The angiotensin II/type 1 angiotensin II receptor pathway is implicated in the dysfunction of albumin endocytosis in renal proximal tubule epithelial cells induced by high glucose levels.

It is well-established that dysfunction of megalin-mediated albumin endocytosis by proximal tubule epithelial cells (PTECs) and the activation of the Renin-Angiotensin System (RAS) play significant roles in the development of Diabetic Kidney Disease (DKD). However, the precise correlation between these factors still requires further investigation. In this study, we aimed to elucidate the potential role of angiotensin II (Ang II), a known effector of RAS, as the mediator of albumin endocytosis dysfunction induced by high glucose (HG) in PTECs. To achieve this, we utilized LLC-PK1 and HK-2 cells, which are well-established in vitro models of PTECs. Using albumin-FITC or DQ-albumin as tracers, we observed that incubation of LLC-PK1 and HK-2 cells with HG (25 mM for 48 h) significantly reduced canonical receptor-mediated albumin endocytosis, primarily due to the decrease in megalin expression. HG increased the concentration of Ang II in the LLC-PK1 cell supernatant, a phenomenon associated with an increase in angiotensin-converting enzyme (ACE) expression and a decrease in prolyl carboxypeptidase (PRCP) expression. ACE type 2 (ACE2) expression remained unchanged. To investigate the potential impact of Ang II on HG effects, the cells were co-incubated with angiotensin receptor inhibitors. Only co-incubation with 10-7 M losartan (an antagonist for type 1 angiotensin receptor, AT1R) attenuated the inhibitory effect of HG on albumin endocytosis, as well as megalin expression. Our findings contribute to understanding the genesis of tubular albuminuria observed in the early stages of DKD, which involves the activation of the Ang II/AT1R axis by HG.

Anti-tumor effects of telmisartan in glioma-astrocyte non-contact co-cultures: A critical role of astrocytic IL-6-mediated paracrine growth promotion.

Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 µM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension.

Analysis of peri-implant bone tissue between hydrophilic and rough implant surfaces in spontaneously hypertensive rats treated with losartan.

OBJECTIVES: to evaluate the morphological and functional characteristics of the peri-implant bone tissue that was formed during the healing process by the placement implants using two different surface treatments: hydrophilic Acqua™ (ACQ) and rough NeoPoros™ (NEO), in spontaneously hypertensive (SHR) and normotensive rats (Wistar) whether or not treated with losartan. METHODOLOGY: In total, 96 male rats (48 Wistar and 48 SHR) were divided into eight subgroups: absolute control rough (COA NEO), absolute control hydrophilic (COA ACQ), losartan control rough (COL NEO), losartan control hydrophilic (COL ACQ), SHR absolute rough (SHR NEO), SHR absolute hydrophilic (SHR ACQ), SHR losartan rough (SHRL NEO), and SHR losartan hydrophilic (SHRL ACQ). The rats medicated with losartan received daily doses of the medication. NeoPoros™ and Acqua™ implants were installed in the tibiae of the rats. After 14 and 42 days of the surgery, the fluorochromes calcein and alizarin were injected in the rats. The animals were euthanized 67 days after treatment. The collected samples were analyzed by immunohistochemistry, biomechanics, microcomputerized tomography, and laser confocal scanning microscopy analysis. RESULTS: The osteocalcin (OC) and vascular endothelium growth factor (VEGF) proteins had moderate expression in the SHRL ACQ subgroup. The same subgroup also had the highest implant removal torque. Regarding microarchitectural characteristics, a greater number of trabeculae was noted in the control animals that were treated with losartan. In the bone mineralization activity, it was observed that the Acqua™ surface triggered higher values of MAR (mineral apposition rate) in the COA, COL, and SHRL groups (p<0.05). CONCLUSION: the two implant surface types showed similar responses regarding the characteristics of the peri-implant bone tissue, even though the ACQ surface seems to improve the early stages of osseointegration.

Losartan May Not Prevent Vestibular Schwannoma Growth or Related Hearing Loss During Observation.

OBJECTIVE: To evaluate the impact of losartan on vestibular schwannoma (VS) growth and related hearing loss during observation. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Sporadic VS patients undergoing initial observation with at least two magnetic resonance imaging and audiologic examinations. INTERVENTION: Losartan. MAIN OUTCOME MEASURES: Endpoints included VS growth, quantitative audiologic changes, survival free of tumor growth, and survival free of nonserviceable hearing. Patient characteristics and endpoints were compared by losartan use. RESULTS: Seventy-nine patients were included, of which 33% were taking losartan. Tumor growth was observed in 50% of patients in the losartan group and 36% in the non-losartan group (p = 0.329). Survival analysis failed to show a significant difference in the hazard rate of VS growth between groups (hazard ratio, 1.38; 95% confidence interval, 0.70-2.70; p = 0.346). Throughout observation, mean decreases in normalized pure-tone average were 5.5 and 9.3 dB in the losartan and non-losartan groups, respectively (p = 0.908). Mean decreases in normalized word recognition score were 11.0 and 16.6% in the losartan and non-losartan groups, respectively (p = 0.757). Nonserviceable hearing developed in 19% of patients in the losartan group and 28% in the non-losartan group (p = 0.734). Survival analysis did not demonstrate a significant difference in the hazard rate of developing nonserviceable hearing between groups (hazard ratio, 1.71; 95% confidence interval, 0.56-5.21; p = 0.337). CONCLUSIONS: Losartan use may not reduce the risk of VS growth or hearing loss during observation. A randomized trial would be ideal to further identify the true effect on growth and hearing.

The Renin-Angiotensin-Aldosterone System Regulates Sarcoidosis Granulomatous Inflammation.

Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation. Objectives: We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses. Methods: Using an established ex vivo model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan), and mineralocorticoid receptors (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis-generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis. Measurements and Main Results: Aldosterone was spontaneously produced by sarcoidosis peripheral blood mononuclear cells, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, peripheral blood mononuclear cells were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1ß, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone, or eplerenone, comparable to that of prednisone. Conclusions: The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses, with important implications for clinical management.

Lipoprotein glomerulopathy with markedly increased arterial stiffness successfully treated with a combination of fenofibrate and losartan: a case report.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness. CASE PRESENTATION: A 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels. CONCLUSION: Herein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.

Losartan ameliorates renal fibrosis by inhibiting tumor necrosis factor signal pathway.

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-ß1 (TGF-ß1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway.

Combination of losartan with pirfenidone: a protective anti-fibrotic against pulmonary fibrosis induced by bleomycin in rats.

Pirfenidone (PFD), one acceptable medication for treating idiopathic pulmonary fibrosis (IPF), is not well tolerated by patients at full doses. Hence, employing of some approaches such as combination therapy may be applicable for increasing therapeutic efficacy of PFD. Losartan (LOS), an angiotensin II receptor antagonist, could be a suitable candidate for combination therapy because of its stabilizing effect on the pulmonary function of IPF patients. Therefore, this study aimed to investigate the effects of LOS in combination with PFD on bleomycin (BLM)-induced lung fibrosis in rats. BLM-exposed rats were treated with LOS alone or in combination with PFD. The edema, pathological changes, level of transforming growth factor-ß (TGF-ß1), collagen content, and oxidative stress parameters were assessed in the lung tissues. Following BLM exposure, the inflammatory response, collagen levels, and antioxidant markers in rat lung tissues were significantly improved by PFD, and these effects were improved by combination with LOS. The findings of this in vivo study suggest that the combined administration of PFD and LOS may provide more potent protection against IPF than single therapy through boosting its anti-inflammatory, anti-fibrotic, and anti-oxidant effects. These results hold promise in developing a more effective therapeutic strategy for treating of lung fibrosis.

EDUCATION FROM DERMATOLOGISTS: THE SIMULTANEOUSLY DEVELOPMENT OF 16 KERATINOCYTIC CANCERS AFTER USE OF METFORMIN IN COMBINATION WITH LOSARTAN/ HYDROCHLOROTHIAZIDE, METOPROLOL AND NIFEDIPINE- IMPORTANT LINKS TO DRUG RELATED (PHOTO)-NITROSO-CARCINOGENESIS AND ONCOPHARMACOGENESIS.

Oncopharmacogenesis and Drug-Induced Skin cancer related Nitrosogenesis are newly introduced concepts in the medical literature that owe their genesis or presence to the carcinogens/ mutagens, also known as nitrosamines/NDSRIs, which are present in a heterogeneous class of drugs. The contribution to the origin of these 2 concepts is entirely due to 1) the functions and efficacy of FDA in terms of control and identification of these carcinogens, and 2) the establishment of clinicopathological correlations by the dermatologists, occurring during drug intake. According to recent FDA data, the concentration of NDMA in just one metformin tablet could be up to more than 5-fold increased. The intake of 3 to 6 tablets per day should result in a carcinogen intake that is 15 to 30 times elevated within the day and within the monomedication alone. It is these circumstances that paraphrase/ ˝betonate˝ concepts such as Onco-Pharmacogenesis and Drug-mediated Nitrosogenesis of skin cancer. Although not officially declared, these mutagens are present and have been in forced tolerance mode for the last 30-40 years. And after their intake, multiple cancers have been found to develop. The concomitant use of other nitrosamine-contaminated drugs such as losartan/hydrochlorothiazide, metoprolol and nefidipine should certainly not be surprising when it could also be associated with the development of exactly 16 keratinocytic tumours as in the case presented by us. Recent evidence in medical literature has linked the nitrosamine N-nitrosomorpholine (NMOR) with the direct development of its subsequent mutagenic action in rodents following irradiation with UVA. This fact leaves open the question of the potentially available photocarcinogenic action of the other nitrosamines in humans found in medicinal preparations. This is what necessitates a clarification of the concept of Photo-Nitroso-Carcinogenesis/ Oncogenesis in humans and its relationship to skin cancer. The overlap of the mutational patterns of some of the nitrosamine-induced mutations in target genes such as p53 and RAS oncogenes, with those of UV light-induced mutations - or practically the same ones mentioned above, suggest a possible significant role of the Drug-Induced Photo-Nitroso-Carcinogenesis of keratinocyte cancer in the context of Onco-Pharmacogenesis. Future analyses should focus on elucidating the photocarcinogenic effect of nitrosamines in drug preparations and differentiating Skin cancer Nitrosogenesis from ˝pure˝ Photo-Carcinogenesis and Nitroso-Photo-Carcinogenesis. The localization of the tumors in the area of the UV-exposed sites within the potential/actual contamination of the 4 preparations (simultaneously) in the described patient are indicative of a possible pathogenetic influence in the context of the already mentioned Nitroso-(Photo)carcinogenesis. Polycontamination of polymedication remains a so far unresolvable problem.

Topical Losartan for Treating Corneal Haze After Ultraviolet-A/Riboflavin Collagen Cross-Linking.

PURPOSE: The purpose of this study was to report our first clinical experience using topical losartan for the treatment of severe corneal haze after epithelium-off corneal cross-linking (CXL). METHODS: A 20-year-old man presented with clinically significant corneal haze in the right eye 1 month following Ultraviolet-A/Riboflavin Epithelium-off Collagen CXL. Haze progressed to a deep stromal scar, and vision was 20/150 with no improvement on refraction, 60 days after CXL. After unsuccessful treatment with topical corticosteroids, the patient elected to start off-label treatment with topical losartan 0.8 mg/mL, administered 6 times per day. RESULTS: After 3 months of initiating topical losartan, the right eye vision improved to preoperative vision of 20/40-1. Corneal haze was significantly reduced as observed on slitlamp examination and on Scheimpflug corneal tomography (Pentacam; OCULUS, Inc. Arlington, WA). CONCLUSIONS: Topical losartan, a transforming growth factor-ß inhibitor, is a potential treatment in clinically significant corneal haze following epithelium-off corneal CXL. This clinical experience highlights the potential efficacy of topical losartan as a novel therapeutic option in such cases, but further clinical studies are needed.

Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.

Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here we demonstrate that FDA-approved therapies (bevacizumab and losartan, respectively) can be repurposed as HDTs to normalize blood vessels and extracellular matrix (ECM), improve drug delivery, and reduce bacterial loads in TB granulomas. Granulomas feature an overabundance of ECM and compressed blood vessels, both of which are effectively reduced by losartan treatment in the rabbit model of TB. Combining both HDTs promotes secretion of proinflammatory cytokines and improves anti-TB drug delivery. Finally, alone and in combination with second-line antitubercular agents (moxifloxacin or bedaquiline), these HDTs significantly reduce bacterial burden. RNA sequencing analysis of HDT-treated lung and granuloma tissues implicates up-regulated antimicrobial peptide and proinflammatory gene expression by ciliated epithelial airway cells as a putative mechanism of the observed antitubercular benefits in the absence of chemotherapy. These findings demonstrate that bevacizumab and losartan are well-tolerated stroma-targeting HDTs, normalize the granuloma microenvironment, and improve TB outcomes, providing the rationale to clinically test this combination in TB patients.

A design of experiment based RP-HPLC method for the simultaneous estimation of antihypertensive drugs with greenness assessment.

The correlation between blood pressure (BP) and cardiovascular risk has a continuous, positive, and linear pattern. Lowering high BP decreases the risk associated with cardiovascular disease. Chlorthalidone (CHD) and Losartan potassium (LOS) combination is used to treat hypertension. The analytical community was concerned with minimizing or reducing the use of toxic chemicals and solvents. Therefore, the current study aimed to develop a rapid, sensitive, and cost-effective green RP-HPLC method to determine CHD and LOS simultaneously in a short analysis of time. Method optimization was performed by Central composite design (CCD), the flow rate and the change of time were chosen as factors. Effective separation was conducted on Zorbax SB-C18 (4.6 mm × 150 mm, 5 µm) column by gradient mobile phase comprising phosphate buffer and ethanol flowing at 0.859 ml/min, and the wavelength detected at 230 nm. As per ICH criteria, the technique was proven to be precise, accurate, and linear over the concentration range of 4.3-8.1 µg/ml for CHD and 35-65 µg/ml for LOS. Furthermore, the method's greenness was examined by three different metrics, confirming that less toxic effect on the environment. Hence, the optimized approach proves to be eco-friendly, simple, and robust for the concurrent evaluation of CHD and LOS in pharmaceutical formulations.

Green synthesis of carbon nanotubes functionalized with iron nanoparticles and coffee husk biomass for efficient removal of losartan and diclofenac: Adsorption kinetics and ANN modeling studies.

The presence of emerging contaminants in wastewater poses a global environmental challenge, requiring the development of innovative materials or methods for their treatment. This study focused on the production of green functionalized carbon nanotubes (CNTs) and using them in the adsorption of the pharmaceuticals Losartan (LOS) and Diclofenac (DIC). The efficiency of the methodology was verified by characterization techniques. Elemental composition analysis indicated a significant increase in the iron content after the green functionalization, proving the effectiveness of the method. Thermogravimetric analysis showed similar thermal degradation profiles for pristine CNTs and functionalized CNTs, indicating better post-functionalization thermal stability. BET analysis revealed mesoporous characteristics of CNTs, with increased surface area and pore volumes after functionalization. X-Ray diffraction confirmed the preservation of the lattice structure of the CNTs post-functionalization and post-adsorption, with changes in peak broadening suggesting surface modifications. LOS and DIC adsorption were evaluated via kinetic studies at four different concentrations (0.1-0.4 mmol/L) that were best represented by the pseudo-second order model, suggesting chemisorption mechanisms, with faster and higher uptakes for DIC (0.084-0.261 mmol/g; teq = 5 min) when compared to LOS (0.058-0.235 mmol/g; teq = 20 min). The curves were also studied via artificial neural networks (ANN) and revealed that the best ANN architecture for representing the experimental data is a network with [3 5 5 2] neurons trained using the Bayesian-Regularization algorithm and the Log-sigmoid (hidden layers) and Linear (output layer) transfer functions. The desorption study showed that CaCl2 had better performance in CNT regeneration, reaching its removal capacity above 50% up to 3 cycles, for both pharmaceuticals. These findings reveal the potential of the developed material as a promising adsorbent for targeted removal of pollutants, contributing to advances in the remediation of emerging contaminants and the application of artificial intelligence in adsorption research.

Cardioprotective effects of losartan and diminazene against the ischemia/reperfusion injury in hyperthyroidism rats.

Hyperthyroidism is a condition where the thyroid gland produces high levels of thyroid hormone. Heart diseases are one of the main complications of hyperthyroidism. Several studies have shown that losartan (LOS) and diminazene aceturate (DIZE) possess cardioprotection effects against cardiac hypertrophy, ischemic heart disease, and heart failure. The research aimed to investigate the cardioprotection of LOS, DIZE, and their combination in the case of levothyroxine (LT4)-induced cardiomyopathy in rats. Hyperthyroidism was induced by LT4 in drinking water (12 mg/L) for 28 days. LOS (10 mg/kg, orally) and/or DIZE (15 mg/kg, subcutaneously) were administrated in rats with hyperthyroidism for 28 days. Decreased serum creatine kinase myoglobin and lactate dehydrogenase levels and cardiac hypertrophy by DIZE and combination therapy in hyperthyroidism rats have been reported. Cardiac hemodynamic findings showed that DIZE and its combination with LOS decreased the LT4-mediated left ventricular developed pressure (LVDP), rate pressure product (RPP), and RPP recovery percentage. Elevated cardiac oxidative stress and inflammation were confirmed by decreasing cardiac superoxide dismutase (SOD) activity and increasing the total oxidative stress and tumor necrosis factor-alpha (TNF-α) levels. SOD activity and TNF-α level were reversed by LOS and DIZE administration, respectively. Generally, DIZE and combination therapy with LOS improved cardiac dysfunction caused by hyperthyroidism in rats, whereas LOS alone has not been able to effectively respond to this dysfunction.

High Dose of Estrogen Protects the Lungs from Ischemia-Reperfusion Injury by Downregulating the Angiotensin II Signaling Pathway.

We explored the sex difference in lung ischemia-reperfusion injury (LIRI) and the role and mechanism of estrogen (E2) and angiotensin II (Ang II) in LIRI. We established a model of LIRI in mice. E2, Ang II, E2 inhibitor (fulvestrant), and angiotensin II receptor blocker (losartan) were grouped for treatment. The lung wet/dry weight ratio, natural killer (NK) cells (by flow cytometry), neutrophils (by flow cytometry), expression of key proteins (by Western blot, immunohistochemistry, ELISA, and immunofluorescence), and expression of related protein mRNA (by qPCR) were detected. The ultrastructure of the alveolar epithelial cells was observed by transmission electron microscopy. We found that E2 and Ang II played an important role in the progression of LIRI. The two signaling pathways showed obvious antagonism, and E2 regulates LIRI in the different sexes by downregulating Ang II, leading to a better prognosis. E2 and losartan reduced the inflammatory cell infiltration in lung tissue and key inflammatory factors in serum while fulvestrant and Ang II had the opposite effect. The protective effect of E2 was related with AKT, p38, COX2, and HIF-1α.

[Preparation and evaluation of chitosan-based light source-loaded soluble microneedles].

The combination of photodynamic therapy and drug delivery microneedle (MN) provides a safe and effective way to treat tumors. In this paper, we designed a controlled and sustained-release drug-loaded microneedle patch (LED-losartan-HEMA/CS-MN, LLH-CSMN) based on chitosan loaded with high-energy photons, investigated its preparation process, and characterized the morphology and size of the microneedle array with losartan as the model drug. The mechanical properties of LLH-CSMN, skin puncture properties, slow release properties and the photothermal properties of high energy photons under long-term operation were investigated. The experimental results showed that the chitosan-based microneedle patch loaded with high-energy photons can effectively open channels on the skin surface for drug delivery and photodynamic therapy. At the same time, the in vitro percutaneous diffusion experiment showed that the microneedles prepared with losartan as the model drug released about 30% of the drug within 1 h, about 60% of the drug in total within 1 d, followed by slow release, and finally released 93% of the drug after 6 d. LLH-CSMN has controllable slow-release characteristics and good long-term photoassisted therapy effect. It provides a new safe and effective way for tumor treatment.

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy.

PURPOSE: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

Modelling and breaking down the biophysical barriers to drug delivery in pancreatic cancer.

The pancreatic ductal adenocarcinoma (PDAC) stroma and its inherent biophysical barriers to drug delivery are central to therapeutic resistance. This makes PDAC the most prevalent pancreatic cancer with poor prognosis. The chemotherapeutic drug gemcitabine is used against various solid tumours, including pancreatic cancer, but with only a modest effect on patient survival. The growing PDAC tumour mass with high densities of cells and extracellular matrix (ECM) proteins, i.e., collagen, results in high interstitial pressure, leading to vasculature collapse and a dense, hypoxic, mechanically stiff stroma with reduced interstitial flow, critical to drug delivery to cells. Despite this, most drug studies are performed on cellular models that neglect these biophysical barriers to drug delivery. Microfluidic technology offers a promising platform to emulate tumour biophysical characteristics with appropriate flow conditions and transport dynamics. We present a microfluidic PDAC culture model, encompassing the disease's biophysical barriers to therapeutics, to evaluate the use of the angiotensin II receptor blocker losartan, which has been found to have matrix-depleting properties, on improving gemcitabine efficacy. PDAC cells were seeded into our 5-channel microfluidic device for a 21-day culture to mimic the rigid, collagenous PDAC stroma with reduced interstitial flow, which is critical to drug delivery to the cancer cells, and for assessment with gemcitabine and losartan treatment. With losartan, our culture matrix was more porous with less collagen, resulting in increased hydraulic conductivity of the culture interstitial space and improved gemcitabine effect. We demonstrate the importance of modelling tumour biophysical barriers to successfully assess new drugs and delivery methods.

Enhanced Tumor Targeting of Radiolabeled Mouse/Human Chimeric Anti-Tn Antibody in Losartan-Treated Mice Bearing Tn-Expressing Lung Tumors.

Aim: ChiTn, a mouse/human chimeric anti-Tn monoclonal antibody, was radiolabeled with iodine-131 (131I) and technetium-99m (99mTc) to assess its biodistribution and internalization in Tn-expressing (Tn+) and wild-type (Tn-) LL/2 lung cancer cells. Results: Selective accumulation and gradual internalization of ChiTn were observed in Tn+ cells. Biodistribution in mice with both Tn+ or Tn- lung tumors indicated that the uptake of radiolabeled ChiTn within tumors increased over time. Dual-labeling experiments with 99mTc and 131I showed different biodistribution patterns, with 99mTc exhibiting higher values in the liver, spleen, and kidneys, while 131I showed higher uptake in the thyroid and stomach. However, tumor uptake did not significantly differ between Tn+ and Tn- tumors. To improve tumor targeting, Losartan, an antihypertensive drug known to enhance tumor perfusion and drug delivery, was investigated. Biodistribution studies in Losartan-treated mice revealed significantly higher radiolabeled ChiTn uptake in Tn+ tumors. No significant changes were observed in the uptake of the control molecule IgG-HYNIC™99mTc. Conclusions: These findings demonstrate the enhanced tumor targeting of radiolabeled ChiTn in Losartan-treated mice with Tn-expressing lung tumors. They highlight the potential of ChiTn as a theranostic agent for cancer treatment and emphasize the importance of Losartan as an adjunctive treatment to improve tumor perfusion and drug delivery.

Engineering Nanosensitizer to Remodel the TME for Hypoimmunogenic "Cold"-"Hot" Tumor Transformations.

α-PD-L1 therapy has shown encouraging results at harnessing the immune system to combat cancer. However, the treatment effect is relatively low due to the dense extracellular matrix (ECM) and tumor immunosuppressive microenvironment (TIME). Therefore, an ultrasound (US)-responsive nanosensitizer (URNS) is engineered to deliver losartan (LST) and polyethylenimine (PEI) to remolde the TME, driving "cold"-"hot" tumor transformation and enhancing the sensitivity of α-PD-L1 therapy. In the tumor site, noninvasive US can make MTNP generate ROS, which cleave ROS-sensitive bonds to dissociate MTNPtK@LST-PEI, shedding PEI and releasing LST from mesoporous spheres. The results demonstrated that URNS combined with α-PD-L1 therapy effectively inhibited tumor growth with an inhibition rate as high as 90%, which was 1.7-fold higher than that of the α-PD-L1 treatment in vivo. In summary, the URNS improves the sensitivity of α-PD-L1 therapy by remodeling the TME, which provides promising insights for optimizing cancer immunotherapy.