Pomiferin targets SERCA, mTOR, and P-gp to induce autophagic cell death in apoptosis-resistant cancer cells, and reverses the MDR phenotype in cisplatin-resistant tumors in vivo.

Drug resistance in cancer has been classified as innate resistance or acquired resistance, which were characterized by apoptotic defects and ABC transporters overexpression respectively. Therefore, to preclude or reverse these resistance mechanisms could be a promising strategy to improve chemotherapeutic outcomes. In this study, a natural product from Osage Orange, pomiferin, was identified as a novel autophagy activator that circumvents innate resistance by triggering autophagic cell death via SERCA inhibition and activation of the CaMKKß-AMPK-mTOR signaling cascade. In addition, pomiferin also directly inhibited the P-gp (MDR1/ABCB1) efflux and reversed acquired resistance by potentiating the accumulation and efficacy of the chemotherapeutic agent, cisplatin. In vivo study demonstrated that pomiferin triggered calcium-mediated tumor suppression and exhibited an anti-metastatic effect in the LLC-1 lung cancer-bearing mouse model. Moreover, as an adjuvant, pomiferin potentiated the anti-tumor effect of the chemotherapeutic agent, cisplatin, in RM-1 drug-resistant prostate cancer-bearing mouse model by specially attenuating ABCB1-mediated drug efflux, but not ABCC5, thereby promoting the accumulation of cisplatin in tumors. Collectively, pomiferin may serve as a novel effective agent for circumventing drug resistance in clinical applications.

Skewed inflammation is associated with aberrant interleukin-37 signaling pathway in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a severe global burden on physical, physiological, and mental health. The role of IL-37, a fundamental inhibitor of immunity, in AD was herein explored. METHOD: Serum levels of IL-37 and T helper (Th) 2-related inflammatory mediators were quantified in subjects with or without AD. The expression of IL-37 receptors was determined by flow cytometry. Proteomics was employed to explore the serum protein profile and novel biomarkers. In vitro cell model, 3D-keratinocytes mimicking skin model, and the serum of subjects with or without AD were investigated to verify the proteomic results. RESULTS: AD patients were found to present with higher levels of total and specific IgE as well as Th2 inflammatory mediators compared with healthy controls (HC). IL-37 level and its receptor IL18Rɑ expression in AD patients were significantly decreased, together with increased population of eosinophils, indicating that the signaling of IL37/IL18Rɑ was dampened. In addition, proteomic analysis revealed a significantly differential protein profile of AD patients compared with HC. IL-37 showed the strongest negative correlation with involucrin, a keratinizing epithelia protein. IL-37 was verified to suppress induced involucrin expression in in vitro skin cell models. AD patients show a significantly higher serum concentration of involucrin compared with HC. Together, our results demonstrated that IL-37 plays a regulatory role in AD. Its deficiency may lead to the aberrant involucrin expression in AD. CONCLUSIONS: The dysregulation of serum protein and skin disruption in AD is related to the insufficiency of IL-37 and its attenuated anti-inflammatory signaling.

IL-37 Targets TSLP-Primed Basophils to Alleviate Atopic Dermatitis.

Atopic dermatitis (AD) represents a severe global burden on physical, physiological and mental health. Innate immune cell basophils are essential for provoking allergic inflammation in AD. However, the roles of novel immunoregulatory cytokine IL-37 in basophils remain elusive. We employed in vitro co-culture of human basophils and human keratinocyte HaCaT cells and an in vivo MC903-induced AD murine model to investigate the anti-inflammatory mechanism of IL-37. In the in vitro model, IL-37b significantly decreased Der p1-induced thymic stromal lymphopoietin (TSLP) overexpression in HaCaT cells and decreased the expression of TSLP receptor as well as basophil activation marker CD203c on basophils. IL-37 could also reduce Th2 cytokine IL-4 release from TSLP-primed basophils ex vivo. In the in vivo model, alternative depletion of basophils ameliorated AD symptoms and significantly lowered the Th2 cell and eosinophil populations in the ear and spleen of the mice. Blocking TSLP alleviated the AD-like symptoms and reduced the infiltration of basophils in the spleen. In CRISPR/Cas9 human IL-37b knock-in mice or mice with direct treatment by human IL-37b antibody, AD symptoms including ear swelling and itching were significantly alleviated upon MC903 challenge. Notably, IL-37b presence significantly reduced the basophil infiltration in ear lesions. In summary, IL-37b could regulate the TSLP-mediated activation of basophils and reduce the release of IL-4. The results, therefore, suggest that IL-37 may target TSLP-primed basophils to alleviate AD.

The Immuno-Modulatory Activities of Pentaherbs Formula on Ovalbumin-Induced Allergic Rhinitis Mice via the Activation of Th1 and Treg Cells and Inhibition of Th2 and Th17 Cells.

Allergic rhinitis (AR) is a highly prevalent allergic disease induced by immunoglobulin (Ig) E-mediated hypersensitivity reaction at the nasal epithelium against inhaled allergens. Previous studies have demonstrated that Pentaherbs formula (PHF), a modified herbal formula comprising five herbal medicines (Flos Lonicerae, Herba Menthae, Cortex Phellodendri, Cortex Moutan and Rhizoma Atractylodis), could suppress various immune effector cells to exert anti-inflammatory and anti-allergic effects in allergic asthma and atopic dermatitis. The present study aimed to further determine the anti-inflammatory activities of PHF in an ovalbumin (OVA)-induced AR BALB/c mouse model. Nasal symptoms such as sneezing and nose rubbing were recorded and the serum total IgE and OVA-specific IgG1, as well as interleukin (IL)-4, IL-5, IL-10, IL-13, chemokines CXCL9 CXCL10, and tumor necrosis factor (TNF)-α concentrations in nasal lavage fluid (NALF) were measured during different treatments. Effects of PHF on the expression of inflammatory mediators in the sinonasal mucosa were quantified using real-time QPCR. PHF was found to suppress allergic symptoms, infiltration of inflammatory cells, and hyperplasia of goblet cells in the nasal epithelium of the OVA-induced AR mice. PHF could reduce OVA-specific IgG1 level in serum, and TNF-α and IL-10 in nasal lavage fluid (NALF), significantly up-regulate the splenic regulatory T (Treg) cell level, increase the Type 1 helper T cell (Th1)/Type 2 helper T cell (Th2) ratio, and reduce the Th17 cells (all p < 0.05). PHF could also alleviate in situ inflammation in sinonasal mucosa of OVA-induced AR mice. In conclusion, oral treatment of PHF showed immuno-modulatory activities in the OVA-induced AR mice by regulating the splenic T cell population to suppress the nasal allergy symptoms and modulating inflammatory mediators, implicating that PHF could be a therapeutic strategy for allergic rhinitis.

The beneficial effects of Ganoderma lucidum on cardiovascular and metabolic disease risk.

CONTEXT: Various herbal medicines are thought to be useful in the management of cardiometabolic disease and its risk factors. Ganoderma lucidum (Curtis) P. Karst. (Ganodermataceae), also known as Lingzhi, has received considerable attention for various indications, including some related to the prevention and treatment of cardiovascular and metabolic disease by ameliorating major cardiovascular risk factors. OBJECTIVE: This review focuses on the major studies of the whole plant, plant extract, and specific active compounds isolated from G. lucidum in relation to the main risk factors for cardiometabolic disease. METHODS: References from major databases including PubMed, Web of Science, and Google Scholar were compiled. The search terms used were Ganoderma lucidum, Lingzhi, Reishi, cardiovascular, hypoglycaemic, diabetes, dyslipidaemia, antihypertensive, and anti-inflammatory. RESULTS: A number of in vitro studies and in vivo animal models have found that G. lucidum possesses antioxidative, antihypertensive, hypoglycaemic, lipid-lowering, and anti-inflammatory properties, but the health benefits in clinical trials are inconsistent. Among these potential health benefits, the most compelling evidence thus far is its hypoglycaemic effects in patients with type 2 diabetes or hyperglycaemia. CONCLUSIONS: The inconsistent evidence about the potential health benefits of G. lucidum is possibly because of the use of different Ganoderma formulations and different study populations. Further large controlled clinical studies are therefore needed to clarify the potential benefits of G. lucidum preparations standardised by known active components in the prevention and treatment of cardiometabolic disease.

Immobilization of cell membrane onto a glucose-Zn-based porous coordination polymer and its application to rapid screening of potentially active compounds from Vaccinium corymbosum L. leaves.

A novel glucose-Zn-based porous coordination polymer (PCP) was selected as a carrier of cell membranes (CMs) to fabricate CM-coated PCP (CMPCP) for rapid screening of potentially active compounds from natural products. The cell disruption and the amount of maximum CMs adsorbed on PCP were optimized according to the amount of immobilized protein. This new kind of matrix exhibited good reproducibility and stability, and was applied for fishing potentially active compounds from the extracts of Vaccinium corymbosum L. leaves (VCL). Using LC-MS/MS, chlorogenic acid and quercetin were identified as the potentially active compounds through comparison of normal and non-alcoholic fatty liver disease (NAFLD)-modeled CMPCP. Our results suggested that the proposed approach based on CMPCP was environmentally friendly, cost-effective, and convenient in terms of green porous material, stable protein loading capacity, and accessible operation process. The developed method could provide a promising platform for efficient drug discovery from natural product resources.Graphical abstract.

Method for Quantification of Ribonucleotides and Deoxyribonucleotides in Human Cells Using (Trimethylsilyl)diazomethane Derivatization Followed by Liquid Chromatography-Tandem Mass Spectrometry.

Investigation into intracellular ribonucleotides (RNs) and deoxyribonucleotides (dRNs) is important for studies of the mechanism of many biological processes, such as RNA and DNA synthesis and DNA repair, as well as metabolic and therapeutic efficacy of nucleoside analogues. However, current methods are still unsatisfactory for determination of nucleotides in complex matrixes. Here we describe a novel method for the determination of RN and dRN pools in cells based on fast derivatization with (trimethylsilyl)diazomethane (TMSD) followed by quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Derivatization was accomplished in 3 min, and each derivatized nucleotide not only had a sufficient retention on reversed-phase column by introduction of methyl groups but also exhibited a unique ion transition which consequently eliminated mutual interference in LC-MS/MS. Chromatographic separation was performed on a C18 column with a simple acetonitrile-water gradient elution system, which avoided contamination and ion suppression caused by ion-pairing reagents. The developed method was fully validated and applied to the analysis of RNs and dRNs in cell samples. Moreover, results demonstrated that the applicability of this method could be extended to nucleoside analogues and their metabolites and could facilitate many applications in future studies.

High-Throughput Immunological Analysis of Dictamni Cortex: Implication in the Quality Control of Herbal Medicine.

Quality inconsistency of herbal medicine is an obstacle that limits the extensive use and study of traditional Chinese medicine. Differences in environmental conditions and processing methods of herbal medicine often result in varying clinical outcomes in patients. Standard chemical markers used for the quality control (QC) of herbal medicine are usually the most abundant and characteristic components, which may not be therapeutically relevant or cannot comprehensively reflect the biological quality of the herbs. In view of this, a novel QC method for better assessment of herbal medicine has been developed via bioactivities analysis. Immunological activities of Dictamni Cortex, a typical herbal medicine for the treatment of various inflammatory diseases, from different geographical locations in China, were evaluated. Upon in vitro treatment of their water and ethanol extracts, distinct patterns of inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-10, IL-6, IL-12p70, IL-1ß, and chemokine CXCL8 were released from the lipopolysaccharides- and/or phytohaemagglutinin-stimulated human peripheral blood mononuclear cells (PBMC). Thus, in addition to the commonly used morphological, chemical, or DNA markers, the novel high-throughput profiling of inflammatory cytokines and chemokines of PBMC upon treatment with herbal extracts could be an important reference to help for the quality control of herbal medicine in the future.

Anti-Inflammatory Activities of Pentaherbs formula and Its Influence on Gut Microbiota in Allergic Asthma.

Allergic asthma is a highly prevalent airway inflammatory disease, which involves the interaction between the immune system, environmental and genetic factors. Co-relation between allergic asthma and gut microbiota upon the change of diet have been widely reported, implicating that oral intake of alternative medicines possess a potential in the management of allergic asthma. Previous clinical, in vivo, and in vitro studies have shown that the Pentaherbs formula (PHF) comprising five traditional Chinese herbal medicines Lonicerae Flos, Menthae Herba, Phellodendri Cortex, Moutan Cortex, and Atractylodis Rhizoma possesses an anti-allergic and anti-inflammatory potential through suppressing various immune effector cells. In the present study, to further investigate the anti-inflammatory activities of PHF in allergic asthma, intragastrical administration of PHF was found to reduce airway hyperresponsiveness, airway wall remodeling and goblet cells hyperplasia in an ovalbumin (OVA)-induced allergic asthma mice model. PHF also significantly suppressed pulmonary eosinophilia and asthma-related cytokines IL-4 and IL-33 in bronchoalveolar lavage (BAL) fluid. In addition, PHF modulated the splenic regulatory T cells population, up-regulated regulatory interleukin (IL)-10 in serum, altered the microbial community structure and the short chain fatty acids content in the gut of the asthmatic mice. This study sheds light on the anti-inflammatory activities of PHF on allergic asthma. It also provides novel in vivo evidence that herbal medicines can ameliorate symptoms of allergic diseases may potentially prevent the development of subsequent atopic disorder such as allergic asthma through the influence of the gut microbiota.

Natural Products from Chinese Medicines with Potential Benefits to Bone Health.

Osteoporosis is a progressive, systemic bone disorder characterized by loss of bone mass and microstructure, leading to reduced bone strength and increased risk of fracture. It is often associated with reduced quality of life and other medical complications. The disease is common in the aging population, particularly among postmenopausal women and patients who receive long-term steroidal therapy. Given the rapid growth of the aging population, increasing life expectancy, the prevalence of bone loss, and financial burden to the healthcare system and individuals, demand for new therapeutic agents and nutritional supplements for the management and promotion of bone health is pressing. With the advent of global interest in complementary and alternative medicine and natural products, Chinese medicine serves as a viable source to offer benefits for the improvement and maintenance of bone health. This review summarizes the scientific information obtained from recent literatures on the chemical ingredients of Chinese medicinal plants that have been reported to possess osteoprotective and related properties in cell-based and/or animal models. Some of these natural products (or their derivatives) may become promising leads for development into dietary supplements or therapeutic drugs.

Precision or Personalized Medicine for Cancer Chemotherapy: Is there a Role for Herbal Medicine.

Although over 100 chemotherapeutic agents are currently available for the treatment of cancer patients, the overall long term clinical benefit is disappointing due to the lack of effectiveness or severe side effects from these agents. In order to improve the therapeutic outcome, a new approach called precision medicine or personalized medicine has been proposed and initiated by the U.S. National Institutes of Health. However, the limited availability of effective medications and the high cost are still the major barriers for many cancer patients. Thus alternative approaches such as herbal medicines could be a feasible and less costly option. Unfortunately, scientific evidence for the efficacy of a majority of herbal medicines is still lacking and their development to meet FDA approval or other regulatory agencies is a big challenge. However, herbal medicines may be able to play an important role in precision medicine or personalized medicine. This review will focus on the existing and future technologies that could speed the development of herbal products for treatment of resistant cancer in individual patients. Specifically, it will concentrate on reviewing the phenotypic (activity based) rather than genotypic (mechanism based) approach to develop herbal medicine useful for personalized cancer chemotherapy.

Aberrant Expression of Bacterial Pattern Recognition Receptor NOD2 of Basophils and Microbicidal Peptides in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease, associated with basophil infiltration into skin lesions and Staphylococcus aureus (S. aureus)-induced inflammation. Pattern recognition receptors (PRRs), including microbicidal peptide human neutrophil α-defensins (HNP) and dermcidin, can exert immunomodulating activity in innate immunity and skin inflammation. We investigated the plasma concentration of HNP and dermcidin, the expression of bacterial toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors of basophils and plasma concentration and ex vivo induction of AD-related inflammatory cytokines and chemokines using ELISA and flow cytometry, in AD patients and control subjects. Plasma concentrations of HNP, dermcidin and AD-related Th2 chemokines CCL17, CCL22 and CCL27 were significantly elevated in AD patients compared with controls (all p < 0.05). Plasma concentrations of CCL27 and CCL22 were found to correlate positively with SCORing atopic dermatitis (SCORAD), objective SCORAD, % area affected, lichenification and disease intensity, and CCL27 also correlated positively with pruritus in AD patients (all p < 0.05). Protein expressions of NOD2 but not TLR2 of basophils were significantly down-regulated in AD patients compared with controls (p = 0.001). Correspondingly, there were lower ex vivo % inductions of allergic inflammatory tumor necrosis factor-α, IL-6 and CXCL8 from peripheral blood mononuclear cells upon NOD2 ligand S. aureus derived muramyl dipeptide stimulation in AD patients comparing with controls. The aberrant activation of bacterial PRRs of basophils and anti-bacterial innate immune response should be related with the allergic inflammation of AD.

New Potential Pharmacological Functions of Chinese Herbal Medicines via Regulation of Autophagy.

Autophagy is a universal catabolic cellular process for quality control of cytoplasm and maintenance of cellular homeostasis upon nutrient deprivation and environmental stimulus. It involves the lysosomal degradation of cellular components such as misfolded proteins or damaged organelles. Defects in autophagy are implicated in the pathogenesis of diseases including cancers, myopathy, neurodegenerations, infections and cardiovascular diseases. In the recent decade, traditional drugs with new clinical applications are not only commonly found in Western medicines, but also highlighted in Chinese herbal medicines (CHM). For instance, pharmacological studies have revealed that active components or fractions from Chaihu (Radix bupleuri), Hu Zhang (Rhizoma polygoni cuspidati), Donglingcao (Rabdosia rubesens), Hou po (Cortex magnoliae officinalis) and Chuan xiong (Rhizoma chuanxiong) modulate cancers, neurodegeneration and cardiovascular disease via autophagy. These findings shed light on the potential new applications and formulation of CHM decoctions via regulation of autophagy. This article reviews the roles of autophagy in the pharmacological actions of CHM and discusses their new potential clinical applications in various human diseases.

Effect of Phyllanthus amarus Extract on 5-Fluorouracil-Induced Perturbations in Ribonucleotide and Deoxyribonucleotide Pools in HepG2 Cell Line.

The aim of this study was to investigate the antitumor activities of Phyllanthus amarus (PHA) and its potential of herb-drug interactions with 5-Fluorouracil (5-FU). Cell viability, ribonucleotides (RNs) and deoxyribonucleotides (dRNs) levels, cell cycle distribution, and expression of thymidylate synthase (TS) and ribonucleotide reductase (RR) proteins were measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) method, flow cytometry and Western blot analysis, respectively. Our standardized PHA extract showed toxicity to HepG2 cells at high concentrations after 72 h exposure and induced G2/M cell cycle arrest. Combined use of 5-FU with PHA resulted in significant decreases in ATP, CTP, GTP, UTP and dTTP levels, while AMP, CMP, GMP and dUMP levels increased significantly compared with use of 5-FU alone. Further, PHA could increase the role of cell cycle arrest at S phase induced by 5-FU. Although PHA alone had no direct impact on TS and RR, PHA could change the levels of RNs and dRNs when combined with 5-FU. This may be due to cell cycle arrest or regulation of key enzyme steps in intracellular RNs and dRNs metabolism.

Effect of Rorrico, extracted from group of Chinese medicines, on influenza A and H1N1 infections.

OBJECTIVE: To investigate the therapeutic and preventive effects of Rorrico on influenza, especially influenza A viral infection, including swine flu (H1N1) in humans. METHODS: Eighty-nine subjects were recruited in Hong Kong and Macau, and divided into treatment group (TG) and prevention group (PG) based on their influenza A and swine flu symptoms. All subjects were prescribed Rorrico or placebo, and monitored by a Chinese medicine practitioner. Blood samples were collected before and after 7-day Rorrico or placebo treatment for laboratory investigations. RESULTS: After treatment, there were some full recoveries and obvious relief of onset symptoms in the TG. Blood test results showed that Rorrico produced (a) no adverse effects on subjects' renal and liver functions, muscle enzyme and hematological status, (b) no up-regulation of pro-inflammatory cytokines tumour necrosis factor-a and interleukin-18 in both TG and PG, (c) mild yet statistically significant elevation of plasma mannose-binding lectin (MBL) in PG. CONCLUSION: Rorrico has no up-regulating effect on the participants' immune response, or, equally likely, the immuno-modulatory effects of Rorrico do not non-specifically or unnecessarily promote inflammation when not required. It is possible that oral administration of Rorrico can promote hepatic synthesis of MBL in healthy PG subjects, thereby conferring increased protection against infection.

Skin autofluorescence associates with vascular calcification in chronic kidney disease.

OBJECTIVE: This study aims to evaluate the relationship between tissue advanced glycation end products, as reflected by skin autofluorescence, and vascular calcification in chronic kidney disease. APPROACH AND RESULTS: Three hundred patients with stage 3 to 5 chronic kidney disease underwent multislice computed tomography to estimate total coronary artery calcium score (CACS) and had tissue advanced glycation end product assessed using a skin autofluorescence reader. Intact parathyroid hormone (P<0.001) displaced estimated glomerular filtration rate as third most significant factor associated with skin autofluorescence after age (P<0.001) and diabetes mellitus (P<0.001) in multiple regression analysis. On univariate multinomial logistic regression analysis, every 1-U increase in skin autofluorescence was associated with a 7.43-fold (95% confidence intervals, 3.59-15.37; P<0.001) increased odds of having CACS ≥400 compared with those with zero CACS. Skin autofluorescence retained significance in predicting CACS ≥400 (odds ratio, 3.63; 95% confidence intervals, 1.44-9.18; P=0.006) when adjusting for age, sex, serum calcium, phosphate, albumin, C-reactive protein, lipids, blood pressure, estimated glomerular filtration rate, and intact parathyroid hormone but marginally lost significance when additionally adjusting for diabetes mellitus (odds ratio, 2.23; 95% confidence intervals, 0.81-6.14; P=0.1). Combination of diabetes mellitus and higher intact parathyroid hormone was associated with greater skin autofluorescence and CACS versus those without diabetes mellitus and having lower intact parathyroid hormone. CONCLUSIONS: Tissue advanced glycation end product, as reflected by skin autofluorescence, showed a significant novel association with vascular calcification in chronic kidney disease. These data suggest that increased tissue advanced glycation end product may contribute to vascular calcification in chronic kidney disease and diabetes mellitus and warrant further experimental investigation.

Effects of karanjin on cell cycle arrest and apoptosis in human A549, HepG2 and HL-60 cancer cells.

BACKGROUND: We have investigated the potential anticancer effects of karanjin, a principal furanoflavonol constituent of the Chinese medicine Fordia cauliflora, using cytotoxic assay, cell cycle arrest, and induction of apoptosis in three human cancer cell lines (A549, HepG2 and HL-60 cells). RESULTS: MTT cytotoxic assay showed that karanjin could inhibit the proliferation and viability of all three cancer cells. The induction of cell cycle arrest was observed via a PI (propidium iodide)/RNase Staining Buffer detection kit and analyzed by flow cytometry: karanjin could dose-dependently induce cell cycle arrest at G2/M phase in the three cell lines. Cell apoptosis was assessed by Annexin V-FITC/PI staining: all three cancer cells treated with karanjin exhibited significantly increased apoptotic rates, especially in the percentage of late apoptosis cells. CONCLUSION: Karanjin can induce cancer cell death through cell cycle arrest and enhance apoptosis. This compound may be effective clinically for cancer pharmacotherapy.

Effect of paricalcitol on left ventricular mass and function in CKD--the OPERA trial.

Vitamin D seems to protect against cardiovascular disease, but the reported effects of vitamin D on patient outcomes in CKD are controversial. We conducted a prospective, double blind, randomized, placebo-controlled trial to determine whether oral activated vitamin D reduces left ventricular (LV) mass in patients with stages 3-5 CKD with LV hypertrophy. Subjects with echocardiographic criteria of LV hypertrophy were randomly assigned to receive either oral paricalcitol (1 µg) one time daily (n=30) or matching placebo (n=30) for 52 weeks. The primary end point was change in LV mass index over 52 weeks, which was measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volume, echocardiographic measures of systolic and diastolic function, biochemical parameters of mineral bone disease, and measures of renal function. Change in LV mass index did not differ significantly between groups (median [interquartile range], -2.59 [-6.13 to 0.32] g/m(2) with paricalcitol versus -4.85 [-9.89 to 1.10] g/m(2) with placebo). Changes in LV volume, ejection fraction, tissue Doppler-derived measures of early diastolic and systolic mitral annular velocities, and ratio of early mitral inflow velocity to early diastolic mitral annular velocity did not differ between the groups. However, paricalcitol treatment significantly reduced intact parathyroid hormone (P<0.001) and alkaline phosphatase (P=0.001) levels as well as the number of cardiovascular-related hospitalizations compared with placebo. In conclusion, 52 weeks of treatment with oral paricalcitol (1 µg one time daily) significantly improved secondary hyperparathyroidism but did not alter measures of LV structure and function in patients with severe CKD.