Different clinical characteristics and outcomes of hypertrophic cardiomyopathy with and without hypertension: seeking the truth.

OBJECTIVE: To determine the different clinical characteristics and outcomes of hypertrophic cardiomyopathy (HCM) patients with and without hypertension (HT). METHODS: A total of 696 HCM patients were included in this study and all HCM diagnoses were confirmed by the genetic test. Patients were analyzed separately in the septal reduction therapy (SRT) cohort and the non-SRT cohort. The primary endpoint was cardiovascular death and the secondary endpoint was all-cause death. Outcome analyses were conducted to evaluate the associations between HT and outcomes in HCM. Medications before enrollment and at discharge were collected in the post-hoc analyses. RESULTS: HCM patients without HT were younger, had a lower body mass index, were more likely to have a family history of HCM, and had a smaller left ventricular (LV) end-diastolic diameter than those with HT in both cohorts. A thicker LV wall, a higher level of N-terminal pro-B-type natriuretic peptide, and a higher extent of LV late gadolinium enhancement were additionally observed in patients without HT in the non-SRT cohort. The presence of HT did not alter the distribution pattern of late gadolinium enhancement, as well as the constituent ratio of eight disease-causing sarcomeric gene variants in both cohorts. Outcome analyses showed that in the non-SRT cohort, patients without HT had higher risks of cardiovascular death (HR = 2.537, P = 0.032) and all-cause death (HR = 3.309, P = 0.032). While such prognostic divergence was not observed in the SRT cohort. Further post-hoc analyses in the non-SRT cohort found that patients without HT received fewer non-dihydropyridine calcium channel blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers before enrollment and at discharge. CONCLUSIONS: HCM patients without HT had worse clinical conditions and higher mortality than patients with HT overall, which may result from active medical therapy in HT patients. Active SRT may have a substantial de-risking effect on patients meeting the indications.

The alleviative effect of flavonol-type Nrf2 activator rhamnazin from Physalis alkekengi L. var. franchetii (Mast.) Makino on pulmonary disorders.

Rhamnazin (RN) is a flavonol isolated from the calyxes and fruits of Physalis alkekengi L. var. franchetii (Mast.) Makino, which has been used for treating pulmonary diseases in traditional Chinese medicine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a therapeutic target for pulmonary diseases. In the present study, the underlying mechanism and pharmacological effect of RN against pulmonary disorders are investigated. Human lung epithelial Beas-2B cell and RAW 264.7 murine macrophage-based cell models, and a cigarette smoke (CS)-induced pulmonary impairment mice model are adopted for investigation in vitro and in vivo. RN is identified to be an Nrf2 activator, which promotes Nrf2 dissociation from Keap1 via reacting with the Cys151 cysteine residue of Keap1, and suppresses Nrf2 ubiquitination. In addition, RN is able to attenuate toxicant-stimulated oxidative stress and inflammatory response in vitro. Importantly, RN significantly relieves CS-induced oxidative insult and inflammation, and RN-induced inhibition of inflammation is related to inhibition of nuclear transcription factor-κB (NF-κB) and induction of cell autophagy. In conclusion, our data indicate that RN is an activator of the Nrf2 pathway and evidently alleviates pulmonary disorders via restricting NF-κB activation and promoting autophagy. RN is a promising candidate for the therapy of pulmonary disorders.

Artocarmitin B enhances intracellular antioxidant capacity via activation of Nrf2 signaling pathway in human lung epithelial cells.

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in redox homeostasis. Activation of Nrf2 pathway by natural molecules effectively inhibits oxidants and toxicants-induced redox imbalance, and thus is able to intervene the onset and progression of many human diseases. In our previous study, a chalcone named as artocarmitin B (ACB), formed by artocarmitin A (ACA) and a trans-feruloyl substituent, was found to be a potential Nrf2 activator. In the present research, we found that ACB up-regulated the expressions of Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutamate-cysteine ligase, modifier subunit (GCLM), inhibited Nrf2 degradation and promoted Nrf2 translocation to the nucleus under non-toxic doses. Moreover, ACB enhanced intracellular antioxidant capability in human lung epithelial cells through up-regulating reduced glutathione (GSH) level. Furthermore, ACB-induced activation of Nrf2 was related to the kinase pathways, including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and protein kinase R-like endoplasmic reticulum kinase (PERK). In terms of activation of Nrf2 pathway, ACB was more potent than ACA and ferulic acid (FA) individually or in combination. Collectively, our results indicate that ACB is an novel Nrf2 activator and enhances intracellular antioxidant capacity in human lung epithelial cells.

Lignan and flavonoid support the prevention of cinnamon against oxidative stress related diseases.

BACKGROUND: Oxidative stress contributes to the pathogenesis of many human diseases. Cinnamon is a worldwide used spice, dietary supplement and traditional medicine, and is used for the therapy of oxidative stress related diseases. A well-established concept is that the functions of cinnamon preventing oxidative stress-induced diseases are attributed to the occurrence of cinnamaldehyde and its analogues. HYPOTHESIS: In our continuous searching of natural molecules with antioxidant capacity, we have found that cinnamaldehyde and its analogues in cinnamon are weak inhibitors of oxidative stress, and thus we speculate that there are novel and/or potent molecules inhibiting oxidative stress in cinnamon. STUDY DESIGN AND METHODS: A systemic phytochemical investigation of cinnamon using column chromatography was performed to identify the chemical constituents of cinnamon, and then their capacity of inhibiting oxidative stress and action of mechanism targeting Nrf2 pathway were investigated using diverse bioassay, including NAD(P)H: quinone reductase (QR) assay, immunoblot analysis, luciferase reporter gene assay, immunofluorescence and flow cytometry. RESULTS: Cinnamon improved the intracellular antioxidant capacity. A systemic phytochemical investigation of cinnamon gave the isolation of twenty-two chemical ingredients. The purified constituents were tested for their potential inhibitory effects against oxidative stress. Besides cinnamaldehyde analogues, a lignan pinoresinol (PRO) and a flavonol (-)-(2R,3R)-5,7-dimethoxy-3', 4'-methylenedioxy-flavan-3-ol (MFO) were firstly identified to be inhibitors of oxidative stress. Further study indicated that PRO and MFO activated Nrf2-mediated antioxidant response, and protected human lung epithelial cells against sodium arsenite [As(III)]-induced oxidative insults. CONCLUSION: The lignan PRO and the flavonoid MFO are two novel Nrf2 activators protecting tissues against oxidative insults, and these two constituents support the application of cinnamon as an agent against oxidative stress related diseases.

Protective effect of the ethanol extract from Ligusticum chuanxiong rhizome against streptozotocin-induced diabetic nephropathy in mice.

ETHNOPHARMACOLOGY RELEVANCE: Rhizome of Ligusticum chuanxiong Hort. (Abbreviated as LC) is a frequently prescribed component in plenty of traditional Chinese medicine (TCM) formulas which are used to treat diabetic nephropathy (DN). The aims of the present study are to investigate the protective effect of the ethanol extract of LC rhizome (EEL) against DN in vivo, evaluate its potential mechanism, and find the evidence supporting its enthopharmacological use as an anti-DN agent. MATERIALS AND METHODS: Hepa 1c1c7 murine hepatoma cells, human breast carcinoma MDA-MB-231 cells, human renal glomerular endothelial cells (HRGEC), and RAW 264.7 murine macrophages were adopted to test the effects of EEL and its active constituents on inhibitions of oxidative stress and inflammation in vitro. A streptozotocin (STZ) -induced DN C57BL/6 mice model was established and used to investigate the preventive effect of EEL against DN in vivo. RESULTS: EEL demonstrated potential inhibitory effects against oxidative stress and inflammation in vitro. Using a STZ-induced DN mice model, it has been found that EEL treatment significantly prevented STZ-induced increases of urine production, urinary albumin excretion (UAE) and urine albumin-to-creatinine ratio (UACR), and markedly attenuated STZ-induced renal damages (e.g. glomerulosclerosis and fibrosis). The predominant bioactive constituents, Z-ligustilide (LGT), ferulic acid (FA), and tetramethylpyrazine (TMP), were inhibitors of oxidative stress and inflammation through acting with Nrf2 and NF-κB pathways. CONCLUSIONS: EEL attenuates structural and functional damages of kidney in STZ-induced DN model in vivo, which might be related to the functions of EEL on inhibitions of oxidative stress and inflammation. These finding definitely supports the ethnopharmacological use of LC as an anti-DN agent.