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.

Telmisartan loading thermosensitive hydrogel repairs gut epithelial barrier for alleviating inflammatory bowel disease.

Inflammatory bowel disease (IBD) remains a global health concern with a complex and incompletely understood pathogenesis. In the course of IBD development, damage to intestinal epithelial cells and a reduction in the expression of tight junction (TJ) proteins compromise the integrity of the intestinal barrier, exacerbating inflammation. Notably, the renin-angiotensin system and angiotensin II receptor type 1 (AT1R) play a crucial role in regulating the pathological progression including vascular permeability, and immune microenvironment. Thus, Telmisartan (Tel), an AT1R inhibitor, loading thermosensitive hydrogel was constructed to investigate the potential of alleviating inflammatory bowel disease through rectal administration. The constructed hydrogel exhibits an advantageous property of rapid transformation from a solution to a gel state at 37°C, facilitating prolonged drug retention within the gut while mitigating irritation associated with rectal administration. Results indicate that Tel also exhibits a beneficial effect in ameliorating colon shortening, colon wall thickening, cup cell lacking, crypt disappearance, and inflammatory cell infiltration into the mucosa in colitis mice. Moreover, it significantly upregulates the expression of TJ proteins in colonic tissues thereby repairing the intestinal barrier damage and alleviating the ulcerative colitis (UC) disease process. In conclusion, Tel-loaded hydrogel demonstrates substantial promise as a potential treatment modality for IBD.

Intestinal Absorption of Nanoparticles to Reduce Oxidative Stress and Vasoconstriction for Treating Diabetic Nephropathy.

The etiology of diabetic nephropathy (DN) is complex, and the incidence is increasing year by year. The patient's kidney showed oxidative stress damage, increasing active oxygen species (ROS) content, and vasoconstriction. Due to poor drug solubility and low renal accumulation, the current treatment regimens have not effectively alleviated glomerulopathy and other kidney damage caused by DN. Therefore, it is of great significance to explore new treatment strategies and drug delivery systems. Here, we constructed an oral nanodelivery system (Tel/CAN@CS-DA) that reduced oxidative stress and vasoconstriction. Deoxycholic acid (DA)-modified nanoparticles entered into intestinal epithelial cells (Caco2 cells) via the bile acid biomimetic pathway, then escaped from the lysosomes and eventually spat out the cells, increasing the oral absorption of nanoparticles. Chitosan (CS) nanoparticles could achieve renal targeting through specific binding with a renal giant protein receptor and deliver drugs to renal tubule epithelial cells (HK-2 cells). In vitro studies also proved that telmisartan (Tel) and canagliflozin (CAN) effectively removed cellular reactive oxygen species (ROS) and reduced HK-2 cell apoptosis caused by high glucose. In the in vivo model induced by streptozotocin (STZ), the results showed that the nanosystem not only elevated AMPK protein expression, inhibited angiotensin II (Ang II) protein expression to effectively reduce oxidative stress level, dilated renal blood vessels but also reduced the degree of inflammation and fibrosis. Overall, Tel/CAN@CS-DA multifunctional oral nanosystem can effectively treat DN with low toxicity, which provides a new idea for the treatment of DN.

Synthesis and Biological Evaluation of Telmisartan Alkylamine Derivatives as Potential Anticancer Agents.

BACKGROUND/AIM: Telmisartan is an angiotensin II receptor type 1 (AT1) antagonist with anticancer properties against solid and hematological cancer cell lines. Using telmisartan as a template, we developed alkylamine derivatives with reduced AT1 activity but increased anticancer activity. MATERIALS AND METHODS: Synthesis of candidate compounds was carried out via hexafluorophosphate benzotriazole tetramethyl uronium coupling reaction, then their inhibition of cell proliferation was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and colony-formation assay was carried out on the lead candidate compound 8 Cell death via apoptosis or necrosis by compound 8 was determined by flow cytometry using annexin V and propidium iodide, tolerability dosing was carried out in ICR mice, and tumor-reduction properties were determined in an MDA-MB-231 xenograft model. RESULTS: Some of the synthesized candidates exhibited good inhibition of cell proliferation with low micromolar half maximal effective concentrations in triple-negative breast cancer cell lines MDA-MB-231 and 4T1. Compound 8 exhibited lower affinity towards AT1 than parent telmisartan, inhibition of colony formation, and cell-cycle analysis revealed apoptosis as potentially important in causing cell death. In vivo evaluation with compound 8 indicated that it was well tolerated at high concentrations in healthy mice. Additionally, compound 8 showed higher growth inhibition in the MDA-MB-231 tumor xenograft mouse model compared to telmisartan. CONCLUSION: Our study indicated that alkylamine derivatives of telmisartan exhibited good solubility and higher inhibition of cancer cell proliferation than telmisartan. Compound 8 was found to be a good lead compound, with potential for development as an anticancer agent.

Telmisartan Protects Mitochondrial Function, Gait, and Neuronal Apoptosis by Activating the Akt/GSK3ß/PGC1α Pathway in an MPTP-Induced Mouse Model of Parkinson's Disease.

BACKGROUND: Mitochondrial dysfunction is one of the major hallmarks of Parkinson's disease (PD). Recently, angiotensin II type 1 and type 2 receptors (AT1R, AT2R) were reported to be present on the mitochondrial membrane. Both are crucial players in the brain renin-angiotensin system (RAS). Current evidence indicates that blockade of brain AT1R protects dopaminergic neurons in PD. METHODS: Thus, the current study was aimed to explore the effects of Telmisartan (Tel), a selective AT1R blocker, on mitochondrial function and a mouse model by exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [250 mg/kg body weight (10 divided i.p. injections, each 25 mg/kg body weight at 3.5 days interval) + Probenecid 250 mg/kg]. Gait function was assessed by beam walk, and mice were euthanized on the 35th day and their brain tissues isolated for Western blot analysis. RESULTS: Pretreatment with Tel significantly protected motor functions during the beam walk in MPTP-treated mice. Tel attenuated the increased levels of AT1R, α-syn, and inflammatory markers such as inducible nitric oxide synthase (iNOS) and ionized calcium-binding adaptor molecule 1 (IBA1) in MPTP-treated mice. In addition, Tel preserved the expression of AT2R, tyrosine hydroxylase (TH), p-Akt/Akt, and p-GSK3ß (Ser-9)/GSK3ß, as well as protecting mitofusin protein 1 (MFN1) and Peroxisome proliferator-activated receptor-gamma coactivator-α (PGC1α), a critical activator of mitochondrial biogenesis. CONCLUSION: These results indicate that Tel protects mitochondrial function and gait in a mouse model of PD by modulating the Akt/GSK3ß/PGC1α pathway.

Nanofabrications of Erythrocyte Membrane-Coated Telmisartan Delivery System Effective for Radiosensitivity of Tumor Cells in Mice Model.

Background: Radiation stimulates the secretion of tumor stroma and induces resistance, recurrence, and metastasis of stromal-vascular tumors during radiotherapy. The proliferation and activation of tumor-associated fibroblasts (TAFs) are important reasons for the production of tumor stroma. Telmisartan (Tel) can inhibit the proliferation and activation of TAFs (resting TAFs), which may promote radiosensitization. However, Tel has a poor water solubility. Methods: In this study, self-assembled telmisartan nanoparticles (Tel NPs) were prepared by aqueous solvent diffusion method to solve the insoluble problem of Tel and achieve high drug loading of Tel. Then, erythrocyte membrane (ECM) obtained by hypotonic lysis was coated on the surface of Tel NPs (ECM/Tel) for the achievement of in vivo long circulation and tumor targeting. Immunofluorescence staining, western blot and other biological techniques were used to investigate the effect of ECM/Tel on TAFs activation inhibition (resting effect) and mechanisms involved. The multicellular spheroids (MCSs) model and mouse breast cancer cells (4T1) were constructed to investigate the effect of ECM/Tel on reducing stroma secretion, alleviating hypoxia, and the corresponding promoting radiosensitization effect in vitro. A mouse orthotopic 4T1 breast cancer model was constructed to investigate the radiosensitizing effect of ECM/Tel on inhibiting breast cancer growth and lung metastasis of breast cancer. Results: ECM/Tel showed good physiological stability and tumor-targeting ability. ECM/Tel could rest TAFs and reduce stroma secretion, alleviate hypoxia, and enhance penetration in tumor microenvironment. In addition, ECM/Tel arrested the cell cycle of 4T1 cells to the radiosensitive G2/M phase. In mouse orthotopic 4T1 breast cancer model, ECM/Tel played a superior role in radiosensitization and significantly inhibited lung metastasis of breast cancer. Conclusion: ECM/Tel showed synergistical radiosensitization effect on both the tumor microenvironment and tumor cells, which is a promising radiosensitizer in the radiotherapy of stroma-vascular tumors.

Effects of telmisartan on metabolic syndrome components: a comprehensive review.

Telmisartan is an antagonist of the angiotensin II receptor used in the management of hypertension (alone or in combination with other antihypertensive agents. It belongs to the drug class of angiotensin II receptor blockers (ARBs). Among drugs of this class, telmisartan shows particular pharmacologic properties, including a longer half-life than any other angiotensin II receptor blockers that bring higher and persistent antihypertensive activity. In hypertensive patients, telmisartan has superior efficacy than other antihypertensive drugs (losartan, valsartan, ramipril, atenolol, and perindopril) in controlling blood pressure, especially towards the end of the dosing interval. Telmisartan has a partial PPARγ-agonistic effect whilst does not have the safety concerns of full agonists of PPARγ receptors (thiazolidinediones). Moreover, telmisartan has an agonist activity on PPARα and PPARδ receptors and modulates the adipokine levels. Thus, telmisartan could be considered as a suitable alternative option, with multi-benefit for all components of metabolic syndrome including hypertension, diabetes mellitus, obesity, and hyperlipidemia. This review will highlight the role of telmisartan in metabolic syndrome and the main mechanisms of action of telmisartan are discussed and summarized. Many studies have demonstrated the useful properties of telmisartan in the prevention and improving of metabolic syndrome and this well-tolerated drug can be greatly proposed in the treatment of different components of metabolic syndrome. However, larger and long-duration studies are needed to confirm these findings in long-term observational studies and prospective trials and to determine the optimum dose of telmisartan in metabolic syndrome.

Existence of Quantum Pharmacology in Sartans: Evidence in Isolated Rabbit Iliac Arteries.

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole-N-biphenyl tetrazole (ACC519T), benzimidazole-bis-N,N'-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K+)2), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K+)2 to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K+)2 significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K+)2 to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension.

[Sartans in the treatment of arterial hypertension: focus on telmisartan and azilsartan. A review].

The activity of the renin-angiotensin-aldosterone system is one of the main pathogenetic mechanisms underlying cardiovascular diseases at all stages of the cardiovascular continuum. This article discusses the role of telmisartan and azilsartan as the most powerful sartans in modern cardiology. Azilsartan and especially telmisartan have a significant organoprotection and are superior to other antihypertensive drugs in terms of lowering blood pressure. However, the effect of azilsartan on hard endpoints has not been studied while the efficacy of telmisartan on hard endpoints has been evaluated in plenty clinical trials including 3 large randomized clinical trials with several thousand patients. The article also presents calculations showing the better cost-effectiveness of telmisartan compared to azilsartan.

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.

Nicotine Impairs the Anti-Contractile Function of Perivascular Adipose Tissue by Inhibiting the PPARγ-Adiponectin-AdipoR1 Axis.

Nicotine is an addictive compound found in cigarette smoke that leads to vascular dysfunction and cardiovascular diseases. Perivascular adipose tissue (PVAT) exerts an anti-contractile effect on the underlying vasculature through the production of adipokines, such as adiponectin, which acts on adiponectin receptors 1 (adipoR1) to cause vasorelaxation. Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates adiponectin gene expression and PVAT development. This study aimed to determine the effect of nicotine on the anti-contractile function of PVAT via the PPARγ-adiponectin-adipoR1 axis. Male Sprague Dawley rats were divided into a control group (given normal saline), a nicotine group (given 0.8 mg/kg of nicotine), and a nicotine + PPARγ agonist group (given nicotine and 5 mg/kg of telmisartan). Thoracic aorta PVAT was harvested after 21 days of treatment. The results showed that nicotine reduced the anti-contractile effect of PVAT on the underlying thoracic aorta. Nicotine also decreased the gene and protein expression of PPARγ, adiponectin, and adipoR1 in PVAT. Treatment with telmisartan restored the anti-contractile effect of PVAT and increased the gene and protein expression of PPARγ, adiponectin, and adipoR1 in PVAT. In conclusion, nicotine attenuates the anti-contractile function of PVAT through inhibition of the PPARγ-adiponectin-adipoR1 axis.

Telmisartan inhibits microglia-induced neurotoxic A1 astrocyte conversion via PPARγ-mediated NF-κB/p65 degradation.

Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1ß, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.

Efficacy of single-pill combination in uncontrolled essential hypertension: A systematic review and network meta-analysis.

This study aimed to evaluate the efficacy of single-pill combination (SPC) antihypertensive drugs in patients with uncontrolled essential hypertension. Through Searching Pubmed, EMBASE, the Cochrane Library, and Web of Science collected only randomized controlled trials on the efficacy of single-pill combination antihypertensive drugs in people with uncontrolled essential hypertension. The search period is from the establishment of the database to July 2022. The methodological quality of the included studies was assessed using the Cochrane Risk of Bias Assessment, and statistical analyses were performed using Review Manage 5.3 and Stata 15.1 software. This review ultimately included 32 references involving 16 273 patients with uncontrolled essential hypertension. The results of the network meta-analysis showed that a total of 11 single-pill combination antihypertensive drugs were included, namely: Amlodipine/valsartan, Telmisartan/amlodipine, Losartan/HCTZ, Candesartan/HCTZ, Amlodipine/benazepril, Telmisartan/HCTZ, Valsartan/HCTZ, Irbesartan/amlodipine, Amlodipine/losartan, Irbesartan/HCTZ, and Perindopril/amlodipine. According to SUCRA, Irbesartan/amlodipine may rank first in reducing systolic blood pressure (SUCRA: 92.2%); Amlodipine/losartan may rank first in reducing diastolic blood pressure (SUCRA: 95.1%); Telmisartan/amlodipine may rank first in blood pressure control rates (SUCRA: 83.5%); Amlodipine/losartan probably ranks first in diastolic response rate (SUCRA: 84.5%). Based on Ranking Plot of the Network, we can conclude that single-pill combination antihypertensive drugs are superior to monotherapy, and ARB/CCB combination has better advantages than other SPC in terms of systolic blood pressure, diastolic blood pressure, blood pressure control rate, and diastolic response rate. However, due to the small number of some drug studies, the lack of relevant studies has led to not being included in this study, which may impact the results, and readers should interpret the results with caution.

Discovery of therapeutic targets for spinal cord injury based on molecular mechanisms of axon regeneration after conditioning lesion.

BACKGROUND: Preinjury of peripheral nerves triggers dorsal root ganglia (DRG) axon regeneration, a biological change that is more pronounced in young mice than in old mice, but the complex mechanism has not been clearly explained. Here, we aim to gain insight into the mechanisms of axon regeneration after conditioning lesion in different age groups of mice, thereby providing effective therapeutic targets for central nervous system (CNS) injury. METHODS: The microarray GSE58982 and GSE96051 were downloaded and analyzed to identify differentially expressed genes (DEGs). The protein-protein interaction (PPI) network, the miRNA-TF-target gene network, and the drug-hub gene network of conditioning lesion were constructed. The L4 and L5 DRGs, which were previously axotomized by the sciatic nerve conditioning lesions, were harvested for qRT-PCR. Furthermore, histological and behavioral tests were performed to assess the therapeutic effects of the candidate drug telmisartan in spinal cord injury (SCI). RESULTS: A total of 693 and 885 DEGs were screened in the old and young mice, respectively. Functional enrichment indicates that shared DEGs are involved in the inflammatory response, innate immune response, and ion transport. QRT-PCR results showed that in DRGs with preinjury of peripheral nerve, Timp1, P2ry6, Nckap1l, Csf1, Ccl9, Anxa1, and C3 were upregulated, while Agtr1a was downregulated. Based on the bioinformatics analysis of DRG after conditioning lesion, Agtr1a was selected as a potential therapeutic target for the SCI treatment. In vivo experiments showed that telmisartan promoted axonal regeneration after SCI by downregulating AGTR1 expression. CONCLUSION: This study provides a comprehensive map of transcriptional changes that discriminate between young and old DRGs in response to injury. The hub genes and their related drugs that may affect the axonal regeneration program after conditioning lesion were identified. These findings revealed the speculative pathogenic mechanism involved in conditioning-dependent regenerative growth and may have translational significance for the development of CNS injury treatment in the future.

Telmisartan Is a Promising Agent for Managing Neuropathic Pain and Delaying Opioid Analgesic Tolerance in Rats.

Despite the large arsenal of analgesic medications, neuropathic pain (NP) management is not solved yet. Angiotensin II receptor type 1 (AT1) has been identified as a potential target in NP therapy. Here, we investigate the antiallodynic effect of AT1 blockers telmisartan and losartan, and particularly their combination with morphine on rat mononeuropathic pain following acute or chronic oral administration. The impact of telmisartan on morphine analgesic tolerance was also assessed using the rat tail-flick assay. Morphine potency and efficacy in spinal cord samples of treated neuropathic animals were assessed by [35S]GTPγS-binding assay. Finally, the glutamate content of the cerebrospinal fluid (CSF) was measured by capillary electrophoresis. Oral telmisartan or losartan in higher doses showed an acute antiallodynic effect. In the chronic treatment study, the combination of subanalgesic doses of telmisartan and morphine ameliorated allodynia and resulted in a leftward shift in the dose-response curve of morphine in the [35S]GTPγS binding assay and increased CSF glutamate content. Telmisartan delayed morphine analgesic-tolerance development. Our study has identified a promising combination therapy composed of telmisartan and morphine for NP and opioid tolerance. Since telmisartan is an inhibitor of AT1 and activator of PPAR-γ, future studies are needed to analyze the effect of each component.

Improving effects of telmisartan on spermatogenic disorder induced by fractionated low-dose irradiation in mice.

BACKGROUND: Male infertility is a hot problem worldwide, but there are few treatments, especially male infertility caused by irradiation is difficult to treat. The aim of this study was to investigate and evaluate novel drugs for the treatment of male infertility caused by irradiation. METHODS: we randomly divided 18 male BALB/c mice into 3 groups: control, irradiated, and telmisartan. Both irradiated and telmisartan group completed whole-body 0.5 Gy five times irradiation, and the telmisartan group received intraperitoneal injection of telmisartan (1.2 mg/kg) daily on the next day after irradiation, and all groups were sampled on day 25 after irradiation. RESULTS: Sperm motility results show that total sperm motility of irradiated group was significantly lower compared with control group, and testicular HE results showed that testis in irradiated group were severely damaged. Compared with irradiated group, the total sperm motility, sperm concentration, testicular index, Johnsen score, and the seminiferous tubule layer numbers were higher in telmisartan group (P < 0.05). The immunohistochemical staining showed γ-H2AX expression is higher in telmisartan group compared with irradiated group. And the relative mRNA expression of PLZF, GFRA1, STRA8, DMRT1, SPO11, SYCP2, OVOL2, CCNA1, TJP3, RUNX2, TXNDC2 TNP1, and PRM3 in telmisartan group was all significantly higher than irradiated group (P < 0.05). CONCLUSION: In conclusion, in vivo experiments confirmed that telmisartan ameliorated the spermatogenic disorder in mice caused by fractionated low-dose irradiation via promoting spermatogenesis.

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.

Synergism of amlodipine and telmisartan or candesartan on blood pressure reduction by using SynergyFinder 3.0 and probability sum test in vivo.

This study was designed to evaluate the synergism of two couples of antihypertensive drugs (amlodipine + telmisartan and amlodipine + candesartan) on blood pressure reduction in vivo by both SynergyFinder 3.0 and probability sum test. Spontaneously hypertensive rats were treated with intragastric administration of amlodipine (0.5, 1, 2, and 4 mg/kg), telmisartan (4, 8, and 16 mg/kg), candesartan (1, 2, and 4 mg/kg), nine combinations for amlodipine and telmisartan, and nine combinations for amlodipine and candesartan. The control rats were treated by 0.5% carboxymethylcellulose sodium. Blood pressure was recorded continuously up to 6 h after administration. Both SynergyFinder 3.0 and the probability sum test were used to evaluate the synergistic action. The synergisms calculated by SynergyFinder 3.0 are consistent with the probability sum test both in two different combinations. There is an obviously synergistic interaction between amlodipine and telmisartan or candesartan. The combinations of amlodipine and telmisartan (2 + 4 and 1 + 4 mg/kg) and amlodipine and candesartan (0.5 + 4 and 2 + 1 mg/kg) might exert an optimum synergism against hypertension. Compared with the probability sum test, SynergyFinder 3.0 is more stable and reliable to analyze the synergism.

Exploring the repurposing potential of telmisartan drug in breast cancer: an in-silico and in-vitro approach.

Anticancer drug resistance is one of the biggest hurdles in the treatment of breast cancer. Drug repurposing is a viable option fordeveloping novel medical treatment strategies since this method is more cost-efficient and rapid. Antihypertensive medicines have recently been found to have pharmacological features that could be used to treat cancer, making them effective candidates for therapeutic repurposing. The goal of our research is to find a potent antihypertensive drug that can be repurposed as adjuvant therapy for breast cancer. In this study, virtual screening was performed using a set of Food and Drug Administration (FDA)-approved antihypertensive drugs as ligands with selected receptor proteins (EGFR, KRAS, P53, AGTR1, AGTR2, and ACE) assuming these proteins are regarded to have a significant role in hypertension as well as breast cancer. Further, our in-silico results were further confirmed by an in-vitro experiment (cytotoxicity assay). All the compounds (enalapril, atenolol, acebutolol, propranolol, amlodipine, verapamil, doxazosin, prazosin, hydralazine, irbesartan, telmisartan, candesartan, and aliskiren) showed remarkable affinity towards the target receptor proteins. However, maximum affinity was displayed by telmisartan. Cell-based cytotoxicity study of telmisartan in MCF7 (breast cancer cell line) confirmed the anticancer effect of telmisartan. IC50 of the drug was calculated to be 7.75 µM and at this concentration, remarkable morphological alterations were observed in the MCF7 cells confirming its cytotoxicity in breast cancer cells. Based on both in-silico and in-vitro studies, we can conclude that telmisartan appears to be a promising drug repurposing candidate for the therapeutic treatment of breast cancer.

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.