Blood-Pressure-Lowering and Endothelium-Dependent Vasorelaxant Effects of Nutgall Tree in Rats.

Hypertension is the crucial modifiable risk factor for cardiovascular diseases, and efforts to identify functional foods that are effective for hypertension control are increasing. The nutgall tree (NT, Rhus chinensis Mill.) is used in traditional medicine and food because of its medicinal value. However, the role of NT in hypertension has not been investigated. Therefore, the hypotensive effect of NT leaf ethanol extract (NTE) was investigated in spontaneously hypertensive rats (SHRs). SHRs were allocated to three groups (control, 300, or 1000 mg/kg NTE), and blood pressure was measured before and after oral administration. Systolic and diastolic blood pressure significantly decreased in the NTE 1000 mg/kg group and was the lowest at 2 h after administration (-26.4 ± 10.3, -33.5 ± 9.8%, respectively). Daily NTE administration for five days also resulted in a similar effect. Further, the vasorelaxant effects and related mechanisms were investigated in the aortas of Sprague Dawley rats. NTE showed the dose-dependent blood-vessel-relaxing effect, and its mechanism involves the NO-sGC-cGMP pathway, activation of K+ channels, and reduction in the vasoconstrictive action of angiotensin II. Therefore, our study provides basic data indicating the potential use of NTE as a functional food for high blood pressure.

Effectiveness of Chinese herbal medicine compared with angiotensin II receptor blockers in patients with diabetic kidney disease: A hospital-based matched cohort study.

Angiotensin II receptor blockers (ARBs) are one of the standard treatments for diabetic kidney disease (DKD). Some patients may opt for Chinese herbal medicine (CHM) of their own free will. However, there is no real-world evidence regarding the effectiveness and safety of CHM. We aimed to explore the effectiveness of CHM for DKD in comparison to ARBs. We enrolled 732 DKD patients (72 used only CHM and 661 used ARBs) from 2007 to 2016, and all patients were followed until December 2016 at China Medical University Hospital in Taiwan. A total of 355 ARB users and 71 CHM users were analyzed after propensity score matching. The estimated glomerular filtration rate (eGFR) after treatment was 84.9 ± 28.1 ml/min/1.73 m2 in CHM users, which was higher than that (67.8 ± 35.4 ml/min/1.73 m2) in ARB users (p < 0.001). The change in the eGFR was -6.0 ± 21.4 ml/min/1.73 m2 in CHM users and -12.9 ± 24.8 ml/min/1.73 m2 in ARB users (p = 0.029). The blood urea nitrogen (BUN) and creatinine levels of patients taking CHM were 22 ± 16 mg/dl and 0.9 ± 0.4 mg/dl, respectively, and were lower than those (30 ± 28 mg/dl and 1.7 ± 2.0 mg/dl) of patients taking ARBs (p = 0.025 and p = 0.003). Using linear regression with adjustments for age, sex, BMI, baseline eGFR, and HbA1c levels, we found that the declines in the eGFR/baseline eGFR and changes in the urine albumin-creatinine ratio (ACR) were comparable between the two groups (p = 0.86 and 0.73). This study suggests that CHM may have comparable effectiveness to ARBs, which provides insights for further investigations.

Lycorine inhibits Ang II-induced heart remodeling and inflammation by suppressing the PI3K-AKT/NF-κB pathway.

BACKGROUND: Ang II induces hypertensive heart failure (HF) via hemodynamic and non-hemodynamic actions. Lycorine (LYC) is an alkaloid derived from Lycoris bulbs, and it possesses anti-cardiovascular disease-related activities. Herein, we explored the potential LYC-mediated regulation of Ang II-induced HF. METHODS: Over 4 weeks, we established a hypertensive HF mouse model by infusing Ang II into C57BL/6 mice using a micro-osmotic pump. For the final two weeks, mice were administered LYC via intraperitoneal injection. The LYC signaling network was then deduced using RNA sequencing. RESULTS: LYC administration strongly suppressed hypertrophy, myocardial fibrosis, and cardiac inflammation. As a result, it minimized heart dysfunction while causing no changes in blood pressure. The Nuclear Factor kappa B (NF-κB) network/phosphoinositol-3-kinase (PI3K)-protein kinase B (AKT) was found to be a major modulator of LYC-based cardioprotection using RNA sequencing study. We further confirmed that in cultured cardiomyocytes and mouse hearts, LYC reduced the inflammatory response and downregulated the Ang II-induced PI3K-AKT/NF-κB network. Moreover, PI3K-AKT or NF-κB axis depletion in cardiomyocytes completely abrogated the anti-inflammatory activities of LYC. CONCLUSION: Herein, we demonstrated that LYC safeguarded hearts in Ang II -stimulated mice by suppressing the PI3K-AKT/NF-κB-induced inflammatory responses. Given the evidence mentioned above, LYC is a robust therapeutic agent for hypertensive HF.

α-Ketoglutarate improves cardiac insufficiency through NAD+-SIRT1 signaling-mediated mitophagy and ferroptosis in pressure overload-induced mice.

BACKGROUND: In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity and aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy and fibrosis in mice with HF and improved cardiac insufficiency. However, the myocardial protective mechanism of AKG remains unclear. We verified the hypothesis that AKG improves mitochondrial function by upregulating NAD+ levels and activating silent information regulator 2 homolog 1 (SIRT1) in cardiomyocytes. METHODS: In vivo, 2% AKG was added to the drinking water of mice undergoing transverse aortic constriction (TAC) surgery. Echocardiography and biopsy were performed to evaluate cardiac function and pathological changes. Myocardial metabolomics was analyzed by liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after surgery. In vitro, the expression of SIRT1 or PINK1 proteins was inhibited by selective inhibitors and siRNA in cardiomyocytes stimulated with angiotensin II (AngII) and AKG. NAD+ levels were detected using an NAD test kit. Mitophagy and ferroptosis levels were evaluated by Western blotting, qPCR, JC-1 staining and lipid peroxidation analysis. RESULTS: AKG supplementation after TAC surgery could alleviate myocardial hypertrophy and fibrosis and improve cardiac function in mice. Metabolites of the malate-aspartate shuttle (MAS) were increased, but the TCA cycle and fatty acid metabolism pathway could be inhibited in the myocardium of TAC mice after AKG supplementation. Decreased NAD+ levels and SIRT1 protein expression were observed in heart of mice and AngII-treated cardiomyocytes. After AKG treatment, these changes were reversed, and increased mitophagy, inhibited ferroptosis, and alleviated damage in cardiomyocytes were observed. When the expression of SIRT1 was inhibited by a selective inhibitor and siRNA, the protective effect of AKG was suppressed. CONCLUSION: Supplementation with AKG can improve myocardial hypertrophy, fibrosis and chronic cardiac insufficiency caused by pressure overload. By increasing the level of NAD+, the SIRT-PINK1 and SIRT1-GPX4 signaling pathways are activated to promote mitophagy and inhibit ferroptosis in cardiomyocytes, which ultimately alleviates cardiomyocyte damage.

Common teratogenic medication exposures-a population-based study of pregnancies in the United States.

BACKGROUND: Risk mitigation for most teratogenic medications relies on risk communication via drug label, and prenatal exposures remain common. Information on the types of and risk factors for prenatal exposures to medications with teratogenic risk can guide strategies to reduce exposure. OBJECTIVE: This study aimed to identify medications with known or potential teratogenic risk commonly used during pregnancy among privately insured persons. STUDY DESIGN: We used the Merative™ MarketScan® Commercial Database to identify pregnancies with live or nonlive (ectopic pregnancies, spontaneous and elective abortions, stillbirths) outcomes among persons aged 12 to 55 years from 2011 to 2018. Start/end dates of medication exposure and pregnancy outcomes were identified via an adapted algorithm based on validation studies. We required continuous health plan enrollment from 90 days before conception until 30 days after the pregnancy end date. Medications with known or potential teratogenic risk were selected from TERIS (Teratogen Information System) and drug monographs based on the level of risk and quality of evidence (138 with known and 60 with potential risk). We defined prenatal exposure on the basis of ≥1 outpatient pharmacy claim or medical encounter for medication administration during target pregnancy periods considering medication risk profiles (eg, risk only in the first trimester or at a certain dose threshold). Sex hormones and hormone analogs, and abortion and postpartum/abortion hemorrhage treatments were not considered as teratogenic medications because of challenges in separating pregnancy-related indications, nor were opioids (because of complex risk-benefit considerations) or antiobesity medications if their only teratogenic mechanism was weight loss. RESULTS: Among all pregnancies, the 10 medications with known teratogenic risk and the highest prenatal exposures were sulfamethoxazole/trimethoprim (1988 per 100,000 pregnancy-years), high-dose fluconazole (1248), topiramate (351), lisinopril (144), warfarin (57), losartan (56), carbamazepine (50), valproate (49), vedolizumab (28 since 2015), and valsartan (25). Prevalence of exposure to sulfamethoxazole/trimethoprim decreased from 2346 to 1453 per 100,000 pregnancy-years from 2011 to 2018, but prevalence of exposure to vedolizumab increased 6-fold since its approval in 2015. Prenatal exposures in the first trimester were higher among nonlive pregnancies than among live-birth pregnancies, with the largest difference observed for warfarin (nonlive 370 vs live birth 78), followed by valproate (258 vs 86) and topiramate (1728 vs 674). Prenatal exposures to medications with potential teratogenic risk were most prevalent for low-dose fluconazole (6495), metoprolol (1325), and atenolol (448). The largest first-trimester exposure differences between nonlive and live-birth pregnancies were observed for lithium (242 vs 89), gabapentin (1639 vs 653), and duloxetine (1914 vs 860). Steady increases in hydralazine and gabapentin exposures were observed during the study years, whereas atenolol exposure decreased (561 to 280). CONCLUSION: Several medications with teratogenic risk for which there are potentially safer alternatives continue to be used during pregnancy. The fluctuating rates of prenatal exposure observed for select teratogenic medications suggest that regular reevaluation of risk mitigation strategies is needed. Future research focusing on understanding the clinical context of medication use is necessary to develop effective strategies for reducing exposures to medications with teratogenic risk during pregnancy.

Costunolide ameliorates angiotensin II-induced atrial inflammation and fibrosis by regulating mitochondrial function and oxidative stress in mice: A possible therapeutic approach for atrial fibrillation.

Atrial fibrillation (AF) is a cardiac disease characterized by disordered atrial electrical activity. Atrial inflammation and fibrosis are involved in AF progression. Costunolide (COS) is a sesquiterpene lactone containing anti-inflammatory and anti-fibrotic activities. This study aims to explore the underlying mechanisms by which COS protects against AF. Male C57BL/6 mice (8- to 10-week-old) were infused with angiotensin (Ang) II for 3 weeks. Meanwhile, different doses of COS (COS-L: 10 mg/kg, COS-H: 20 mg/kg) were administered to mice by intragastric treatment. The results showed irregular and rapid heart rates in Ang II-treated mice. Moreover, the levels of inflammatory cytokines and fibrotic factors were elevated in mice. COS triggered a reduction of Ang II-induced inflammation and fibrosis, which conferred a protective effect. Mechanistically, mitochondrial dysfunction with mitochondrial respiration inhibition and aberrant ATP levels were observed after Ang II treatment. Moreover, Ang-II-induced excessive reactive oxygen species caused oxidative stress, which was further aggravated by inhibiting Nrf2 nuclear translocation. Importantly, COS diminished these Ang-II-mediated effects in mice. In conclusion, COS attenuated inflammation and fibrosis in Ang-II-treated mice by alleviating mitochondrial dysfunction and oxidative stress. Our findings represent a potential therapeutic option for AF treatment.

Hypotensive and Vasorelaxant Effects of Sanguisorbae Radix Ethanol Extract in Spontaneously Hypertensive and Sprague Dawley Rats.

Hypertension requires proper management because of the increased risk of cardiovascular disease and death. For this purpose, functional foods containing tannins have been considered an effective treatment. Sanguisorbae radix (SR) also contains various tannins; however, there have been no studies on its vasorelaxant or antihypertensive effects. In this study, the vasorelaxant effect of the ethanol extract of SR (SRE) was investigated in the thoracic aorta of Sprague Dawley rats. SRE (1, 3, 10, 30, and 100 µg/mL) showed this effect in a dose-dependent manner, and its mechanisms were related to the NO/cGMP pathway and voltage-gated K+ channels. Concentrations of 300 and 1000 µg/mL blocked the influx of extracellular Ca2+ and inhibited vasoconstriction. Moreover, 100 µg/mL of SRE showed a relaxing effect on blood vessels constricted by angiotensin II. The hypotensive effect of SRE was investigated in spontaneously hypertensive rats (SHR) using the tail-cuff method. Blood pressure significantly decreased 4 and 8 h after 1000 mg/kg of SRE administration. Considering these hypotensive effects and the vasorelaxant mechanisms of SRE, our findings suggests that SRE can be used as a functional food to prevent and treat hypertension. Further studies are needed for identifying the active components and determining the optimal dosage.

Mangiferin Protects against Angiotensin-II-Enhanced Hypertrophic Markers and Apoptosis in H9c2 Cardiomyocytes.

Hypertrophic cardiomyopathy accompanies numerous cardiovascular diseases, and the intervention of cardiac hypertrophy is an important issue to prevent detrimental consequences. Mangiferin (MGN) is a glucosylxanthone found in Mangifera indica, which exhibits anti-oxidant and anti-inflammatory properties. Various studies have demonstrated the cardioprotective potential of MGN, but the mechanisms behind its beneficial effects have not been fully revealed. Here, angiotensin-II (Ang-II) was used to induce cardiac hypertrophy, and we examined cell size, expression of hypertrophy markers (e.g., ANP, BNP, and [Formula: see text]-MHC), and oxidative stress (e.g., the ratio of NADPH/NADP[Formula: see text], the expression of p22phox and p67phox, and ROS and SOD production) of cardiomyocytes. Moreover, we assessed the activation of mitogen-activated protein kinase (MAPK) signaling (e.g., p38 and ERK) and the NF-[Formula: see text]Bp65/iNOS axis. Additionally, an annexin V/PI assay was employed to evaluate whether MGN administration can attenuate Ang-II-elicited apoptosis. Lastly, the expression of Ang-II type 1 receptor (AT1) was measured to confirm its involvement in MGN-mediated protection. Our results showed that treatment with MGN attenuated the Ang-II-induced cell size, expression of hypertrophy markers, and oxidative stress in cardiomyocytes. MGN also abrogated the activation of MAPK signaling and the NF-[Formula: see text]Bp65/iNOS axis. Additionally, MGN prevented apoptosis and downregulated the elevation of AT1 in cardiomyocytes that had been exposed to Ang-II. Altogether, these results demonstrated the potential of using MGN to ameliorate the Ang-II-associated cardiac hypertrophy, which may be due to its anti-oxidant and anti-inflammatory effects through suppression of MAPK signaling and the NF-[Formula: see text]Bp65/iNOS axis.

Infused juice concentrate of Japanese plum Prunus mume attenuates inflammatory vascular remodeling in a mouse model of hypertension induced by angiotensin II.

Fruit from the Prunus mume tree is a traditional food in Japan. Recently, bainiku-ekisu, an infused juice concentrate of Japanese Prunus mume, is attracting attention as a health promoting supplement. Angiotensin II (Ang II) plays a central role in development of hypertension. It has been reported that bainiku-ekisu treatment attenuates the growth-promoting signaling induced by Ang II in vascular smooth muscle cells. However, whether bainiku-ekisu has any effect on an animal model of hypertension remains unknown. Therefore, this study was designed to explore the potential anti-hypertensive benefit of bainiku-ekisu utilizing a mouse model of hypertension with Ang II infusion. Male C57BL/6 mice were infused with Ang II for 2 weeks and given 0.1% bainiku-ekisu containing water or normal water for 2 weeks with blood pressure evaluation. After 2 weeks, mice were euthanized, and the aortas were collected for evaluation of remodeling. Aortic medial hypertrophy was observed in control mice after Ang II infusion, which was attenuated in bainiku-ekisu group with Ang II infusion. Bainiku-ekisu further attenuated aortic induction of collagen producing cells and immune cell infiltration. Development of hypertension induced by Ang II was also prevented by bainiku-ekisu. Echocardiograph indicated protection of Ang II-induced cardiac hypertrophy by bainiku-ekisu. In vascular fibroblasts, bainiku-ekisu attenuated vascular cell adhesion molecule-1 induction, an endoplasmic reticulum stress marker, inositol requiring enzyme-1α phosphorylation, and enhancement in glucose consumption in response to Ang II. In conclusion, Bainiku-ekisu prevented Ang II-induced hypertension and inflammatory vascular remodeling. Potential cardiovascular health benefit to taking bainiku-ekisu should be further studied.

Selenium deficiency causes hypertension by increasing renal AT1 receptor expression via GPx1/H2O2/NF-κB pathway.

Epidemiological studies show an association between low body selenium and the risk of hypertension. However, whether selenium deficiency causes hypertension remains unknown. Here, we report that Sprague-Dawley rats fed a selenium-deficient diet for 16 weeks developed hypertension, accompanied with decreased sodium excretion. The hypertension of selenium-deficient rats was associated with increased renal angiotensin II type 1 receptor (AT1R) expression and function that was reflected by the increase in sodium excretion after the intrarenal infusion of the AT1R antagonist candesartan. Selenium-deficient rats had increased systemic and renal oxidative stress; treatment with the antioxidant tempol for 4 weeks decreased the elevated blood pressure, increased sodium excretion, and normalized renal AT1R expression. Among the altered selenoproteins in selenium-deficient rats, the decrease in renal glutathione peroxidase 1 (GPx1) expression was most prominent. GPx1, via regulation of NF-κB p65 expression and activity, was involved in the regulation of renal AT1R expression because treatment with dithiocarbamate (PDTC), an NF-κB inhibitor, reversed the up-regulation of AT1R expression in selenium-deficient renal proximal tubule (RPT) cells. The up-regulation of AT1R expression with GPx1 silencing was restored by PDTC. Moreover, treatment with ebselen, a GPX1 mimic, reduced the increased renal AT1R expression, Na+-K+-ATPase activity, hydrogen peroxide (H2O2) generation, and the nuclear translocation of NF-κB p65 protein in selenium-deficient RPT cells. Our results demonstrated that long-term selenium deficiency causes hypertension, which is due, at least in part, to decreased urine sodium excretion. Selenium deficiency increases H2O2 production by reducing GPx1 expression, which enhances NF-κB activity, increases renal AT1R expression, causes sodium retention and consequently increases blood pressure.

Angiotensin II Receptor Blockers Reduce Tau/Aß42 Ratio: A Cerebrospinal Fluid Biomarkers' Case-Control Study.

(1) Background: The role of antihypertensives in Alzheimer's Disease (AD) prevention is controversial. This case-control study aims to assess whether antihypertensive medication has a protective role by studying its association with amyloid and tau abnormal levels. Furthermore, it suggests a holistic view of the involved pathways between renin-angiotensin drugs and the tau/amyloidß42 ratio (tau/Aß42 ratio); (2) Methods: The medical records of the participant patients were reviewed, with a focus on prescribed antihypertensive drugs and clinical variables, such as arterial blood pressure. The Anatomical Therapeutic Chemical classification was used to classify each drug. The patients were divided into two groups: patients with AD diagnosis (cases) and cognitively healthy patients (control); (3) Results: Age and high systolic blood pressure are associated with a higher risk of developing AD. In addition, combinations of angiotensin II receptor blockers are associated with a 30% lower t-tau/Aß42 ratio than plain angiotensin-converting enzyme inhibitor consumption; (4) Conclusions: Angiotensin II receptor blockers may play a potential role in neuroprotection and AD prevention. Likewise, several mechanisms, such as the PI3K/Akt/GSK3ß or the ACE1/AngII/AT1R axis, may link cardiovascular pathologies and AD presence, making its modulation a pivotal point in AD prevention. The present work highlights the central pathways in which antihypertensives may affect the presence of pathological amyloid and tau hyperphosphorylation.

XinLi formula, a traditional Chinese decoction, alleviates chronic heart failure via regulating the interaction of AGTR1 and AQP1.

BACKGROUND: XinLi formula (XLF) is a traditional Chinese medicine used in clinical practice to treat chronic heart failure (CHF) in humans, with remarkable curative effect. However, the mechanism remains unknown. PURPOSE: The goal of the current investigation was to determine how XLF affected CHF in a rat model of the condition brought on by ligation of the left anterior descending coronary artery, and to investigate the underlying mechanism. STUDY DESIGN AND METHODS: Cardiac function was detected by echocardiography. The contents of myocardial enzymes, Ang II, ALD, TGF-ß1, and inflammatory factors were measured by ELISA. Myocardial injury and myocardial fibrosis were evaluated by HE and Masson staining. Myocardial edema was assessed by cardiac mass index and transmission electron microscopy. Using Western blot and immunohistochemistry to examining the protein expression of inflammasome, TGF-ß1, AGTR1, and AQP1 in the left ventricle. Furthermore, the interaction of AGTR1 and AQP1 was evaluated by co-immunoprecipitation. RESULTS: XLF attenuated myocardial enzymes and myocardial injury, and improved cardiac function in rats with CHF after myocardial infarction. It also reduced Ang II and ALD levels in CHF rats, and suppressed the expression of AGTR1 and TGF-ß1, finally alleviated myocardial fibrosis. By mechanism, XLF inhibited the expression of NLRP3 inflammasome proteins, reduced the plasma contents of IL-1ß, IL-18, IL-6 and TNF-α. Additionally, XLF inhibited the expression of AQP1 and the interaction of AGTR1 and AQP1, alleviating myocardial edema. The common structure of the main chemical constituents of XLF were glycoside compounds with glycosyl. CONCLUSION: XLF ameliorated CHF, which was evidenced by the alleviation of myocardial fibrosis by inhibiting AGTR1/NLRP3 signal, as well as the attenuation of myocardial edema by suppressing the interaction of AGTR1 and AQP1.

Acute phosphatidylinositol 4,5 bisphosphate depletion destabilizes sarcolemmal expression of cardiac L-type Ca2+ channel CaV1.2.

CaV1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through Gq-coupled AT1 receptors, angiotensin II triggers a decrease in PIP2, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels. PIP2 depletion suppresses CaV1.2 currents in heterologous expression systems but the mechanism of this regulation and whether a similar phenomenon occurs in cardiomyocytes is unknown. Previous studies have shown that CaV1.2 currents are also suppressed by angiotensin II. We hypothesized that these two observations are linked and that PIP2 stabilizes CaV1.2 expression at the PM and angiotensin II depresses cardiac excitability by stimulating PIP2 depletion and destabilization of CaV1.2 expression. We tested this hypothesis and report that CaV1.2 channels in tsA201 cells are destabilized after AT1 receptor-triggered PIP2 depletion, leading to their dynamin-dependent endocytosis. Likewise, in cardiomyocytes, angiotensin II decreased t-tubular CaV1.2 expression and cluster size by inducing their dynamic removal from the sarcolemma. These effects were abrogated by PIP2 supplementation. Functional data revealed acute angiotensin II reduced CaV1.2 currents and Ca2+ transient amplitudes thus diminishing excitation-contraction coupling. Finally, mass spectrometry results indicated whole-heart levels of PIP2 are decreased by acute angiotensin II treatment. Based on these observations, we propose a model wherein PIP2 stabilizes CaV1.2 membrane lifetimes, and angiotensin II-induced PIP2 depletion destabilizes sarcolemmal CaV1.2, triggering their removal, and the acute reduction of CaV1.2 currents and contractility.

Thymus vulgaris, a natural pharmacy against COVID-19: A molecular review.

Introduction: A worldwide pandemic infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a deadly disease called COVID-19. Interaction of the virus and the Angiotensin converting-enzyme 2 (ACE2) receptor leads to an inflammatory-induced tissue damage. Thymus vulgaris L. (TvL) is a plant with a long history in traditional medicine that has antimicrobial, antiseptic, and antiviral properties. Thymol and Carvacrol are two important biological components in Thyme that have anti-inflammatory, antioxidant, and immunomodulatory properties. This study is a molecular review on the potential effects of TvL and its active compounds on SARS-COV2 infection. Method: This is a narrative review in which using PubMed, Scopus, ISI, Cochrane, ScienceDirect, Google scholar, and Arxiv preprint databases, the molecular mechanisms of therapeutic and protective effects of TvL and its active compounds have been discussed regarding the molecular pathogenesis in COVID-19. Results: Thyme could suppress TNF-alpha, IL-6, and other inflammatory cytokines. It also enhances the anti-inflammatory cytokines like TGF-beta and IL-10. Thyme extract acts also as an inhibitor of cytokines IL-1-beta and IL-8, at both mRNA and protein levels. Thymol may also control the progression of neuro-inflammation toward neurological disease by reducing some factors. Thyme and its active ingredients, especially Thymol and Carvacrol, have also positive effects on the renin-angiotensin system (RAS) and intestinal microbiota. Conclusions: Accordingly, TvL and its bioactive components may prevent COVID-19 complications and has a potential protective role against the deleterious consequences of the disease.

Structural characterization and protective effect against renal fibrosis of polysaccharide from Ligustrum lucidum Ait.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Ligustri Lucidi (FLL), the fruit of Ligustrum lucidum Ait., is a traditional Chinese medicine that has been used for tonifying the kidney and liver for decades. AIM OF THE STUDY: This study aimed to explore and identify polysaccharides from FLL and elucidate its protective effect against renal fibrosis. MATERIALS AND METHODS: Polysaccharides were extracted and isolated from FLL. The purified fraction was identified by serial phytochemical work, such as gel-permeation chromatography, ion chromatography, gas chromatography-mass spectrometry, and nuclear magnetic resonance. Mice with unilateral ureteral obstruction (UUO) were applied as a renal fibrosis model. The male UUO mice were pretreated with heteropolysaccharide (Poly) 1 week prior to surgery and continuously treated for 7 days after the operation. Renal fibrosis was assessed by Periodic Acid-Schiff (PAS) staining and Masson's trichrome staining in paraffin-embedded slides. The murine mesangial cells SV40-MES13 upon angiotensin II (Ang II) treatment were developed as an in vitro fibrotic model. The cells were treated by Poly in the presence of Ang II. Molecular expression was detected by RT-PCR, immunoblotting, and immunofluorescence staining. RESULTS: We identified a heteropolysaccharide composed of arabinose and galactose (molar ratio, 0.73:0.27) with a predicted chemical structure characterized by a backbone composed of 1,5-α-Araf, 1,3,5-α-Araf, 1,6-α-Galp, and 1,3,6-ß-Galp and side chains comprised of T-α-Araf, T-α-Arap, and 1,3-α-Araf. Pretreatment of UUO mice with Poly effectively alleviated glomerulosclerosis and tubulointerstitial fibrosis. Moreover, Poly pretreatment down-regulated the expression of extracellular matrix (ECM) protein fibronectin (FN), profibrotic factor VEGF, proinflammatory cytokines MCP-1 and Rantes in the obstructed kidney. Similarly, the incubation of SV40-MES13 cells with Poly significantly inhibited Ang II-induced elevation in accumulation and expression level of FN and attenuated Ang II-evoked up-regulation in protein expression of MCP-1 and Rantes. CONCLUSIONS: Our study isolated and identified a naturally occurring heteropolysaccharide in FLL and revealed its potential in protecting the kidneys from fibrosis.

Sclareol attenuates angiotensin II-induced cardiac remodeling and inflammation via inhibiting MAPK signaling.

Chronic inflammation plays an important role in hypertensive heart failure. Suppressing angiotensin II (Ang II)-induced cardiac inflammation may contribute to the treatment of hypertension-associated heart failure. Sclareol, a natural product initially isolated from the leaves and flowers of Salvia sclarea, possesses antiinflammatory and immune-regulation activity in various systems. However, its effect on Ang II-induced cardiac remodeling remains unknown. In this study, we have explored the potential effects of sclareol on Ang II-induced heart failure. In vivo experiments were conducted in mice with Ang II-pump infusion for 28 days. Sclareol administration at 5 mg·kg-1 ·d-1 significantly reduced the expression of myocardial injury markers. Sclareol also exerts protective effects against Ang II-induced cardiac dysfunction in mice which is associated with alleviated cardiac inflammation and fibrosis. Transcriptome analysis revealed that inhibition of the Ang II-activated mitogen-activated protein kinase (MAPK) pathway contributed to the protective effect of sclareol. Sclareol inhibits Ang II-activated MAPKs pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Blockage of MAPKs in cardiomyocytes abolished the antiinflammatory effects of sclareol. In conclusion, we show that sclareol protects hearts against Ang II-induced injuries through inhibiting MAPK-mediated inflammation, indicating the potential use of sclareol in the prevention of hypertensive heart failure.

Protective Effect and Mechanism of Kuntai Capsule on Angiotensin II -Induced Hypertension in Ovariectomized Rats.

OBJECTIVE: To explore the protective effect and mechanism of Kuntai (KT) Capsule on angiotensin II (Ang II)-induced hypertension in ovariectomized (OVX) rats. METHODS: Fifty-four rats were randomly divided into 6 groups according to a random number table, 9 in each group: control, OVX sham+Ang II, OVX, OVX+Ang II, OVX+Ang II +E2, and OVX+Ang II +KT. OVX rats model was constructed by retroperitoneal bilateral ovariectomy. After 4 weeks of pretreatment with KT Capsule [0.8 g/(kg·d) and 17- ß -estradiol (E2, 1.2 mg/(kg·d)] respectively, Ang II was injected into a micro-osmotic pump with a syringe to establish a hypertensive rat model. Blood pressure of rat tail artery was measured in a wake state of rats using a non-invasive sphygmomanometer. Blood pressure changes were compared between the intervention groups (OVX+Ang II +KT, OVX+Ang II +E2) and the negative control group (OVX+Ang II). Serum malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected respectively. The expressions of oxidative stress-related protein superoxide dismutase2 (SOD2) and anti-thioredoxin (TRX), autophagy marker protein [beclin1, light chain (LC) 3 II/I ratio and autophagy canonical pathway protein phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT)-mammalian target of rapamycin (mTOR)] were evaluated by Western blotting. RESULTS: Compared with the OVX+Ang II group, the systolic blood pressure of OVX+Ang II +KT group was significantly lowered (P<0.05) but not the diastolic blood pressure. Besides, SOD2 and TRX protein levels in mycardial tissues were significantly reduced in the OVX+Ang II +KT group compared with the OVX+Ang II group (P<0.05). Oxidative stress serum markers MDA and SOD were down- and up-regulated in the OVX+Ang II +KT group, respectively (P<0.05). Compared with OVX+Ang II group, the levels of cardiac proteins beclin-1 and LC3II/LC3 I in OVX+Ang II +KT group were also up-regulated (P<0.05), and the expression levels of p-PI3K, p-AKT and mTOR protein were down-regulated (P<0.05). CONCLUSION: KT could protect blood pressure of Ang II-induced OVX rats by inhibiting oxidative stress and up-regulating protective autophagy.

Leonurine attenuates angiotensin II-induced cardiac injury and dysfunction via inhibiting MAPK and NF-κB pathway.

BACKGROUND: Hypertension is a common risk factor for heart failure, and excessive angiotensin II (Ang II) leads to hypertensive cardiac alterations such as hypertrophy, cardiac fibrosis, remodeling, and dysfunction. Leonurine is the major active alkaloid compound obtained from the traditional Chinese herbal medicine, Leonurus japonicus Houtt. The effects of leonurine on Ang II-induced hypertensive cardiac injury remain unknown. HYPOTHESIS/PURPOSE: In the present study, we investigated the cardioprotective effects of leonurine in Ang II-infused mice and explored the underlying mechanisms in cardiomyocytes. METHODS: Cardiac injury was induced by Ang II infusion in experimental mice with or without leonurine (at 10 or 20 mg/kg) treatment. H9c2 cells and neonatal rat primary cardiomyocytes were used to investigate the mechanisms through which leonurine exerts its protection effects. RESULTS: The results showed that leonurine significantly alleviated Ang II-induced cardiac hypertrophy, fibrosis, and inflammation in both mice and cultured cardiomyocytes. Echocardiography revealed that leonurine preserved cardiac function in mice. Further investigations revealed that leonurine inhibited the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways to reduce inflammatory response and injuries in Ang II-challenged cardiomyocytes. Inhibition of MAPKs and NF-κB in cardiomyocytes abolished the anti-inflammatory effects of leonurine. CONCLUSIONS: Our study provides evidence that leonurine exerts protective effects against Ang II-induced hypertensive cardiac remodeling and dysfunction by inhibiting the MAPK and NF-κB pathways. Leonurine may be a promising agent for treating hypertensive heart failure.