Protective effect of modified Huangqi Chifeng decoction on immunoglobulin A nephropathy through toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-kappa B signaling pathway.

OBJECTIVE: To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction (, MHCD) in immunoglobulin A nephropathy (IgAN) rats. METHODS: To establish the IgAN rat model, the bovine serum albumin, lipopolysaccharide, and carbon tetrachloride 4 method was employed. The rats were then randomly assigned to the control, model, telmisartan, and high-, medium-, and low-dose MHCD groups, and were administered the respective treatments via intragastric administration for 8 weeks. The levels of 24-h urinary protein, serum creatinine (CRE), and blood urea nitrogen (BUN) were measured in each group. Pathological alterations were detected. IgA deposition was visualized through the use of immunofluorescence staining. The ultrastructure of the kidney was observed using a transmission electron microscope. The expression levels of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-ß1 (TGF-ß1) were examined by immunohistochemistry and quantitative polymerase chain reaction. Levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB) P65, were examined by immunohistochemistry, Western blotting, and quantitative polymerase chain reaction. RESULTS: The 24-h urine protein level in each group increased significantly at week 6, and worsen from then on. But this process can be reversed by treatments of telmisartan, and high-, medium-, and low-dose of MHCD, and these treatments did not affect renal function. Telmisartan, and high-, and medium-dose of MHCD reduced IgA deposition. Renal histopathology demonstrated the protective effect of high-, medium-, and low-dose of MHCD against kidney injury. The expression levels of MCP-1, IL-6, and TGF-ß1 in kidney tissues were downregulated by low, medium and high doses of MHCD treatment. Additionally, treatment of low, medium and high doses of MHCD decreased the protein and mRNA levels of TLR4, MyD88, and NF-κB. CONCLUSIONS: MHCD exerted nephroprotective effects on IgAN rats, and MHCD regulated the expressions of key targets in TLR4/MyD88/NF-κB signaling pathway, thereby alleviating renal inflammation by inhibiting MCP-1, IL-6 expressions, and ameliorating renal fibrosis by inhibiting TGF-ß1 expression.

An Emerging Strategy for Neuroinflammation Treatment: Combined Cannabidiol and Angiotensin Receptor Blockers Treatments Effectively Inhibit Glial Nitric Oxide Release.

Cannabidiol (CBD), the major non-psychoactive phytocannabinoid found in cannabis, has anti-neuroinflammatory properties. Despite the increasing use of CBD, little is known about its effect in combination with other substances. Combination therapy has been gaining attention recently, aiming to produce more efficient effects. Angiotensin II activates the angiotensin 1 receptor and regulates neuroinflammation and cognition. Angiotensin receptor 1 blockers (ARBs) were shown to be neuroprotective and prevent cognitive decline. The present study aimed to elucidate the combined role of CBD and ARBs in the modulation of lipopolysaccharide (LPS)-induced glial inflammation. While LPS significantly enhanced nitric oxide synthesis vs. the control, telmisartan and CBD, when administered alone, attenuated this effect by 60% and 36%, respectively. Exposure of LPS-stimulated cells to both compounds resulted in the 95% inhibition of glial nitric oxide release (additive effect). A synergistic inhibitory effect on nitric oxide release was observed when cells were co-treated with losartan (5 µM) and CBD (5 µM) (by 80%) compared to exposure to each compound alone (by 22% and 26%, respectively). Telmisartan and CBD given alone increased TNFα levels by 60% and 40%, respectively. CBD and telmisartan, when given together, attenuated the LPS-induced increase in TNFα levels without statistical significance. LPS-induced IL-17 release was attenuated by CBD with or without telmisartan (by 75%) or telmisartan alone (by 60%). LPS-induced Interferon-γ release was attenuated by 80% when telmisartan was administered in the absence or presence of CBD. Anti-inflammatory effects were recorded when CBD was combined with the known anti-inflammatory agent dimethyl fumarate (DMF)/monomethyl fumarate (MMF). A synergistic inhibitory effect of CBD and MMF on glial release of nitric oxide (by 77%) was observed compared to cells exposed to MMF (by 35%) or CBD (by 12%) alone. Overall, this study highlights the potential of new combinations of CBD (5 µM) with losartan (5 µM) or MMF (1 µM) to synergistically attenuate glial NO synthesis. Additive effects on NO production were observed when telmisartan (5 µM) and CBD (5 µM) were administered together to glial cells.

Effects of modified Huangqi Chifeng decoction on the IL-17 signaling pathway in an IgA nephropathy rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Immunoglobulin A nephropathy (IgAN) is an immune-related primary glomerular disease prevalent worldwide, with complicated clinical manifestations and an unclear pathogenesis. IgAN is the main cause of chronic renal failure and places a significant burden on patients and society. The modified Huangqi Chifeng decoction (MHCD) is an effective prescription for the clinical treatment of IgAN while its specific mechanism remains to be further elucidated. AIM OF THE STUDY: Based on the findings of previous network pharmacology-related method-based studies, this study aimed to further explore the mechanism of action of MHCD for IgAN treatment. MATERIALS AND METHODS: IgAN rat model was established by bovine serum protein + carbon tetrachloride + lipopolysaccharide. After successful modeling, the rats in the original model group were divided into 5 group: model group, telmisartan group, and MHCD high-, medium- and low-dose groups by random number table (n = 10 respectively). The corresponding drugs were applied for 8 weeks, and the experiment lasted for 21 weeks. At the end of the experiment, 24h urine protein quantification, serum biochemistry and IL-6 and IL-17A levels were measured. The pathological changes of kidney were observed by light microscope, immunofluorescence microscope and the changes of glomerular ultrastructure were observed by transmission electron microscope. The expression levels of IL-17 signaling pathway related proteins (HSP90, MMP9, NF-κB P65 and p-NF-κB P65) were detected by Western Blot and immunohistochemistry. RESULT: Telmisartan and MHCD treatment can reduce the 24h urinary protein level and improved blood stasis states of IgAN rats, alleviate the renal pathological injury, decrease the serum levels of IL-6, IL-17A and the expression levels of HSP90, MMP9 and p-NF-κB P65 related proteins in IL-17 signaling pathway. CONCLUSION: MHCD can down-regulate the expression of IL-17 signaling pathway-related factors in IgAN model rats, improve the state of blood stasis, and alleviate the pathological damage of kidney in rats.

Evaluating the potential of tauroursodeoxycholic acid as add-on therapy in amelioration of streptozotocin-induced diabetic kidney disease.

The bile acid tauroursodeoxycholic acid (TUDCA) is of natural origin and is used in traditional Chinese medicine for centuries. Earlier its use was limited to biliary disorders but owing to its pleiotropic effects dietary TUDCA supplementation is under clinical trials for diseases including type 1 and 2 diabetic complications. The current study aims to evaluate the potential and underlying molecular mechanism of the TUDCA as a monotherapy and as an add-on therapy to telmisartan, an angiotensin II type 1 receptor (AT1R) blocker against diabetic kidney disease (DKD). We employed both in-vitro and in-vivo approaches where NRK-52E cells were incubated with high glucose, and DKD was induced in Wistar rats using streptozotocin (55 mg/kg, i.p.). After 4 weeks, animals were administered with TUDCA (250 mg/kg, i.p.), telmisartan (10 mg/kg, p.o.), and their combination for 4 weeks. Plasma was collected for the biochemical estimation and kidneys were used for immunoblotting, PCR, and histopathological analysis. Similarly, for in-vitro experiments, cells were exposed to 1000 µM of TUDCA and 10 µM of telmisartan, and their combination, followed by cell lysate collection and immunoblotting analysis. We observed that the addition of TUDCA to conventional telmisartan treatment was more effective in restoring the renal function decline and suppressing the apoptotic and fibrotic signaling as compared to monotherapies of AT1R blocker and ER stress inhibitor. The results implicate the utility of traditionally used TUDCA as a potential renoprotective compound. Since, both TUDCA and telmisartan are approved for clinical usage, thus concomitant administration of them could be a novel therapeutic strategy against DKD.

[Telmisartan chronotherapy and its influence on the indicators of the daily profile blood pressure.]

Arterial hypertension is one of the most common life-threatening diseases, adequate control of which is largely achieved by antihypertensive drugs, including the use of telmisartan. The aim of the study was to evaluate the effect of telmisartan chronotherapy on the parameters of daily monitoring of blood pressure during the daytime and at night in elderly patients with hypertension. The study is based on a comprehensive examination of 150 patients aged 60-74 years suffering from hypertension, who are divided into 2 groups: the main (n=76) and control (n=74). Patients with hypertension in the main group received telmisartan at a dose of 80 mg/day in the evening (20.00-22.00 hours), and in the control group - in the morning at the same dose (80 mg/day). Before treatment, after 3 months and after 6 months, patients of both groups underwent daily monitoring of blood pressure with the «BPLab monitor Mn SDP-3¼. It was found that the evening intake of telmisartan at a dose of 80 mg/day has a more significant effect than the morning intake of the same dose of telmisartan on the indicators of daily monitoring of systolic blood pressure and diastolic blood pressure in the evening, the systolic blood pressure time index in the evening. Chronotherapy with telmisartan in elderly patients with hypertension more effectively normalizes the daily blood pressure profile with the transfer of «non-dipper¼ to «dipper¼, reduces the hypertensive load and contributes to the achievement of target blood pressure levels.

Uptake and bio-transformation of telmisartan by cress (Lepidium sativum) from sewage treatment plant effluents using high-performance liquid chromatography/drift-tube ion-mobility quadrupole time-of-flight mass spectrometry.

In the present study, the uptake and metabolization of the sartan drug telmisartan by a series of plants was investigated. Thereby for seven potential metabolites, modifications on the telmisartan molecule such as hydroxylation and/or glycosylation could be tentatively identified. For two additional signals detected at accurate masses m/z 777.3107 and m/z 793.3096, no suggestions for molecular formulas could be made. Further investigations employing garden cress (Lepidium sativum) as a model plant were conducted. This was done in order to develop an analytical method allowing the detection of these substances also under environmentally relevant conditions. For this reason, the knowledge achieved from treatment of the plants with rather high concentrations of the parent drug (10 mg L-1) was compared with results obtained when using solutions containing telmisartan in the µg - ng L-1 range. Thereby the parent drug and up to three tentative drug-related metabolites could still be detected. Finally cress was cultivated in water taken from a local waste water treatment plant effluent containing 90 ng L-1 of telmisartan and harvested and the cress roots were extracted. In this extract, next to the parent drug one major metabolite, namely telmisartan-glucose could be identified.

Neuroprotective Effects of Telmisartan and Nifedipine Against Cuprizone-Induced Demyelination and Behavioral Dysfunction in Mice: Roles of NF-κB and Nrf2.

Multiple sclerosis is a chronic inflammatory neurodegenerative disease of the central nervous system which injures the myelin sheath. Telmisartan and nifedipine are antihypertensive drugs that recently showed neuroprotective properties against neurodegenerative diseases. This study evaluated the neuroprotective effect of telmisartan or nifedipine in cuprizone-induced demyelination in mice by examining the underlying mechanisms. C57BL/6 mice received a diet containing 0.7% (w/w) cuprizone for 7 days followed by 3 weeks on a 0.2% cuprizone diet. Telmisartan (5 mg/kg/day, p.o.) or nifedipine (5 mg/kg/day, p.o.) was administered for 3 weeks starting from the second week. Telmisartan or nifedipine improved locomotor activity and enhanced motor coordination as demonstrated by open field, rotarod, and grip strength tests. Furthermore, telmisartan or nifedipine restored myelin basic protein mRNA and protein expression and increased luxol fast blue-staining intensity. Telmisartan or nifedipine attenuated cuprizone-induced oxidative stress and apoptosis by decreasing brain malondialdehyde and caspase-3 along with restoring reduced glutathione and brain-derived neurotrophic factor levels. Telmisartan or nifedipine exerted an anti-inflammatory effect by reducing the expression of nuclear factor kappa B (NF-κB p65) as well as pro-inflammatory cytokines and elevating the expression of IκB-α. In parallel, telmisartan or nifedipine upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and the levels of heme oxygenase-1 and NADPH quinone oxidoreductase 1 enzymes. In conclusion, the current study provides evidence for the protective effect of telmisartan and nifedipine in cuprizone-induced demyelination and behavioral dysfunction in mice possibly by modulating NF-κB and Nrf2 signaling pathways.

Evaluation of novobiocin and telmisartan for anti-CHIKV activity.

Chikungunya has re-emerged as an epidemic with global distribution and high morbidity, necessitating the need for effective therapeutics. We utilized already approved drugs with a good safety profile used in other diseases for their new property of anti-chikungunya activity. It provides a base for a fast and efficient approach to bring a novel therapy from bench to bedside by the process of drug-repositioning. We utilized an in-silico drug screening with FDA approved molecule library to identify inhibitors of the chikungunya nsP2 protease, a multifunctional and essential non-structural protein required for virus replication. Telmisartan, an anti-hypertension drug, and the antibiotic novobiocin emerged among top hits on the screen. Further, SPR experiments revealed strong in-vitro binding of telmisartan and novobiocin to nsP2 protein. Additionally, small angle x-ray scattering suggested binding of molecules to nsP2 and post-binding compaction and retention of monomeric state in the protein-inhibitor complex. Protease activity measurement revealed that both compounds inhibited nsP2 protease activity with IC50 values in the low micromolar range. More importantly, plaque formation assays could show the effectiveness of these drugs in suppressing virus propagation in host cells. We propose novobiocin and telmisartan as potential inhibitors of chikungunya replication. Further research is required to establish the molecules as antivirals of clinical relevance against chikungunya.

Telmisartan alone or in combination with etanercept improves anemia associated with rheumatoid arthritis in rats: a possible role of anti-inflammatory and reno-protective effects.

BACKGROUND: There are conflicting data regarding angiotensin receptor blockers (ARBs) induced anemia and its beneficial anti-inflammatory effect in rheumatoid arthritis. The aim of the present study was to investigate the effect of telmisartan administration either alone or in combination with etanercept on anemia of chronic inflammatory diseases in a model of rheumatoid arthritis in rats. METHODS: Rheumatoid arthritis (RA) was induced by Freund's Complete Adjuvant (FCA; 1 mg/0.1 ml paraffin oil), injected subcutaneously on days 0, 30 and 40. Rats with RA received dimethyl sulfoxide (DMSO), etanercept (0.3 mg/kg 3 times/week; sc), telmisartan (1.5 mg/kg/day; orally) or combination of etanercept and telmisartan. Arthritis parameters (footpad circumference change and paw volume change), erythrocyte indices (hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin level changes), iron profile (serum iron and serum ferritin), serum levels of erythropoietin (EPO), hepcidin, tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 were evaluated, along with measuring serum urea and creatinine levels. RESULTS: All treated groups showed improvement of the measured parameters in comparison to RA-control subgroup. Telmisartan either alone or in combination with etanercept significantly improved arthritis and erythrocyte indices. Telmisartan showed significant increase in EPO and decrease in hepcidin compared to etanercept. Combination group showed significant improvement in serum iron, ferritin, EPO, hepcidin, TNF-α, IL-6, urea and creatinine, compared to etanercept. Telmisartan either alone or in combination, but not etanercept alone, significantly decreased creatinine level. CONCLUSION: Telmisartan improved anemia and arthritis parameters and showed anti-inflammatory and reno-protective effects, in a rat model of rheumatoid arthritis.

Intraperitoneal Administration of Telmisartan Prevents Postsurgical Adhesion Band Formation.

BACKGROUND: Angiotensin II receptor blockers (ARBs) have a potential role in reducing inflammation and fibrosis. We have integrated systems and molecular biology approaches to investigate the therapeutic potential of ARBs in preventing postsurgical adhesion band formation. MATERIAL AND METHODS: we have followed the ARRIVE guidelines point by point during experimental studies. Telmisartan (1 and 9 mg/kg), valsartan (1 and 9 mg/kg), and losartan (1 and 10 mg/kg) were administered intraperitoneally in different groups of male albino Wistar rat. After 7 d of treatment, macroscopic evidence and score of fibrotic bands based on scaling methods was performed. Moreover, the anti-inflammatory and antifibrosis effects of telmisartan on reduction of fibrotic bands were investigated by using histopathology, ELISA, and real-time polymerase chain reaction methods. RESULTS: Telmisartan, but not losartan or valsartan, prevented the frequency as well as the stability of adhesion bands. Telmisartan appears to elicit anti-inflammatory responses by attenuating submucosal edema, suppressing proinflammatory cytokines, decreasing proinflammatory cell infiltration, and inhibiting oxidative stress at the site of peritoneal surgery. We also showed that telmisartan prevents fibrotic adhesion band formation by reducing excessive collagen deposition and suppression of profibrotic genes expression at the peritoneum adhesion tissues. CONCLUSIONS: These results support the potential application of telmisartan in preventing postsurgical adhesion band formation by inhibiting key pathologic responses of inflammation and fibrosis in postsurgery patients.

Telmisartan Influences the Antiproliferative Activity of Linoleic Acid in Human Colon Cancer Cells.

Aim: Linoleic acid (LA) and telmisartan as PPARgamma agonists exhibit anticancer activity. The LA effect is observed for high non-achievable in vivo concentrations and in short treatment period, therefore we evaluate the effect of supplemental LA and pharmacological telmisartan plasma concentrations on human primary (SW480) and metastatic (SW620) colon cancer cells and immortal keratinocytes (HaCaT) cells in long-term treatment. Methods: Cell viability and proliferation were determined by TB and MTT and pro-apoptotic effect was measured by Annexin V binding assays, respectively.Results: LA decreased cancer cell viability and proliferation in a concentration-dependent manner, whereas no significant effect was found for HaCaT cells. Telmisartan (0.2 µM) suppresses antiproliferative effect of 60 µM LA on cancer cells in short-term treatment. Long-term administration of 60 µM LA reduced cancer cells viability after one week, while telmisartan delayed this effect by two weeks. Growth of all cell lines with 20 µM LA was unchanged during all treatment time. Telmisartan decreased late apoptosis of cancer and normal cells with 60 and 120 µM LA. Conclusion: The cytotoxic LA action depends not only on its concentration but also duration of treatment. Telmisartan exhibits biphasic but not synergistic effect on LA cytotoxicity in cancer cells.

Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets.

The AT1 receptor blocker telmisartan (TEL) prevents diet-induced obesity. Hypothalamic lipid metabolism is functionally important for energy homeostasis, as a surplus of lipids induces an inflammatory response in the hypothalamus, thus promoting the development of central leptin resistance. However, it is unclear as to whether TEL treatment affects the lipid status in the hypothalamus. C57BL/6N mice were fed with chow (CONchow) or high-fat diet (CONHFD). HFD-fed mice were gavaged with TEL (8 mg/kg/day, 12 weeks, TELHFD). Mice were phenotyped regarding weight gain, energy homeostasis, and glucose control. Hypothalamic lipid droplets were analyzed by fluorescence microscopy. Lipidomics were assessed by performing liquid chromatography-mass spectrometry in plasma and hypothalami. Adipokines were investigated using immunosorbent assays. Glial fibrillary acidic protein (GFAP) was determined by Western blotting and immunohistochemical imaging. We found that body weight, energy homeostasis, and glucose control of TEL-treated mice remained normal while CONHFD became obese. Hypothalamic ceramide and triglyceride levels as well as alkyne oleate distribution were normalized in TELHFD. The lipid droplet signal in the tanycyte layer was higher in CONHFD than in CONchow and returned to normal under TELHFD conditions. High hypothalamic levels of GFAP protein indicate astrogliosis of CONHFD mice while normalized GFAP, TNFα, and IL1α levels of TELHFD mice suggest that TEL prevents hypothalamic inflammation. In conclusion, TEL has anti-obese efficacy and prevented lipid accumulation and lipotoxicity, which is accompanied by an anti-inflammatory effect in the murine hypothalamus. Our findings support the notion that a brain-related mechanism is involved in TEL-induced weight loss.

Stachydrine hydrochloride alleviates pressure overload-induced heart failure and calcium mishandling on mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Leonurus japonicus Houtt. has a long history in the treatment of cardiovascular diseases. Stachydrine hydrochloride, the main bioactive ingredient extracted from Leonurus japonicus Houtt., has been shown to have cardioprotective effects. However, the underlying mechanisms of stachydrine hydrochloride haven't been comprehensively studied so far. AIM OF THE STUDY: The aim of this study was to investigate the protective role of stachydrine hydrochloride in heart failure and elucidate its possible mechanisms of action. MATERIALS AND METHODS: In vivo, transverse aorta constriction was carried out in C57BL/6J mice, and thereafter, 7.2 mg/kg telmisartan (a selective AT1R antagonist as positive control) and 12 mg/kg stachydrine hydrochloride was administered daily intragastrically for 4 weeks. Cardiac function was evaluated by assessing morphological changes as well as echocardiographic and haemodynamic parameters. In vitro, neonatal rat cardiomyocytes or adult mice cardiomyocytes were treated with stachydrine hydrochloride and challenged with phenylephrine (α-AR agonist). Ventricular myocytes were isolated from the hearts of C57BL/6J mice by Langendorff crossflow perfusion system. Intracellular calcium was measured by an ion imaging system. The length and movement of sarcomere were traced to evaluate the systolic and diastolic function of single myocardial cells. RESULTS: Stachydrine hydrochloride improved the cardiac function and calcium transient amplitudes, and inhibited the SR leakage and the amount of sparks in cardiac myocytes isolated from TAC mice. We also demonstrated that stachydrine hydrochloride could ameliorated phenylephrine-induced enhance in sarcomere contraction, calcium transients and calcium sparks. Moreover, our data shown that stachydrine hydrochloride blocked the hyper-phosphorylation of CaMKII, RyR2, PLN, and prevented the disassociation of FKBP12.6 from RyR2. CONCLUSION: Our results suggest that stachydrine hydrochloride exerts beneficial therapeutic effects against heart failure. These cardioprotective effects may be associated with the regulation of calcium handling by stachydrine hydrochloride through inhibiting the hyper-phosphorylation of CaMKII.

Holistic QbD approach for hot-melt extrusion process design space evaluation: Linking materials science, experimentation and process modeling.

The aim of this work was to investigate the relationship between formulation material properties, process parameters and process performance for the manufacturing of amorphous solid dispersions via hot-melt extrusion (HME) using experimentation coupled with process modeling. Specifically, we evaluated the impact of the matrix copovidone melt rheology with and without the addition of a plasticizing surfactant, polysorbate 80, while also varying the process parameters, barrel temperature and screw speed, and keeping fill volume constant. To correlate the process performance to a critical quality attribute, we used telmisartan as an indicator substance by processing at temperatures below its solubility temperature in the polymeric matrix. We observed a broader design space of HME processes for the plasticized formulation with respect to screw speed than for the copovidone-only matrix formulation. This observation was determined by the range of observed melt temperatures in the extruder, both measured and simulated. The reason was not primarily linked to a reduced shear-thinning behavior, characterized by the power law index, n, but instead more to an overall reduced melt viscosity during extrusion and zero-shear rate viscosity, η0, accordingly. We also found that the amount of residual crystallinity of telmisartan correlated with the simulated maximum melt temperature in the extruder barrel. This finding confirmed the applicability of the temperature-dependent API-matrix solubility phase diagram for HME to process development. Given the complex inter-dependent relationships between material properties, process and performance, process modeling combined with reduced laboratory experimentation was established as a holistic approach for the evaluation of Quality-by-Design-based HME process design spaces.

Vitamin D Regulates the Expressions of AQP-1 and AQP-4 in Mice Kidneys.

AIM: Vitamin D plays an important role in water and salt homeostasis. The aim of our study was to investigate the underlying relationship of Vitamin D and Aquaporins (AQP). METHODS: The behaviors of 1α (OH)-ase knockout mice and wild type mice were observed before analysis. The ICR mice were treated with vehicle or paricalcitol, a vitamin D analogue, followed by animals receiving a standard diet and free access to drinking water either with aliskiren (renin blocker; 37.5 mg aliskiren in 100 ml water), or telmisartan (a angiotensin II type I receptor blocker; 40 mg telmisartan in 100 ml water) a week before study. The expressions of AQP-1, AQP-4, and renin in mice kidneys were detected by western bolting, immunohistochemistry, and immunofluorescence. RESULTS: Diuresis and polydipsia were observed in 1α (OH)-ase knockout mice, and a decreased water intake and urine output in ICR mice was observed after paricalcitol treatment. Compared with wild type, the AQP-1 expressions were increased in renal papilla and AQP-4 expressions were decreased in renal proximal tubule of 1α(OH) ase knockout mice. In addition, AQP-1 was decreased in renal papilla and AQP-4 expressions were increased in proximal tubule by suppressing renin activity or supplement of Vitamin D analogue. After injecting renin into the lateral ventricle of the 1α(OH)ase knockout mice, the renin expression level was decreased in the kidney, followed by the decrease of AQP-1 in renal papilla and increase of AQP-4 in proximal tubule. CONCLUSIONS: Overall, Vitamin D and renin inhibitors have synergistic effects in regulating water channels in mice kidneys.

Effects of stress on behavior and resting-state fMRI in rats and evaluation of Telmisartan therapy in a stress-induced depression model.

BACKGROUND: The etiology of depression and its effective therapeutic treatment have not been clearly identified. Using behavioral phenotyping and resting-state functional magnetic resonance imaging (r-fMRI), we investigated the behavioral impact and cerebral alterations of chronic unpredictable mild stress (CUMS) in the rat. We also evaluated the efficacy of telmisartan therapy in this rodent model of depression. METHODS: Thirty-two rats were divided into 4 groups: a control group(C group), a stress group(S group), a stress + telmisartan(0.5 mg/kg)group (T-0.5 mg/kg group) and a stress + telmisartan(1 mg/kg) group (T-1 mg/kg group). A behavioral battery, including an open field test (OFT), a sucrose preference test (SPT), and an object recognition test (ORT), as well as r-fMRI were conducted after 4 weeks of CUMS and telmisartan therapy. The r-fMRI data were analyzed using the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) approach. The group differences in the behavior and r-fMRI test results as well as the correlations between these 2 approaches were examined. RESULTS: CUMS reduced the number of rearings and the total moved distance in OFT, the sucrose preference in SPT, and novel object recognition ability in ORT. The telmisartan treatment (1 mg/kg) significantly improved B-A/B + A in the ORT and improved latency scores in the OFT and SPT. The S group exhibited a decreased ReHo in the motor cortex and pons, but increased ReHo in the thalamus, visual cortex, midbrain, cerebellum, hippocampus, hypothalamus, and olfactory cortex compared to the C group. Telmisartan (1 mg/kg)reversed or attenuated the stress-induced changes in the motor cortex, midbrain, thalamus, hippocampus, hypothalamus, visual cortex, and olfactory cortex. A negative correlation was found between OFT rearing and ReHo values in the thalamus. Two positive correlations were found between ORT B-A and the ReHo values in the olfactory cortexand pons. CONCLUSIONS: Telmisartan may be an effective complementary drug for individuals with depression who also exhibit memory impairments. Stress induced widespread regional alterations in the cerebrum in ReHo measures while telmissartan can reverse part of theses alterations. These data lend support for future research on the pathology of depression and provide a new insight into the effects of telmisartan on brain function in depression.

Upward Shift and Steepening of the Blood Pressure Response to Exercise in Hypertensive Subjects at High Altitude.

BACKGROUND: Acute exposure to high-altitude hypobaric hypoxia induces a blood pressure rise in hypertensive humans, both at rest and during exercise. It is unclear whether this phenomenon reflects specific blood pressure hyperreactivity or rather an upward shift of blood pressure levels. We aimed at evaluating the extent and rate of blood pressure rise during exercise in hypertensive subjects acutely exposed to high altitude, and how these alterations can be counterbalanced by antihypertensive treatment. METHODS AND RESULTS: Fifty-five subjects with mild hypertension, double-blindly randomized to placebo or to a fixed-dose combination of an angiotensin-receptor blocker (telmisartan 80 mg) and a calcium-channel blocker (nifedipine slow release 30 mg), performed a cardiopulmonary exercise test at sea level and after the first night's stay at 3260 m altitude. High-altitude exposure caused both an 8 mm Hg upward shift (P<0.01) and a 0.4 mm Hg/mL/kg per minute steepening (P<0.05) of the systolic blood pressure/oxygen consumption relationship during exercise, independent of treatment. Telmisartan/nifedipine did not modify blood pressure reactivity to exercise (blood pressure/oxygen consumption slope), but downward shifted (P<0.001) the relationship between systolic blood pressure and oxygen consumption by 26 mm Hg, both at sea level and at altitude. Muscle oxygen delivery was not influenced by altitude exposure but was higher on telmisartan/nifedipine than on placebo (P<0.01). CONCLUSIONS: In hypertensive subjects exposed to high altitude, we observed a hypoxia-driven upward shift and steepening of the blood pressure response to exercise. The effect of the combination of telmisartan/nifedipine slow release outweighed these changes and was associated with better muscle oxygen delivery. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01830530.

Design of fixed dose combination and physicochemical characterization of enteric-coated bilayer tablet with circadian rhythmic variations containing telmisartan and pravastatin sodium.

The aim of this study was to investigate a fixed dose combination (FDC) of telmisartan (TEL) and pravastatin sodium (PRA) in enteric-coated bilayer tablets, which was designed for once-daily bedtime dose in order to match circadian rhythmic variations of hypertension and cholesterol synthesis and optimize the patient friendly dosing treatment. Due to the poor aqueous solubility of TEL, ternary solid dispersions (SD) consisting of TEL, polyethylene glycol 6000 (PEG 6000) and magnesium oxide (MgO) were designed to enhance its dissolution rate in intestinal fluid. MgO was added as an effective alkalizer to maintain the high microenvironmental pH of the saturated solution in the immediate vicinity of TEL particles because TEL is known to be ionizable but poorly soluble in intestinal fluid. In contrast, PRA is known to be very unstable in low pH conditions. In the SD system, TEL was present in an amorphous structure and formed an intermolecular hydrogen bonding with MgO, giving complete drug release without precipitation in intestinal fluid. In addition, the amount of hydrophilic carrier (PEG 6000) was also a factor. In the design of tablet formulation, the diluents and superdisintegrants could play a key role in release profiles. Then, to fulfill the unmet needs of the two model drugs and match circadian rhythmic variations of hypertension and cholesterol synthesis, enteric-coated bilayer tablet consisting of TEL SD and PRA was finally prepared using Acryl-EZE® as an enteric coating material. Prior to enteric coating, a seal coating layer (Opadry®, 2% weight gains) was firstly introduced to separate the core bilayer tablet from the acidic enteric coating polymers to avoid premature degradation. Dissolution profiles of finished tablets revealed that enteric-coated bilayer tablets with 6% weight gains remained intact in acidic media (pH 1.0) for 2h and then released drugs completely within 45min after switching to the intestinal media (pH 6.8). It was observed that enteric-coated bilayer tablets were stable during 3 month under the accelerated condition of 40°C/75% RH. The delayed drug release and bedtime dosage regimen using enteric-coated bilayer tablet containing TEL and PRA, matching the circadian rhythms of hypertension and hyperlipidemia can provide therapeutic benefits for elderly patients in terms of maximizing the therapeutic effects.

Tetrazolone as an acid bioisostere: application to marketed drugs containing a carboxylic acid.

Matched molecular pair analysis was used to evaluate the ability of a tetrazolone group to act as a bioisostere of a carboxylic acid. Compound 7, a tetrazolone of the anti-hypertensive drug, telmisartan 6, was shown to be a potent AT1 antagonist (Kb = 0.14 nM), with activity comparable to telmisartan itself (Kb = 0.44 nM). Additionally, compound 9, a tetrazolone congener of the marketed anti-cancer agent, bexarotene 8, was shown to be an agonist at the retinoid X receptor alpha (EC50 = 64 nM). Compounds containing a tetrazolone group showed similar microsomal stability and plasma protein binding to marketed acid counterparts, while also reducing the value for clog P. Furthermore, compound 7 displayed an improved rat pharmacokinetic profile cf. telmisartan 6. Taken together, the results demonstrate that a tetrazolone group may serve as a bioisostere for a carboxylic acid.

Renoprotective effect of a combination of garlic and telmisartan against ischemia/reperfusion-induced kidney injury in obese rats.

Obesity enhances the frequency and severity of acute kidney injury (AKI). Telmisartan pre-treatment was used experimentally in the amelioration of ischemia/reperfusion (IR)-induced AKI. However, there is a lack of evidence regarding its beneficial effects on AKI in obese animals. The present study, therefore, aimed to explore the protective effects of garlic and/or telmisartan against renal damage induced by unilateral IR in obese rats. Meloxicam was used as a standard anti-inflammatory agent. Prophylactic oral administration of meloxicam (3 mg kg(-1)), garlic (500 mg kg(-1)) and/or telmisartan (5 and 10 mg kg(-1)) for 4 wk protected against renal function deterioration induced by IR in obese rats. Both doses of telmisartan significantly reduced serum total cholesterol and triacyglycerol levels as well as peri-renal adipocytes size and renal fibrosis. Renal nuclear factor-kappa B immunoreactivity, tumor necrosis factor-alpha content as well as interleukin-10, adiponectin receptor 1 and macrophages (M1, M2) polarization markers (CD11c, CD206) mRNA expressions were down-regulated in ischemic kidney tissues and white adipose tissues around them by all treatments. Moreover, garlic, telmisartan and their combinations significantly suppressed oxidative stress in renal ischemic tissues. Histological picture was also improved by these treatments. Interestingly, the combinations provided a greater protection than their monotherapy in a dose-dependent manner. We suppose that this combination may be a promising prophylactic regimen for managing AKI in case of obesity. Thus, future experimental and clinical large-scale studies are necessary.