Attenuating Renal Interstitial Fibrosis by Shenqi Pill via Reducing Inflammation Response Regulated by NF-κB Pathway In Vitro and In Vivo.

INTRODUCTION: One of the most significant clinical features of chronic  kidney disease is renal interstitial fibrosis (RIF). This study aimed  to investigate the role and mechanism of Shenqi Pill (SQP) on RIF. METHODS: RIF model was established by conducting unilateral  ureteral obstruction (UUO) surgery on rat or stimulating human  kidney-2 (HK-2) cell with transforming growth factor ß1 (TGFß1).  After modeling, the rats in the SQP low dose group (SQP-L), SQP  middle dose group (SQP-M) and SQP high dose group (SQP-H)  were treated with SQP at 1.5, 3 or 6 g/kg/d, and the cells in the  TGFß1+SQP-L/M/H were treated with 2.5%, 5%, 10% SQP-containing  serum. In in vivo assays, serum creatinine (SCr) and blood urea  nitrogen (BUN) content were measured, kidney histopathology  was evaluated., and α-smooth muscle actin (α-SMA) expression  was detected by immunohistochemistry. Interleukin-1ß (IL-1ß),  interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) content,  inhibitor of kappa B alpha (IKBα) and P65 phosphorylation were  assessed. Meanwhile, cell viability, inflammatory cytokines content,  α-SMA expression, IKBα and P65 phosphorylation were detected  in vitro experiment.  Results. SQP exhibited reno-protective effect by decreasing SCr  and BUN content, improving renal interstitial damage, blunting  fibronectin (FN) and α-SMA expression in RIF rats. Similarly, after  the treatment with SQP-containing serum, viability and α-SMA  expression were remarkably decreased in TGFß1-stimulated HK-2  cell. Furthermore, SQP markedly down-regulated IL-1ß, IL-6, and  TNF-α content, IKBα and RelA (P65) phosphorylation both in vivo and in vitro.  Conclusion. SQP has a reno-protective effect against RIF in vivo and in vitro, and the effect is partly linked to nuclear factor-kappa  B (NF-κB) pathway related inflammatory response, which indicates  that SQP may be a candidate drug for RIF. DOI: 10.52547/ijkd.7546.

Calpain inhibition decreases myocardial fibrosis in chronically ischemic hypercholesterolemic swine.

OBJECTIVES: Calpain activation during ischemia is known to play critical roles in myocardial remodeling. We hypothesize that calpain inhibition (CI) may serve to reverse and/or prevent fibrosis in chronically ischemic myocardium. METHODS: Yorkshire swine were fed a high-cholesterol diet for 4 weeks followed by placement of an ameroid constrictor on the left circumflex artery to induce myocardial ischemia. 3 weeks later, animals received either: no drug; high-cholesterol control group (CON; n = 8); low-dose CI (0.12 mg/kg; LCI, n = 9); or high-dose CI (0.25 mg/kg; HCI, n = 8). The high-cholesterol diet and CI were continued for 5 weeks, after which myocardial tissue was harvested. Tissue samples were analyzed by western blot for changes in protein content. RESULTS: In the setting of hypercholesterolemia and chronic myocardial ischemia, CI decreased the expression of collagen in ischemic and nonischemic myocardial tissue. This reduced collagen content was associated with a corresponding decrease in Jak/STAT/MCP-1 signaling pathway, suggesting a role for Jak 2 signaling in calpain activity. CI also decreases the expression of focal adhesion proteins (vinculin) and stabilizes the expression of cytoskeletal and structural proteins (N-cadherin, α-fodrin, desmin, vimentin, filamin, troponin-I). CI had no significant effect on metabolic and hemodynamic parameters. CONCLUSIONS: Calpain inhibition may be a beneficial medical therapy to decrease collagen formation in patients with coronary artery disease and associated comorbidities.

Novel pectin-like polysaccharide from Panax notoginseng attenuates renal tubular cells fibrogenesis induced by TGF-ß.

Renal fibrosis is the final common result of a variety of progressive injuries leading to chronic renal failure. However, there are no effective clinical available drugs for the treatment. Notoginsenoside from Panax notoginseng could ameliorate renal fibrosis. We hypothesized that polysaccharide from this herb might have similar bioactivity. Here, we elucidated structure of a novel pectin-like polysaccharide designed SQD4S2 with a netty antenna backbone of glucogalacturonan substituted by glucoarabinan, glucurogalactan and galactose residues from this herb. Interestingly, SQD4S2 could reverse the morphological changes of human renal tubular HK-2 cells induced by TGF-ß. Mechanism study suggested that this bioactivity might associate with N-cadherin (CDH2), Snail (SNAI1), Slug (SNAI2) depression and E-cadherin (CDH1) enhancement. In addition, SQD4S2 could impede critical fibrogenesis associated molecules such as α-SMA, fibronectin, vimentin, COL1A1, COL3A1, FN1 and ACTA2 expression induced by TGF-ß in HK-2 cells. Current findings outline a novel leading polysaccharide for against renal fibrosis new drug development.

Zishen Qingre Tongluo Formula Improves Renal Fatty Acid Oxidation and Alleviated Fibrosis via the Regulation of the TGF-ß1/Smad3 Signaling Pathway in Hyperuricemic Nephrology Rats.

Hyperuricemia, an independent risk factor for ensuing chronic kidney disease (CKD), contributed to tubulointerstitial fibrosis and insufficiency of renal fatty acid oxidation. Many studies have shown that renal fatty acid oxidation dysfunction is related to the TGF-ß1/Smad3 signaling pathway. We experimented the effects of Zishen Qingre Tongluo Formula (ZQTF) on the adenine/yeast-induced HN rats and uric acid-induced renal mouse tubular epithelial cells (mTECs), determined whether this effect was related to the TGF-ß1/Smad3 signaling pathway, and further investigated the relationship between this effect and renal fatty acid oxidation. Rats were given intraperitoneally with adenine (100 mg/kg) and feed chow with 10% yeast for 18 days and then received ZQTF (12.04 g/kg/day) via intragastric gavage for eight weeks. The TGF-ß1/Smad3 signaling pathway and renal fatty acid oxidation protein were detected by using western blotting, real-time PCR, and immunohistochemistry staining. mTECs induced by UA were used to investigate the relationship between the TGF-ß1/Smad3 signaling pathway and renal fatty acid oxidation. After treatment with ZQTF, levels of UA, 24 h UTP, BUN, and Scr were significantly decreased and histologic injuries were visibly ameliorated in HN rats. Western blotting, real-time PCR, and immunohistochemistry staining revealed that PGC-1α, PPARγ, and PPARα significantly increased, and fibronectin, collagen 1, and P-Smad3 significantly decreased in HN rats and UA-induced mTECs after ZQTF treatment. SIS3 (a specific inhibitor of Smad3) treatment significantly increased the expressions of PGC-1α, PPARγ, and PPARα and decreased the expressions of fibronectin, collagen 1, and P-Smad3 in UA-induced mTECs. Our study demonstrated that ZQTF exhibited renoprotective effects by promoting renal fatty acid oxidation via the regulation of the TGF-ß1/Smad3 signaling pathway. Thus, the present results indicated that ZQTF was a novel antifibrotic strategy for hyperuricemic nephropathy.

Angiotensin (ang) 1-7 inhibits ang II-induced atrial fibrosis through regulating the interaction of proto-oncogene tyrosine-protein kinase Src (c-Src) and Src homology region 2 domain-containing phosphatase-1 (SHP-1)).

To verify whether Ang-(1-7) produces an antagonistic effect on Ang II-mediated atrial remodeling. Ang II-induced HL-1 cell model and a rat model of Ang II-induced atrial remodeling were constructed and intervened with Ang II Ang-(1-7), AngII +Ang-(1-7), Ang II+ c-Src specific inhibitor (SU6656), and Ang II + Ang-(1-7) + SSG (SHP-1/2 specific inhibitor, stibogluconate), respectively. The systolic blood pressure of the rat caudal artery was detected. And trial fibrosis was detected by Picrosirius red staining and Masson's trichrome staining. Expressions of transforming growth factor-ß (TGF-ß), tissue inhibitor of metalloproteinases 1 (TIMP1), Matrix metalloproteinase 2 (MMP-2), connective tissue growth factor (CTGF), galectin-3, α-smooth muscle actin (α-SMA), and collagen I/III were subjected to qPCR and western blot. Furthermore, SHP-1 binding to c-Src was verified by co-immunoprecipitation (Co-IP). Results showed that the expressions of TGF-ß, TIMP1, MMP-2, CTGF, α-SMA, galectin-3, and collagen I were increased markedly in the Ang II intervention group, and the expressions of p-ERK1/2, p-Akt, and p-p38MAPK were also increased dramatically. Ang-(1-7) or SU6656 addition could inhibit the action of Ang II factor, thereby minimizing the expressions of the previously described genes and proteins. Simultaneously, SSG supplement reversed the antagonistic effect of Ang-(1-7) on Ang II, and the latter elevated the blood pressure and induced atrial fibrosis in rats. Ang-(1-7) could reverse the changes related to Ang II-induced atrial fibrosis in rats. In conclusion, Ang-(1-7) antagonized Ang II-induced atrial remodeling by regulating SHP-1 and c-Src, thereby affecting the MAPKs/Akt signaling pathway.

Protective Effects of Nootkatone on Renal Inflammation, Apoptosis, and Fibrosis in a Unilateral Ureteral Obstructive Mouse Model.

Nootkatone is one of the major active ingredients of Alpiniae oxyphyllae, which has been used as both food and medicinal plants for the treatment of diarrhea, ulceration, and enuresis. In this study, we aimed to investigate whether nootkatone treatment ameliorated the progression of chronic kidney diseases (CKD) and clarified its underlying mechanisms in an obstructive nephropathy (unilateral ureteral obstructive; UUO) mouse model. Our results revealed that nootkatone treatment preventively decreased the pathological changes and significantly mitigated the collagen deposition as well as the protein expression of fibrotic markers. Nootkatone could also alleviate oxidative stress-induced injury, inflammatory cell infiltration, and renal cell apoptotic death in the kidneys of UUO mice. These results demonstrated for the first time that nootkatone protected against the progression of CKD in a UUO mouse model. It may serve as a potential therapeutic candidate for CKD intervention.

Curcumin mediates repulsive guidance molecule B (RGMb) in the treatment mechanism of renal fibrosis induced by unilateral ureteral obstruction.

In this study, we explored the role and mechanism of repulsive guidance molecule B (RGMb, also known as Dragon) in the protective effects of curcumin against renal fibrosis and verified Dragon's effect on renal tubular epithelial cell apoptosis and cell programmability. Unilateral ureteral obstruction (UUO) was surgically induced in rats to establish a model of renal interstitial fibrosis (RIF). The rats were then treated with curcumin. Curcumin prominently decreased the serum creatinine (SCr) and blood urea nitrogen (BUN) levels, and also improved the tubular injury in the UUO-induced rats. Curcumin significantly downregulated the TGF-ß1, P-Smad2/3, cleaved caspase-3, cleaved caspase-8 and Dragon levels. Dragon knockdown also markedly reduced the TGF-ß1, P-Smad2/3, Smad2/3, cleaved caspase-3, cleaved caspase-8, fibronectin, collagen I, collagen IV, vimentin, and α-SMA expression levels. Conversely, Dragon overexpression caused higher expression levels of these proteins, and curcumin reversed this effect. Furthermore, Dragon knockdown increased the E-cadherin levels, whereas Dragon overexpression decreased these levels. Overexpressing Dragon significantly decreased the cell viability, and curcumin reversed this effect. In conclusion, curcumin acted on Dragon and attenuated RIF in UUO rat models. Curcumin downregulated the TGF-ß1/Smad signaling pathway and inhibited Dragon and fibrogenic molecules in both rats and HK-2 cells.

Metformin and Glaucoma-Review of Anti-Fibrotic Processes and Bioenergetics.

Glaucoma is the leading cause of irreversible blindness globally. With an aging population, disease incidence will rise with an enormous societal and economic burden. The treatment strategy revolves around targeting intraocular pressure, the principle modifiable risk factor, to slow progression of disease. However, there is a clear unmet clinical need to find a novel therapeutic approach that targets and halts the retinal ganglion cell (RGC) degeneration that occurs with fibrosis. RGCs are highly sensitive to metabolic fluctuations as a result of multiple stressors and thus their viability depends on healthy mitochondrial functioning. Metformin, known for its use in type 2 diabetes, has come to the forefront of medical research in multiple organ systems. Its use was recently associated with a 25% reduced risk of glaucoma in a large population study. Here, we discuss its application to glaucoma therapy, highlighting its effect on fibrotic signalling pathways, mitochondrial bioenergetics and NAD oxidation.

Hirsutella sinensis fungus improves cardiac function in mouse model of heart failure.

Cordyceps sinensis, including Hirsutella sinensis, is a highly valuable traditional Chinese medicine and is used to treat patients with pulmonary heart disease in clinical practice. However, the underlying mechanisms of its effects remain unclear. In this study, a mouse model of heart failure established by non-thoracic, transverse aortic constriction (TAC) was developed to determine the underlying mechanisms of therapeutic effects of Hirsutella sinensis fungus (HSF) powder. The results showed that HSF treatment remarkably ameliorated myocardial hypertrophy, collagen fiber hyperplasia, and cardiac function in mice with heart failure. Using transcriptional and epigenetic analyses, we found that the mechanism of HSF mainly involved a variety of signaling pathways related to myocardial fibrosis and determined that HSF could reduce the levels of TGF-ß1 proteins in heart tissue, as well as type I and III collagen levels. These data suggest that HSF alleviates heart failure, inhibits irreversible ventricular remodeling, and improves cardiac function through the regulation of myocardial fibrosis-related signaling pathways, which can provide novel opportunities to improve heart failure therapy.

A Review of Traditional Chinese Medicine in Treating Renal Interstitial Fibrosis via Endoplasmic Reticulum Stress-Mediated Apoptosis.

Renal interstitial fibrosis (RIF) is the main pathological manifestation of end-stage renal disease. Recent studies have shown that endoplasmic reticulum (ER) stress is involved in the pathogenesis and development of RIF. Traditional Chinese medicine (TCM), as an effective treatment for kidney diseases, can improve kidney damage by affecting the apoptotic signaling pathway mediated by ER stress. This article reviews the apoptotic pathways mediated by ER stress, including the three major signaling pathways of unfolded protein response, the main functions of the transcription factor C/EBP homologous protein. We also present current research on TCM treatment of RIF, focusing on medicines that regulate ER stress. A new understanding of using TCM to treat kidney disease by regulating ER stress will promote clinical application of Chinese medicine and discovery of new drugs for the treatment of RIF.

Parthenolide plays a protective role in the liver of mice with metabolic dysfunction­associated fatty liver disease through the activation of the HIPPO pathway.

Metabolic dysfunction­associated fatty liver disease (MAFLD) is a serious threat to human health. Parthenolide (PAR) displays several important pharmacological activities, including the promotion of liver function recovery during hepatitis. The aim of the present study was to assess the effect of PAR on MAFLD in a mouse model. Body weight, liver to body weight ratios, histological score, alanine transaminase, aspartate transaminase, total cholesterol and triglyceride levels were determined to evaluate liver injury. Liver hydroxyproline concentrations were also assessed. The expression levels of lipid metabolism­related genes (sterol regulatory element binding protein­1c, fatty acid synthase, acetyl CoA carboxylase 1, stearoyl CoA desaturase 1 and carbohydrate response element­binding protein, peroxisome proliferator­activated receptor α, carnitine palmitoyl transferase 1α and acyl­CoA dehydrogenase short chain), liver fibrosis­associated genes (α­smooth muscle actin, tissue inhibitor of metalloproteinase 1 and TGF­ß1), pro­inflammatory cytokines (TNF­α, IL­1ß and IL­6) and oxidative stress­associated enzymes (malondialdehyde, superoxide dismutase and glutathione peroxidase) were measured in mice with MAFLD. The expression levels of genes associated with the HIPPO pathway were also measured. In vivo experiments using a specific inhibitor of HIPPO signalling were performed to verify the role of this pathway in the effects of PAR. PAR exerted beneficial effects on liver injury, lipid metabolism, fibrosis, inflammation and oxidative stress in mice with MAFLD, which was mediated by activation of the HIPPO pathway.

The effect of Guanxin Shutong capsule on alleviating the myocardial fibrosis in heart failure rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Guanxin Shutong (GXST) capsule is a renowned traditional Chinese medicine widely used for the treatment of cardiovascular diseases in the clinic. However, no pharmacological experimental studies of GXST has been reported on the treatment of pressure overload-induced heart failure. This study aimed to investigate the effects of GXST capsule on ameliorating myocardial fibrosis conditions in pressure overload-induced heart failure rats. MATERIAL AND METHODS: Rats were randomly divided into 6 groups: Normal group, Model group, GXST-treated group at a dose of 0.5 g/kg, 1 g/kg, 2 g/kg, respectively, and digoxin positive control group at a dose of 1 mg/kg. After 4 weeks of administration, cardiac function was evaluated by echocardiography. Cardiac injury and fibrotic conditions were evaluated by H&E staining, Masson staining, and Sirius Red staining. Myocardial fibrosis was evaluated by immunohistochemistry staining and Western blot. RESULTS: GXST significantly inhibited cardiac fibrosis, reduced the excessive deposition of collagen, and finally improved cardiac function. GXST reversed ventricular remodeling might be through the TGF-ß/Smad3 pathway. CONCLUSION: GXST capsule demonstrated a strong anti-fibrosis effect in heart failure rats by inhibiting the TGF-ß/Smad3 signaling pathway.

Huoxin Pill inhibits isoproterenol-induced transdifferentiation and collagen synthesis in cardiac fibroblasts through the TGF-ß/Smads pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The abnormal proliferation and differentiation of cardiac fibroblasts (CFs) are universally regarded as the key process for the progressive development of cardiac fibrosis following various cardiovascular diseases. Huoxin Pill (Concentrated pill, HXP) is a Chinese herbal formula for treating coronary heart disease. However, the cellular and molecular mechanisms of HXP in the treatment of myocardial fibrosis are still unclear. AIM OF THE STUDY: To investigate the effects of HXP on CFs transdifferentiation and collagen synthesis under isoproterenol (ISO) conditions, as well as the potential mechanism of action. MATERIALS AND METHODS: In vivo, we established a rat model of cardiac fibrosis induced by ISO, and administered with low or high dose of HXP (10 mg/kg/day or 30 mg/kg/day). The level of α-SMA was detected by immunohistochemistry examination, and combined with RNA-sequencing analysis to determine the protective effect of HXP on myocardial fibrosis rats. In vitro, by culturing primary rat CFs, we examined the effects of HXP on the proliferation and transdifferentiation of CFs using CCK8, scratch wound healing and immunofluorescence assays. Western blot was used to determine protein expression. RESULTS: The findings revealed that HXP protects against ISO-induced cardiac fibrosis and CFs transdifferentiation in rats. RNA-sequencing and pathway analyses demonstrated 238 or 295 differentially expressed genes (DEGs) and multiple enriched signal pathways, including transforming growth factor-beta (TGF-ß) receptor signaling activates Smads, downregulation of TGF-ß receptor signaling, signaling by TGF-ß receptor complex, and collagen formation under treatment with low or high-dose of HXP. Moreover, HXP also markedly inhibited ISO-induced primary rat CFs proliferation, transdifferentiation, collagen synthesis and the upregulation of TGF-ß1 and phosphorylated Smad2/3 protein expression. CONCLUSION: HXP suppresses ISO-induced CFs transdifferentiation and collagen synthesis, and it may exert these effects in part by inhibiting the activation of the TGF-ß/Smads pathway. This may be a new therapeutic tool for cardiac fibrosis.

Protocol for in vitro skin fibrosis model to screen the biological effects of antifibrotic compounds.

Controversies remain over the standard procedures for the modeling of skin fibrosis and its use in in vitro testing of different drugs. Here, we report a reproducible protocol for producing a skin fibrosis model using human dermal fibroblasts seeded in collagen hydrogel. Detailed procedures for the fabrication of cell/hydrogel constructs, fibrosis induction, protein extraction for western blotting analysis are presented along with how this model can be employed for investigating the possible anti-fibrotic functions of certain chemical compounds.

Taohong siwu decoction attenuates myocardial fibrosis by inhibiting fibrosis proliferation and collagen deposition via TGFBR1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial fibrosis after myocardial infarction (MI) leads to cardiac remodeling and loss of function. Taohong siwu decoction (THSWD), a well-known traditional Chinese medicinal prescription, has been clinically used to treat various cardiovascular and cerebrovascular diseases, but its potential functions in myocardial fibrosis after MI remain uncharacterized. AIM OF THE STUDY: The purpose of current study was to explore the potential mechanism action and anti-myocardial fibrosis effects of treatment with THSWD in vivo and in vitro. MATERIALS AND METHODS: Mouse underwent ligation of coronary artery to induce MI and divided equally into the sham group, model group and THSWD treatment groups. After 4 weeks, the effects of THSWD treatment on cardiac function were estimated by echocardiography. HE staining was used to detect the pathologic changes and Masson trichrome staining was used to estimate tissue fibrosis. To further explore the regulatory molecular mechanisms of THSWD, transcriptome analysis was performed. Furthermore, in vitro, we investigated the effect of THSWD on cell proliferation and collagen deposition in primary cardiac fibrosis cells and its possible mechanism of action. Overexpression of TGFBR1 was achieved by infection with an adenovirus vector encoding TGFBR1. RESULTS: Treatment with THSWD significantly decreased myocardial fibrosis and recovered cardiac function in the post-MI mouse. The transcriptomics data imply that the TGF-ß pathway might be a target in the anti-fibrosis effect of THSWD. THSWD inhibits TGF-ß1-induced proliferation of primary cardiac fibroblasts. THSWD decreased collagen expression and TGFBR1 and Smad2/3 phosphorylation. Moreover, the inhibitory effect of THSWD on CFs proliferation and collagen deposition, as well as TGFBR1 signaling pathway-associated proteins expression was partially abrogated by overexpression of TGFBR1. CONCLUSION: Collectively, the results implicate that THSWD attenuates myocardial fibrosis by inhibiting fibrosis proliferation and collagen deposition via inhibiting TGFBR1, and might be a potential therapeutic agent for treatment of myocardial fibrosis post-MI.

Untargeted metabolomics and lipidomics uncovering the cardioprotective effects of Huanglian Jiedu Decoction on pathological cardiac hypertrophy and remodeling.

ETHNOPHARMACOLOGICAL RELEVANCE: As a classic herbal prescription, Huanglian Jiedu Decoction (HLJDD) exhibits positive effects against cardiac dysfunction. However, its cardioprotective effects and potential mechanism(s) of action still need to be systematically investigated. AIM OF THE STUDY: This study aimed to reveal the underlying therapeutic mechanism of HLJDD on transverse aortic constriction (TAC)-induced pathological cardiac hypertrophy and remodeling. MATERIALS AND METHODS: TAC-induced cardiac hypertrophy and remodeling mice model was established to evaluate the therapeutic effects of HLJDD. Serum untargeted metabolomics and lipidomic profiling were performed using ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry coupled with multivariate statistical analyses. RESULTS: Oral administration of HLJDD (2.5 g/kg/day, 5.0 g/kg/day) significantly improved the heart morphology, enhanced the heart function, and alleviated the accumulation of fibrosis in the interstitial space and the infiltration of inflammatory cells in TAC-stimulated mice. Serum untargeted metabolomics analysis showed that significant alterations were observed in metabolic signatures between the TAC-model and sham group. Principal component analysis and orthogonal partial least-squares discriminant analysis screened 59 differential metabolic features and 13 metabolites were identified. The disturbed metabolic pathways in TAC group mainly related to lipid metabolism. Further serum lipidomic profiling showed that most lipids including cholesterol esters, ceramides, glycerides, fatty acids and phospholipids were decreased in TAC group and these alterations were reversed after HLJDD intervention. CONCLUSION: HLJDD alleviates TAC-induced pathological cardiac hypertrophy and remodeling, and its potential therapeutic mechanism involves the regulation of lipid metabolism.

Inhibition of proliferation-linked signaling cascades with atractylenolide I reduces myofibroblastic phenotype and renal fibrosis.

Renal fibrosis is a frequent axis contributing to the occurrence of end-stage nephropathy. Previously, it has been reported that atractylenolide Ⅰ (ATL-1), a natural compound extracted from Atractylodes macrocephala, has anti-cancer and antioxidant effects. However, the renal anti-fibrotic effects of action remain unclear. In this study, the anti-fibrotic effects of ATL-1 were examined in fibroblasts, tubular epithelial cells (TECs) triggered by TGF-ß1 in vitro, and using a unilateral ureteral obstruction (UUO) mouse model in vivo. We found that ATL-1 represses the myofibroblastic phenotype and fibrosis development in UUO kidneys by targeting the fibroblast-myofibroblast differentiation (FMD), as well as epithelial-mesenchymal transition (EMT). The anti-fibrotic effects of ATL-1 were associated with reduced cell growth in the interstitium and tubules, leading to suppression of the proliferation-linked cascades activity consisting of JAK2/STAT3, PI3K/Akt, p38 MAPK, and Wnt/ß-catenin pathways. Besides, ATL-1 treatment repressed TGF-ß1-triggered FMD and the myofibroblastic phenotype in fibroblasts by antagonizing the activation of proliferation-linked cascades. Likewise, TGF-ß1-triggered excessive activation of the proliferation-linked signaling in TECs triggered EMT. The myofibroblastic phenotype was repressed by ATL-1. The anti-fibrotic and anti-proliferative effects of ATL-1 were linked to the inactivation of Smad2/3 signaling, partially reversing FMD, as well as EMT and the repression of the myofibroblastic phenotype. Thus, the inhibition of myofibroblastic phenotype and fibrosis development in vivo and in vitro through proliferation-linked cascades of ATL-1 makes it a prospective therapeutic bio-agent to prevent renal fibrosis.

The Mineralocorticoid Receptor Antagonist Eplerenone Suppresses Interstitial Fibrosis in Subcutaneous Adipose Tissue in Patients With Type 2 Diabetes.

Activation of the mineralocorticoid receptor (MR) may promote dysfunctional adipose tissue in patients with type 2 diabetes, where increased pericellular fibrosis has emerged as a major contributor. The knowledge of the association among the MR, fibrosis, and the effects of an MR antagonist (MRA) in human adipocytes remains very limited. The present substudy, including 30 participants, was prespecified as part of the Mineralocorticoid Receptor Antagonist in Type 2 Diabetes (MIRAD) trial, which randomized patients to either high-dose eplerenone or placebo for 26 weeks. In adipose tissue biopsies, changes in fibrosis were evaluated by immunohistological examination and by the expression of mRNA and protein markers of fibrosis. Treatment with an MRA reduced pericellular fibrosis, synthesis of the major subunits of collagen types I and VI, and the profibrotic factor α-smooth muscle actin compared with placebo in subcutaneous adipose tissue. Furthermore, we found decreased expression of the MR and downstream molecules neutrophil gelatinase-associated lipocalin, galectin-3, and lipocalin-like prostaglandin D2 synthase with an MRA. In conclusion, we present original data demonstrating reduced fibrosis in adipose tissue with inhibition of the MR, which could be a potential therapeutic approach to prevent the extracellular matrix remodeling of adipose tissue in type 2 diabetes.

Protective effects of propolis on hepatic steatosis and fibrosis among patients with nonalcoholic fatty liver disease (NAFLD) evaluated by real-time two-dimensional shear wave elastography: A randomized clinical trial.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, while no drugs have been approved for its treatment. The pieces of evidence indicate that propolis as a novel anti-inflammatory agent might be a promising candidate to treat NAFLD. We aimed to evaluate the efficacy of propolis on hepatic steatosis and fibrosis in patients with NAFLD. This randomized clinical trial was conducted on 54 patients with NAFLD. Patients were randomly assigned to receive propolis tablets at a dose of 250 mg twice daily for 4 months or placebo. The improvement in hepatic steatosis and fibrosis was evaluated using two-dimensional shear wave elastography. Improvement in the hepatic steatosis was significantly higher in the propolis group than the placebo group, even after adjustment for baseline value and changes in weight, energy intake, and physical activity (odds ratio [OR]: 5.67; 95% confidence intervals [CI]: 1.41-22.8; p = .014). A significant reduction was observed on the liver stiffness in the propolis group (-0.65 ± 0.56 kPa; p = .001), whereas it increased in the placebo group (0.27 ± 0.59 kPa; p = .037). Also, the intake of propolis significantly decreased high-sensitivity C-reactive protein (hs-CRP) levels compared with the placebo group (-0.371; 95%CI: -0.582 to -0.16 mg/L; p = .01). Changes in serum levels of fasting blood sugar, alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, cholesterol, and triglyceride did not differ significantly between the two groups (p > .05). There was no significant improvement in insulin resistance in both groups (p > .05). Propolis seems to have protective effects on hepatic steatosis and fibrosis and to reduce the serum levels of hs-CRP in patients with NAFLD.

Diagnosis and management of iron deficiency in chronic inflammatory conditions (CIC): is too little iron making your patient sick?

While iron deficiency remains the most common cause of anemia worldwide, low iron stores are associated with symptoms regardless of the presence of typical microcytic, hypochromic anemia and may be hard to recognize in patients with concurrent inflammation. Diagnosing and treating iron deficiency become more of a challenge because markers of iron status are influenced by low-grade inflammation present in common conditions, such as chronic kidney disease, cirrhosis, or heart failure. Here I present a pragmatic way of interpreting diagnostic lab tests to help clinicians recognize patients who are most likely to benefit from iron supplementation, choose between oral and parenteral administration, and make personalized decisions when patients do not fit usual guidelines.