Small molecule inhibitors of epithelial-mesenchymal transition for the treatment of cancer and fibrosis.

Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial-mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc-finger E-box-binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor-ß1, RAC-α serine/threonine-protein kinase, Wnt, nuclear factor-kappa B, peroxisome proliferator-activated receptor, Notch, and RAS), RNA-binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

Microbiome-metabolomics reveals gut microbiota associated with glycine-conjugated metabolites and polyamine metabolism in chronic kidney disease.

Dysbiosis of the gut microbiome and related metabolites in chronic kidney disease (CKD) have been intimately associated with the prevalence of cardiovascular diseases. Unfortunately, thus far, there is a paucity of sufficient knowledge of gut microbiome and related metabolites on CKD progression partly due to the severely limited investigations. Using a 5/6 nephrectomized (NX) rat model, we carried out 16S rRNA sequence and untargeted metabolomic analyses to explore the relationship between colon's microbiota and serum metabolites. Marked decline in microbial diversity and richness was accompanied by significant changes in 291 serum metabolites, which were mediated by altered enzymatic activities and dysregulations of lipids, amino acids, bile acids and polyamines metabolisms. Interestingly, CCr was directly associated with some microbial genera and polyamine metabolism. However, SBP was directly related to certain microbial genera and glycine-conjugated metabolites in CKD rats. Administration of poricoic acid A (PAA) and Poria cocos (PC) ameliorated microbial dysbiosis as well as attenuated hypertension and renal fibrosis. In addition, treatments with PAA and PC lowered serum levels of microbial-derived products including glycine-conjugated compounds and polyamine metabolites. Collectively, the present study confirmed the CKD-associated gut microbial dysbiosis and identified a novel dietary and therapeutic strategy to improve the gut microbial dysbiosis and the associated metabolomic disorders and retarded the progression of kidney disease in the rat model of CKD.

Aryl hydrocarbon receptor activation mediates kidney disease and renal cell carcinoma.

The aryl hydrocarbon receptor (AhR) is a well-known ligand-activated cytoplasmic transcription factor that contributes to cellular responses against environmental toxins and carcinogens. AhR is activated by a range of structurally diverse compounds from the environment, microbiome, natural products, and host metabolism, suggesting that AhR possesses a rather promiscuous ligand binding site. Increasing studies have indicated that AhR can be activated by a variety of endogenous ligands and induce the expression of a battery of genes. AhR regulates a variety of physiopathological events, including cell proliferation, differentiation, apoptosis, adhesion and migration. These new roles have expanded our understanding of the AhR signalling pathways and endogenous metabolites interacting with AhR under homeostatic and pathological conditions. Recent studies have demonstrated that AhR is linked to cardiovascular disease (CVD), chronic kidney disease (CKD) and renal cell carcinoma (RCC). In this review, we summarize gut microbiota-derived ligands inducing AhR activity in patients with CKD, CVD, diabetic nephropathy and RCC that may provide a new diagnostic and prognostic approach for complex renal damage. We further highlight polyphenols from natural products as AhR agonists or antagonists that regulate AhR activity. A better understanding of structurally diverse polyphenols and AhR biological activities would allow us to illuminate their molecular mechanism and discover potential therapeutic strategies targeting AhR activation.

Dietary natural flavonoids treating cancer by targeting aryl hydrocarbon receptor.

The role of aryl hydrocarbon receptor (AhR) as a ligand-activated transcription factor in the field of cancer has gradually been unveiled. A strong body of evidence indicated that AhR is implicated in cell proliferation and apoptosis, immune metabolism and other processes, which further affected tumor growth, survival, migration, and invasion. Therefore, AhR targeted therapy may become a new method for cancer treatment and provide a new direction for clinical tumor treatment. Astonishingly, the largest source of exposure of animals and humans to AhR ligands (synthetic and natural) comes from the diet. Myriad studies have described that various natural dietary chemicals can directly activate and/or inhibit the AhR signaling pathway. Of note, numerous natural products contribute to AhR active, of which dietary flavonoids are the largest class of natural AhR ligands. As interest in AhR and its ligands increases, it seems sensible to summarize current research on these ligands. In this review, we highlight the role of AhR in tumorigenesis and focus on the double effect of AhR in cancer therapy. We explored the molecular mechanism of AhR ligands on cancer through a few AhR agonists/antagonists currently in clinical practice. Ultimately, we summarize and highlight the latest progression of dietary flavonoids as AhR ligands in cancer inhibition, including the limitations and deficiencies of it in clinical research. This review will offer a comprehensive understanding of AhR and its dietary ligands which may dramatically pave the way for targeted cancer treatment.

Pharmacokinetics of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside in rat using ultra-performance LC-quadrupole TOF-MS.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG) from Polygoni multiflori has been demonstrated to possess a variety of pharmacological activities, including antioxidant, anti-inflammatory and hepatoprotective activities. Ultra-performance LC-quadrupole TOF-MS with MS Elevated Energy data collection technique and rapid resolution LC with diode array detection and ESI multistage MS(n) methods were developed for the pharmacokinetics, tissue distribution, metabolism, and excretion studies of THSG in rats following a single intravenous or oral dose. The three metabolites were identified by rapid resolution LC-MS(n). The concentrations of the THSG in rat plasma, bile, urine, feces, or tissue samples were determined by ultra-performance LC-MS. The results showed that THSG was rapidly distributed and eliminated from rat plasma. After the intravenous administration, THSG was mainly distributing in the liver, heart, and lung. For the rat, the major distribution tissues after oral administration were heart, kidney, liver, and lung. There was no long-term storage of THSG in rat tissues. Total recoveries of THSG within 24 h were low (0.1% in bile, 0.007% in urine, and 0.063% in feces) and THSG was excreted mainly in the forms of metabolites, which may resulted from biotransformation in the liver.

[Chemical constituents of surface layer of Poria cocos and their pharmacological properties (I)].

The surface layer of the sclerotia of Poria cocos, named Fu-Ling-Pi, is used as a diuretic in traditional Chinese medicine to treat edema and urinary dysfunction. Recent studies have showed that the triterpenes (lanostane and 3,4-secolanostane skeletons) and polysaccharides (beta-pachyman) are the main components of Fu-Ling-Pi and they exhibited various biological activities, such as anti-tumor, antibacterial and antioxidant, etc. This review was focused on the chemistry, pharmacology, and clinical uses of this drug and it may provide scientific foundation for further development and utilization of Fulingpi.

Small molecules as a source for acute kidney injury therapy.

Acute kidney injury (AKI) is a sudden loss of kidney function that causes a rise in serum creatinine and a decrease in urine output, which leads to high morbidity and mortality. However, effective therapeutic drugs have not yet been developed due to the poor understanding of the cellular and molecular mechanisms of AKI. Recent studies have revealed that AKI leads to renal disorders, including inflammation, cell apoptosis, oxidative stress, mitochondrial dysfunction and autophagy, and multiple signaling pathways are involved in these disorders during the pathogenesis of AKI, which suggests that drugs specifically targeting these signaling pathways may be effective in preventing and treating AKI. In addition, a great number of small molecules show a therapeutic effect on AKI by targeting these signaling pathways and may be promising therapeutic drugs in the treatment of AKI. Moreover, an in-depth analysis of failed clinical trials is carried out to find out an effective strategy for AKI therapy. Taken together, this review focuses on the cellular and molecular mechanisms of AKI and the small molecules that alleviate AKI, which will provide new insight into AKI therapy.

The Angelica dahurica: A Review of Traditional Uses, Phytochemistry and Pharmacology.

Angelica dahurica (A. dahurica) root is a famous edible medicinal herb that has been used in China for thousands of years. To date, more than 300 chemical constituents have been discovered from A. dahurica. Among these ingredients, coumarins and volatile oils are the major active compounds. Moreover, a few other compounds have also been isolated from the root of A. dahurica, such as alkaloids, phenols, sterols, benzofurans, polyacetylenes and polysaccharides. Modern pharmacological studies demonstrated that the root of A. dahurica and its active components displayed various bioactivities such as anti-inflammation, anti-tumor, anti-oxidation, analgesic activity, antiviral and anti-microbial effects, effects on the cardiovascular system, neuroprotective function, hepatoprotective activity, effects on skin diseases and so on. Based on these studies, this review focused on the research publications of A. dahurica and aimed to summarize the advances in the traditional uses, phytochemistry and pharmacology which will provide reference for the further studies and applications of A. dahurica.

Small molecules against the origin and activation of myofibroblast for renal interstitial fibrosis therapy.

Renal interstitial fibrosis (RIF) is a common pathological response in a broad range of prevalent chronic kidney diseases and ultimately leads to renal failure and death. Although RIF causes a high morbi-mortality worldwide, effective therapeutic drugs are urgently needed. Myofibroblasts are identified as the main effector during the process of RIF. Multiple types of cells, including fibroblasts, epithelial cells, endothelial cells, macrophages and pericytes, contribute to renal myofibroblasts origin, and lots of mediators, including signaling pathways (Transforming growth factor-ß1, mammalian target of rapamycin and reactive oxygen species) and epigenetic modifications (Histone acetylation, microRNA and long non-coding RNA) are participated in renal myofibroblasts activation during renal fibrogenesis, suggesting that these mediators may be the promising targets for treating RIF. In addition, many small molecules show profound therapeutic effects on RIF by suppressing the origin and activation of renal myofibroblasts. Taken together, the review focuses on the mechanisms of the origin and activation of renal myofibroblasts in RIF and the small molecules against them improving RIF, which will provide a new insight for RIF therapy.

MicroRNAs in organ fibrosis: From molecular mechanisms to potential therapeutic targets.

Fibrosis is caused by chronic tissue injury and characterized by the excessive deposition of extracellular matrix (ECM) that ultimately results in organ failure and death. Owing to lacking of effective treatment against tissue fibrosis, it causes a high morbidity and mortality worldwide. Thus, it is of great importance to find an effective therapy strategy for the treatment of fibrosis. MicroRNAs (miRNAs) play vital roles in many biological processes by targeting downstream genes. Numerous studies demonstrated that miRNAs served as biomarkers of various diseases, suggesting the potential therapeutic targets for diseases. It was recently reported that miRNAs played an important role in the development of organ fibrosis, which showed a promising prospect against fibrosis by targeting intervention. Here, we summarize the roles of miRNAs in the process of organ fibrosis, including liver, lung, heart and kidney, and highlight miRNAs being novel therapeutic targets for organ fibrosis.

Identification of endogenous 1-aminopyrene as a novel mediator of progressive chronic kidney disease via aryl hydrocarbon receptor activation.

BACKGROUND AND PURPOSE: Increasing evidence has indicated that the high risk of cardiovascular disease in chronic kidney disease (CKD) patients cannot be sufficiently explained by classic risk factors. EXPERIMENTAL APPROACH: Based on the least absolute shrinkage and selection operator method, we identified significantly altered renal tissue metabolites during progressive CKD in a 5/6 nephrectomized rat model and in CKD patients. KEY RESULTS: Six aryl-containing metabolites (ACMs) were significantly increased from Week 1 to Week 20. They were associated with the activation of aryl hydrocarbon receptor (AhR) and its target genes including CYP1A1, CYP1A2 and CYP1B1, which were further validated by molecular docking. Our study further demonstrated that AhR signalling could be activated by ACM in patients with idiopathic membranous nephropathy, diabetic nephropathy and IgA nephropathy. Most importantly, 1-aminopyrene (AP) showed strong positive and negative correlation with serum creatinine and creatinine clearance, respectively. AP significantly up-regulated the mRNA expressions of AhR and its three target genes in both mice and NRK-52E cells, while this effect was partially weakened in AhR small hairpin RNA-treated mice and NRK-52E cells. Furthermore, dietary flavonoid supplementation ameliorated CKD and renal fibrosis through partially inhibiting the AhR activity via lowering the ACM levels. The antagonistic effect of flavonoids on AhR was deeply influenced by the number and location of hydroxyl and glycosyl groups. CONCLUSION AND IMPLICATIONS: We uncovered that endogenous AP is a novel mediator of CKD progression via AhR activation; thus, AhR might serve as a promising target for CKD treatment.

The Matrix Metalloproteinase-13 Inhibitor Poricoic Acid ZI Ameliorates Renal Fibrosis by Mitigating Epithelial-Mesenchymal Transition.

SCOPE: Fibrosis plays a key role in the progression of various diseases. Matrix metalloproteinases (MMPs) are important for epithelial-mesenchymal transition (EMT), which contributes to organ fibrosis. Four new poricoic acids are identified, poricoic acid ZI, ZJ, ZK, and ZL, as novel MMP inhibitors from edible mushroom Poria cocos. METHODS: Molecular docking, siRNA techniques, TGF-ß1-treated renal cells, and unilateral ureteral obstructed (UUO) mice are used to explore the potential efficacy of the novel MMP inhibitors in mitigating the fibrotic process. RESULTS: Treatment with four poricoic acids downregulates profibrotic protein expression in TGF-ß1-induced HK-2 cells. Similar results are observed in NRK-52E and NRK-49F cells, indicating that poricoic acids can suppress EMT. Furthermore, both in vitro and in vivo experiments demonstrate that poricoic acid ZI (PZI) exerts a stronger inhibitory effect on protein expression and enzymatic activity of MMP-13 than the other three compounds, which is consistent with the docking results. The inhibitory effect of PZI on MMP-13 is partially attenuated by MMP-13 RNAi in HK-2 cells and UUO mice. CONCLUSIONS: The findings indicate that as a specific MMP-13 inhibitor, PZI attenuates EMT and renal fibrosis. Therefore, the MMP-13 inhibitor PZI can be a novel therapeutic candidate for limiting EMT and renal fibrosis.

Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/AxlNFκB/Nrf2 axis.

Renal ischemia-reperfusion injury (IRI) is a complex syndrome, which causes chronic kidney disease (CKD) after recovery from IRI-mediated acute kidney injury (AKI). There is no single therapy that could effectively prevent the renal injury after ischemia. In this study, the effects of melatonin or poricoic acid A (PAA) and their combination were investigated in protecting against AKI-to-CKD transition in rats and hypoxia/reoxygenation (H/R)-induced injury in cultured renal NRK-52E cells. Melatonin and PAA significantly reduced the magnitude of rise in serum creatinine and urea levels in IRI rats at days 3 and 14. Our results further showed that treatment with melatonin and PAA ameliorated renal fibrosis and podocyte injury by attenuating oxidative stress and inflammation via regulation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) pathways in IRI rats. Melatonin and PAA protected against AKI-to-CKD transition by regulating growth arrest-specific 6 (Gas6)/AxlNFκB/Nrf2 signaling cascade. Melatonin and PAA initiallyupregulated Gas6/Axl signaling to reduce oxidative stress and inflammation in AKI and subsequently downregulated Gas6/Axl signaling to attenuate renal fibrosis and progression to CKD. Melatonin and PAA inhibited expression of extracellular matrix proteins. Poricoic acid A enhances melatonin-mediated inhibition of AKI-to-CKD transition by the regulating Gas6/AxlNFκB/Nrf2 signaling cascade. Notably, our study first identified Axl as a promising therapeutic target for prevention of AKI-to-CKD transition.

Unilateral ureteral obstruction causes gut microbial dysbiosis and metabolome disorders contributing to tubulointerstitial fibrosis.

Chronic kidney disease (CKD) increases the risk and prevalence of cardiovascular disease (CVD) morbidity and mortality. Recent studies have revealed marked changes in the composition of the microbiome and the metabolome and their potential influence in renal disease and CVD via the accumulation of microbial-derived uremic toxins. However, the effect of unilateral ureteral obstruction (UUO) on the gut microbiome and circulating metabolites is unknown. Male Sprague-Dawley rats were randomized to UUO and sham-operated control groups. Renal histology, colonic microbiota, and plasma metabolites were examined two weeks later. We employed 16S rRNA sequence and untargeted metabolomic analyses to explore the changes in colonic microbiota and plasma metabolites and their relationship with tubulointerstitial fibrosis (TIF). The UUO rats exhibited tubular atrophy and dilatation, interstitial fibrosis and inflammatory cell infiltration in the obstructed kidney. UUO rats showed significant colonic enrichment and depletion of genera. Significant differences were identified in 219 plasma metabolites involved in lipid, amino acid, and bile acid metabolism, which were consistent with gut microbiota-related metabolism. Interestingly, tryptophan and its metabolites kynurenine, 5-hydroxytryptophan and 5-hydroxytryptamine levels, which were linked with TIF, correlated with nine specific genera. Plasma tryptophan level was positively correlated with Clostridium IV, Turicibacter, Pseudomonas and Lactobacillales, and negatively correlated with Oscillibacter, Blautia, and Intestinimonas, which possess the genes encoding tryptophan synthase (K16187), indoleamine 2,3-dioxygenase (K00463) and tryptophan 2,3-dioxygenase (K00453) and their corresponding enzymes (EC:1.13.11.52 and EC:1.13.11.11) that exacerbate TIF. In conclusion, UUO results in profound changes in the gut microbiome and circulating metabolites, events that contribute to the pathogenesis of inflammation and TIF.

Activated NF-κB/Nrf2 and Wnt/ß-catenin pathways are associated with lipid metabolism in CKD patients with microalbuminuria and macroalbuminuria.

Early diagnosis of CKD patients at risk for microalbuminuria or macroalbuminuria could facilitate clinical outcomes and long-term survival. Considering the few and limited efficacy of current biomarkers in early detection, we aim to discover plasma lipids that effectively predict the development of CKD paitents with microalbuminuria or macroalbuminuria. A total of 380 healthy controls and 1156 patients with CKD stages 3 to 5 were stratified by urine albumin-creatinine ratio as microalbuminuria (30-300 mg/g) and macroalbuminuria (>300 mg/g). Fasting plasma samples were determined by UPLC-HDMS based on lipidomics. Quantitative real-time polymerase chain reaction, Western blot and immunohistochemical analyses were used to validate the lipid metabolism-associated pathways. Pathway analysis demonstrated that these lipids were closely associated with PPARγ, inflammatory mediator regulation of TRP channels and RAS signaling, which were intimately involved in activated NF-κB and Nrf2 pathways. We further carried out pathway validation and demonstrated that NF-κB pathway was activated in patients with macroalbuminuria compared with CKD patients with microalbuminuria, while Nrf2-associated protein expression was downregulated, which was accompanied by the up-regulation of Wnt/ß-catenin signaling pathway. Four lipids including DTA, 5,8-TDA, GGD3 and DHA that showed great potential in the discrimination of CKD patients with microalbuminuria and healthy controls were selected by logistic regression analysis. Additionally, six lipid species including CDCA, glucosylceramide, GGD2, TTA, DHA and EDA that contributed to the discrimination of CKD patients with microalbuminuria and macroalbuminuria were selected by logistic LASSO regression Gangliosides were first identified and might be promising therapeutic targets for CKD patients with the different degree of albuminuria. Collectively, this study first demonstrates the association of plasma inflammation, oxidative stress, Wnt/ß-catenin and lipid metabolism in CKD patients with microalbuminuria and macroalbuminuria.

Natural Products as a Source for Antifibrosis Therapy.

Although fibrosis is a final pathological feature of many chronic diseases, few interventions are available that specifically target the pathogenesis of fibrosis. Natural products are becoming increasingly recognized as effective therapies for fibrosis. The highlights of common cellular and molecular mechanisms of fibrosis facilitate the discovery of effective antifibrotic drugs. We describe some new profibrotic mechanisms and corresponding therapeutic targets using natural products. Interleukin, ephrin-B2, Gas6/TAM, Wnt/ß-catenin, hedgehog pathway, PPARγ, lysophosphatidic acid, and CTGF are promising therapeutic targets. Natural products can target these mediators and inhibit chronic inflammation, myofibroblast activation, epithelial-mesenchymal transition, and extracellular matrix accumulation to alleviate fibrosis. Of note, natural products have the potential to inhibit fibrosis in one organ, simultaneously targeting fibrosis in multiple other organs, which provides us new strategies to find antifibrotic drugs.

Natural products for the prevention and treatment of kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is one of the common causes resulting in a high morbidity and mortality. Renal fibrosis is the main pathological features of CKD. Natural products have begun to gain widely popularity worldwide for promoting healthcare and preventing CKD, and have been used as a conventional or complementary therapy for CKD treatment. PURPOSE: The present paper reviewed the therapeutic effects of natural products on CKD and revealed the molecular mechanisms of their anti-fibrosis. METHODS: All the available information on natural products against renal fibrosis was collected via a library and electronic search (using Web of Science, Pubmed, ScienceDirect, Splinker, etc.). RESULTS: Accumulated evidence demonstrated that natural products exhibited the beneficial effects for CKD treatment and against renal fibrosis. This review presents an overview of the molecular mechanism of CKD and natural products against renal fibrosis, followed by an in-depth discussion of their molecular mechanism of natural products including isolated compounds and crude extracts against renal fibrosis in vitro and in vivo. A number of isolated compounds have been confirmed to retard renal fibrosis. CONCLUSION: The review provides comprehensive insights into pathophysiological mechanisms of CKD and natural products against renal fibrosis. Particular challenges are presented and placed within the context of future applications of natural products against renal fibrosis.

New insights into TGF-ß/Smad signaling in tissue fibrosis.

Transforming growth factor-ß1 (TGF-ß1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-ß signalings play different roles in fibrogenesis. TGF-ß1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-ß1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-ß1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-ß1/Smad pathway thereby protects against TGF-ß1-mediated fibrosis. This review presents an overview of the molecular mechanisms of TGF-ß/Smad signaling pathway in renal, hepatic, pulmonary and cardiac fibrosis, followed by an in-depth discussion of their molecular mechanisms of intervention effects both in vitro and in vivo. The role of TGF-ß/Smad signaling pathway in tumor or cancer is also discussed. Additionally, the current advances also highlight targeting TGF-ß/Smad signaling pathway for the prevention of tissue fibrosis. The review reveals comprehensive pathophysiological mechanisms of tissue fibrosis. Particular challenges are presented and placed within the context of future applications against tissue fibrosis.

Central role of dysregulation of TGF-ß/Smad in CKD progression and potential targets of its treatment.

Chronic kidney disease (CKD) has emerged as a major cause of morbidity and mortality worldwide. Interstitial fibrosis, glomerulosclerosis and inflammation play the central role in the pathogenesis and progression of CKD to end stage renal disease (ESRD). Transforming growth factor-ß1 (TGF-ß1) is the central mediator of renal fibrosis and numerous studies have focused on inhibition of TGF-ß1 and its downstream targets for treatment of kidney disease. However, blockade of TGF-ß1 has not been effective in the treatment of CKD patients. This may be, in part due to anti-inflammatory effect of TGF-ß1. The Smad signaling system plays a central role in regulation of TGF-ß1 and TGF-ß/Smad pathway plays a key role in progressive renal injury and inflammation. This review provides an overview of the role of TGF-ß/Smad signaling pathway in the pathogenesis of renal fibrosis and inflammation and an effective target of anti-fibrotic therapies. Under pathological conditions, Smad2 and Smad3 expression are upregulated, while Smad7 is downregulated. In addition to TGF-ß1, other pathogenic mediators such as angiotensin II and lipopolysaccharide activate Smad signaling through both TGF-ß-dependent and independent pathways. Smads also interact with other pathways including nuclear factor kappa B (NF-κB) to regulate renal inflammation and fibrosis. In the context of renal fibrosis and inflammation, Smad3 exerts profibrotic effect, whereas Smad2 and Smad7 play renal protective roles. Smad4 performs its dual functions by transcriptionally promoting Smad3-dependent renal fibrosis but simultaneously suppressing NF-κB-mediated renal inflammation via Smad7-dependent mechanism. Furthermore, TGF-ß1 induces Smad3 expression to regulate microRNAs and Smad ubiquitination regulatory factor (Smurf) to exert its pro-fibrotic effect. In conclusion, TGF-ß/Smad signaling is an important pathway that mediates renal fibrosis and inflammation. Thus, an effective anti-fibrotic therapy via inhibition of Smad3 and upregulation of Smad7 signaling constitutes an attractive approach for treatment of CKD.

Metabolomics in dyslipidemia.

Hyperlipidemia is an important public health problem with increased incidence and prevalence worldwide. Current clinical biomarkers, triglyceride, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol lack the necessary specificity and sensitivity and only increase significantly after serious dyslipidemia. Therefore, sensitive biomarkers are needed for hyperlipidemia. Hyperlipidemia-specific biomarkers would improve clinical diagnosis and therapeutic treatment at early disease stages. The aim of metabolomics is to identify untargeted and global small-molecule metabolite profiles from cells, biofluids, and tissues. This method offers the potential for a holistic approach to improve disease diagnoses and our understanding of underlying pathologic mechanisms. This review summarizes analytical techniques, data collection and analysis for metabolomics, and metabolomics in hyperlipidemia animal models and clinical studies. Mechanisms of hypolipemia and antilipemic drug therapy are also discussed. Metabolomics provides a new opportunity to gain insight into metabolic profiling and pathophysiologic mechanisms of hyperlipidemia.