</a>&#41;&#46; Studies have shown that infection and galactose-deficient IgA accumulation induces the secretion of chemotactic factors by glomerular membrane cells&#44; thereby contributing to hyperplasia of the glomerular membrane and injury to mesangial cells &#40;<a class="elsevierStyleCrossRef" href="#bib35">35</a>&#44;<a class="elsevierStyleCrossRef" href="#bib36">36</a>&#41;&#46; In this study&#44; we found that HKL blocks the expression of CCL20&#44; CCL22&#44; and CCL27 in intercapillary cells&#44; thereby mitigating the migration of Th22 cells&#46;</p><p id="para250" class="elsevierStylePara elsevierViewall">To validate the accuracy of the above experiments&#44; we evaluated the proliferation and viability of Th22 cells in patients with IgAN and found that HKL treatment decreased the proliferation and viability of Th22 cells&#44; further confirming the above findings&#46; These molecular findings suggest that HKL inhibits the activity of Th22 cells by regulating the TGF-&#946;1&#47;Smad3 signaling pathway&#44; thereby ameliorating IgAN &#40;<a class="elsevierStyleCrossRef" href="#fig7">Figure 7</a>&#41;&#46;</p><elsevierMultimedia ident="fig7"></elsevierMultimedia><p id="para260" class="elsevierStylePara elsevierViewall">In conclusion&#44; by targeting the TGF-&#946;1&#47;Smad3 signaling pathway&#44; HKL can improve kidney injury in IgAN rats and can inhibit the excessive proliferation and metastasis of Th22 cells significantly better than treatment with a single drug&#46;</p></span><span id="cesec210" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle260">AUTHOR CONTRIBUTIONS</span><p id="para270" class="elsevierStylePara elsevierViewall">Shuwen Pei S wrote the manuscript&#46; Pei S and Yan Li Y designed the study&#44; collected the data and performed the statistical analysis&#46; All of the authors reviewed and approved the final version of the manuscript&#46;</p></span></span>"
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        1 => array:2 [
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          "titulo" => "INTRODUCTION"
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          "titulo" => "MATERIALS AND METHODS"
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              "titulo" => "Ethical approval"
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              "titulo" => "Participants"
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              "titulo" => "Quantitative reverse transcription polymerase chain reaction &#40;qRT-PCR&#41;"
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            3 => array:2 [
              "identificador" => "cesec60"
              "titulo" => "Construction of IgAN rat models"
            ]
            4 => array:2 [
              "identificador" => "cesec70"
              "titulo" => "Measurement of protein levels and red blood cell counts in urine"
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            5 => array:2 [
              "identificador" => "cesec80"
              "titulo" => "Hematoxylin &#38; eosin &#40;HE&#41; staining and pathological criteria"
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              "titulo" => "Immunohistochemical &#40;IHC&#41; analysis"
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              "titulo" => "Evaluation of the chemotaxis of Th22 cells"
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              "titulo" => "MTT and WST-1 assays"
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          "titulo" => "RESULTS"
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              "identificador" => "cesec140"
              "titulo" => "Key components of the TGF-&#946;1&#47;Smad3 signaling pathway are upregulated in patients with IgAN"
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              "identificador" => "cesec150"
              "titulo" => "HKL reduces levels of urinary proteins and ameliorates glomerular injury in rats with IgAN"
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              "titulo" => "HKL inhibits the expression of the TGF-&#946;1&#47;Smad3 signaling pathway in IgAN rats"
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              "identificador" => "cesec170"
              "titulo" => "HKL inhibits the chemotaxis of Th22 cells"
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              "identificador" => "cesec180"
              "titulo" => "HKL inhibits the proliferation and activity of Th22 cells"
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              "titulo" => "Molecular mechanism underlying HKL-induced inhibition of the activity of Th22 cells"
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          "titulo" => "DISCUSSION"
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          "titulo" => "AUTHOR CONTRIBUTIONS"
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          "titulo" => "REFERENCES"
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    "fechaRecibido" => "2021-08-09"
    "fechaAceptado" => "2021-10-15"
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          "palabras" => array:5 [
            0 => "IgA Nephropathy"
            1 => "Huangkui Capsules"
            2 => "Leflunomide"
            3 => "Th22 Cells"
            4 => "TGF-&#946;1&#47;Smad3 Signaling Pathway"
          ]
        ]
      ]
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    "resumen" => array:1 [
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES&#58;</span><p id="spara100" class="elsevierStyleSimplePara elsevierViewall">To investigate the efficacy and potential molecular mechanism of Huangkui capsule in combination with leflunomide &#40;HKL&#41; for the treatment of immunoglobulin A nephropathy &#40;IgAN&#41;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara110" class="elsevierStyleSimplePara elsevierViewall">IgAN rat models were constructed by treating rats with bovine serum albumin&#44; lipopolysaccharide&#44; and tetrachloromethane&#46; Th22 cells were isolated from the blood samples of patients with IgAN using a CD4&#43; T cell isolation kit&#46; The expression levels of the components of the TGF-&#946;1&#47;Smad3 signaling pathway&#44; namely&#44; TGF-&#946;1&#44; Smad2&#44; Smad3&#44; Smad4&#44; and Smad7&#44; were detected using quantitative reverse transcription polymerase chain reaction&#46; Cell proliferation was determined using the MTT assay&#44; cell viability was determined using the WST 1 method&#44; and the chemotaxis of Th22 cells was observed using the wound healing assay&#46; Changes in the histology of the kidney tissues were analyzed using hematoxylin and eosin staining&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara120" class="elsevierStyleSimplePara elsevierViewall">Compared with IgAN rats&#44; the rats subjected to HKL treatment showed good improvement in kidney injuries&#44; and the combined drug treatment performed much better than the single-drug treatment&#46; In addition&#44; following HKL treatment&#44; the viability&#44; proliferation&#44; and chemotaxis of Th22 cells dramatically decreased &#40;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;01&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#41;&#46; In addition&#44; CCL20&#44; CCL22&#44; and CCL27 levels decreased and the expression of the key components of the TGF-&#946;1&#47;Smad3 signaling pathway was downregulated in IgAN rats and Th22 cells &#40;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#41;&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSIONS&#58;</span><p id="spara130" class="elsevierStyleSimplePara elsevierViewall">By targeting the TGF-&#946;1&#47;Smad3 signaling pathway&#44; HKL treatment can improve kidney injury in IgAN rats as well as the excessive proliferation and metastasis of Th22 cells&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "ceabs10"
            "titulo" => "OBJECTIVES&#58;"
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          1 => array:2 [
            "identificador" => "ceabs20"
            "titulo" => "METHODS&#58;"
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          2 => array:2 [
            "identificador" => "ceabs30"
            "titulo" => "RESULTS&#58;"
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          3 => array:2 [
            "identificador" => "ceabs40"
            "titulo" => "CONCLUSIONS&#58;"
          ]
        ]
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    ]
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      0 => array:1 [
        "nota" => "<p class="elsevierStyleNotepara" id="cenpara40">No potential conflict of interest was reported&#46;</p>"
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            "apendice" => "<p id="para280" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="fig8"></elsevierMultimedia></p>"
            "etiqueta" => "APPENDIX"
            "identificador" => "cesec220"
          ]
        ]
      ]
    ]
    "multimedia" => array:9 [
      0 => array:7 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Key components of the TGF-&#946;1&#47;Smad3 signaling pathway are upregulated in patients with IgAN&#46; &#40;A-D&#41; Expression levels of TGF-&#946;1 &#40;A&#41;&#44; Smad2 &#40;B&#41;&#44; Smad3 &#40;C&#41;&#44; and Smad4 &#40;D&#41; are upregulated in patients with IgAN&#46; &#40;E&#41; The expression level of Smad7 is downregulated in patients with IgAN&#46; IgAN&#58; Immunoglobulin A nephropathy&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001 and &#42;&#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;00001&#44; Mann-Whitney <span class="elsevierStyleItalic">U</span> test &#40;A&#41;&#44; unpaired Student&#39;s <span class="elsevierStyleItalic">t</span>-test &#40;B-E&#41;&#46;</p>"
        ]
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      1 => array:7 [
        "identificador" => "fig2"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">HKL reduces the levels of urinary proteins and ameliorates glomerular injury in IgAN rats&#46; &#40;A-B&#41; HKL reduces urinary protein levels &#40;A&#41; and red blood cell counts &#40;B&#41; in IgAN rats&#46; &#40;C-G&#41; Pathological analysis of the kidney tissues of the rats in each group &#40;black arrows indicate proliferation of glomerular mesangial cells and green arrows indicate infiltration of inflammatory cells in the tubulointerstitial area&#41;&#46; &#40;H-L&#41; IHC of kidney tissues of rats in each group&#46; HKC&#58; Huangkui capsule&#44; LEF&#58; leflunomide&#44; HKL&#58; HKC in combination with LEF&#44; IgAN&#58; Immunoglobulin A nephropathy&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001 and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; Mann-Whitney <span class="elsevierStyleItalic">U</span> test&#46;</p>"
        ]
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        "identificador" => "fig3"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">HKL inhibits the expression of the TGF-&#946;1&#47;Smad3 signaling pathway in IgAN rats&#46; &#40;A-D&#41; Expression of TGF-&#946;1 &#40;A&#41;&#44; Smad2 &#40;B&#41;&#44; Smad3&#44; &#40;C&#41;&#44; and Smad4 &#40;D&#41; in rats of all groups&#59; &#40;E&#41; HKL upregulates the expression of Smad7 in IgAN rats&#46; HKC&#58; Huangkui capsule&#44; LEF&#58; leflunomide&#44; HKL&#58; HKC in combination with LEF&#44; IgAN&#58; Immunoglobulin A nephropathy&#44; &#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; Kruskal-Wallis test followed by Dunn&#39;s multiple comparisons test&#46;</p>"
        ]
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      3 => array:7 [
        "identificador" => "fig4"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 1214
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            "Tamanyo" => 385501
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        "descripcion" => array:1 [
          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">HKL inhibits the chemotaxis of Th22 cells&#46; &#40;A&#41; Chemotaxis of Th22 cells in each group&#46; &#40;B-F&#41; Detection of migrated Th22 cells via crystal violet staining&#46; &#40;G-I&#41; ELISA analysis of the levels of CCL20 &#40;G&#41;&#44; CCL22 &#40;H&#41;&#44; and CCL27 &#40;I&#41; in each group&#46; HKC&#58; Huangkui capsule&#44; LEF&#58; leflunomide&#44; HKL&#58; HKC in combination with LEF&#44; IgAN&#58; Immunoglobulin A nephropathy&#44; &#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; Kruskal-Wallis test followed by Dunn&#39;s multiple comparisons test&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig5"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 631
            "Ancho" => 1752
            "Tamanyo" => 82123
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">HKL inhibits the proliferation and activity of Th22 cells&#46; &#40;A&#41; Results of the MTT assay show the change in the proliferation of Th22 cells in each group&#46; &#40;B&#41; Results of the WST-1 assay show the changes in the viability of Th22 cells in each group&#46; HKC&#58; Huangkui capsule&#44; LEF&#58; leflunomide&#44; HKL&#58; HKC in combination with LEF&#44; IgAN&#58; Immunoglobulin A nephropathy&#44; &#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; Kruskal-Wallis test followed by Dunn&#39;s multiple comparisons test&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "fig6"
        "etiqueta" => "Figure 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 925
            "Ancho" => 1753
            "Tamanyo" => 144031
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara60" class="elsevierStyleSimplePara elsevierViewall">Molecular mechanism of HKL inhibiting the activity of Th22 cells&#46; &#40;A-D&#41;&#59; qRT-PCR results reveal that HKL downregulates the expression of the TGF-&#946;1&#47;Smad3 signaling pathway&#46; &#40;E&#41; HKL upregulates Smad7 expression&#46; &#40;F&#41; The quantity of Th22 cells is positively correlated with TGF-&#946;1 levels&#46; HKC&#58; Huangkui capsule&#44; LEF&#58; leflunomide&#44; HKL&#58; HKC in combination with LEF&#44; IgAN&#58; Immunoglobulin A nephropathy&#44; &#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;001&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; and &#42;&#42;&#42;<span class="elsevierStyleItalic">p&#60;</span>0&#46;0001&#44; Kruskal-Wallis test followed by Dunn&#8217;s multiple comparisons test&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "fig7"
        "etiqueta" => "Figure 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
            "Alto" => 1015
            "Ancho" => 902
            "Tamanyo" => 53394
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara70" class="elsevierStyleSimplePara elsevierViewall">Functional model of HKL for the treatment of IgAN&#46; TGF-&#946;1&#44; as a central regulatory factor&#44; regulates the downstream expression of Smad2&#44; Smad3&#44; Smad4&#44; and Smad7&#44; thereby inhibiting the activity of Th22 cells&#46; HKL&#58; Huangkui capsule in combination with leflunomide&#44; IgAN&#58; Immunoglobulin A nephropathy&#46;</p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spara90" class="elsevierStyleSimplePara elsevierViewall">M&#58; mesangial hypercellularity &#40;M0&#60;50&#37;&#59; M1&#10878;50&#37; of the glomeruli&#41;&#44; E&#58; endocapillary hypercellularity &#40;E0&#58; absent&#59; E1&#58; present&#41;&#44; S&#58; segmental glomerulosclerosis &#40;S0&#58; absent&#59; S1&#58; present&#41;&#44; T&#58; tubular atrophy&#47;interstitial fibrosis &#40;T0&#58; 0-24&#37;&#59; T1&#58; 25-49&#37;&#59; and T2&#58;&#10878;50&#37; of the cortical area&#41;&#44; C&#58; cellular&#47;fibrocellular crescents &#40;C0&#58; absent&#59; C1&#58; 1-24&#37;&#59; and C2&#58;&#10878;25&#37; of the glomeruli&#41;&#44; HKC&#58; Huangkui capsule&#44; LEF&#58; leflunomide&#44; HKL&#58; HKC in combination with LEF&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MEST-C classification&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pretreatment of HKC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pretreatment of HKL&nbsp;\t\t\t\t\t\t\n
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                              Q Li \n
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos