Histopathology Of Heart Research Articles

Synergistic ameliorating effect of dithiophenolate chitosan nanoparticle and Solanum nigrum combination against lead-induced cardiotoxicity in rats.

Lead (Pb) toxicity is one of the most common causes of human cardiotoxicity. We evaluated the therapeutic role of Solanum nigrum extract (SNE) and dithiophenolate-chitosan nanoparticle (DTP-CSNP) on Pb-induced cardiotoxicity in rats, and the results were compared with the dimercaptosuccinic acid (DMSA, reference drug). Additionally, the combination effect of SNE and DTP-CSNP against Pb-induced cardiotoxicity was assessed. The study focused on the determination of the antioxidant, anti-inflammatory, anti-apoptotic, and cardiotherapeutic functions of SNE (375 mg/kg), DTP-CSNP (20 and 40 mg/kg), and their combination (SNE+DTP40). The characterization of SNE and DTP-CSNP was studied. The results showed that SNE contains phenolics, flavonoids, ascorbic acid, and minerals, which may play an important role in its therapeutic effect. SNE, DTP20, and DTP40 exhibited a therapeutic impact against cardiotoxicity by reducing Pb levels, oxidative stress, inflammation, and cell death. Moreover, they regulated the abnormal levels of cardiac biomarkers induced by Pb toxicity. DTP-CSNP showed a superior therapeutic effect to DMSA, and the SNE+DTP40 combination displayed a synergistic anti-cardiotoxic effect (combination index ˂ 1). These results were in harmony with heart histopathology. Thus, the combination of both SNE and DTP-CSNP has powerful efficacy in the treatment of cardiotoxicity and can be a good alternative to DMSA.

Therapeutic effects of FGF21 mimetic bFKB1 on MASH and atherosclerosis in Ldlr-/-.Leiden mice.

Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-β klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr-/-).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (-21%) and adipose tissue mass (-22%) without reducing food intake. The treatment also improved plasma insulin (-80%), cholesterol (-48%), triglycerides (-76%), alanine transaminase (ALT: -79%), and liver weight (-43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis -34%; microvesicular steatosis -100%; inflammation -74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (-49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (-16%) and inflammation (-52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (-38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.

Low-intensity focused ultrasound combined with microbubbles for non-invasive downregulation of rabbit carotid body activity in the treatment of hypertension.

Targeting the carotid body (CB) is a new approach in treating hypertension. This study investigates the efficacy and safety of ultrasound combined with microbubbles in targeting CB to treat hypertension. Twenty-seven hypertensive rabbits were randomly assigned to three groups: microbubbles only (sham group, n = 11), ultrasound plus microbubbles (LIFU group, n = 11), and bilateral carotid sinus nerve denervation (CSND group, n = 5). Four weeks post-intervention, blood pressure, hypoxic ventilatory response (HVR), blood pressure variability (BPV), heart rate variability (HRV), biochemical indicators, neurohormones, and histopathology were assessed in all groups. The results indicated significant reductions in systolic and diastolic blood pressure in the LIFU and CSND groups post-intervention, along with decreases in BPV, HRV, and catecholamines. HVR results showed a 35.10% reduction in CB activity in the LIFU group compared to the sham group, which was significantly lower than the reduction in the CSND group compared to the sham group (73.85%). Histopathology and transmission electron microscopy confirmed CB damage and cell apoptosis, with immunofluorescence showing a reduction in type I and II cells. In conclusion, LIFU combined with microbubbles can reduce blood pressure by lowering CB and sympathetic nerve activity.

Cardioprotective effect of S-adenosyl L-methionine due to antioxidant and anti-inflammatory properties on isoproterenol-induced chronic heart failure in Wistar rats.

The development and progression of chronic heart failure (CHF), hypertrophy, and remodeling strongly correlate with myocardial inflammation and oxidative stress. S-adenosylmethionine (SAMe), available as a dietary supplement, exerts anti-inflammatory and antioxidant effects. Previous reports show that by regulating angiogenesis and fibrosis, S-adenosyl-L-methionine improves ventricular remodeling. The study objectives were to investigate the cardioprotective effect of SAMe in isoproterenol (ISO)-induced CHF and explore the anti-inflammatory and antioxidant properties of SAMe in this model. After animal ethics permission, CHF was induced using ISO of 10 mg/kg for 14 consecutive days in 24 Wistar rats. There were four groups of six rats in each group: Sham Control, Disease Control (DC), ISO + SAMe 100 mg, and ISO + SAMe 200 mg. The variables assessed were heart to body weight ratio (HW/BW mg/g), bio-distribution of Flourine 18-Fluorodeoxyglucose (18F-FDG) in heart tissue, tumor necrosis factor-α (TNF-α) and glutathione (GSH) levels in heart tissue, histopathology, and positron emission tomography imaging. SAMe in ISO-induced CHF animals showed a significant decrease in the HW/BW compared to DC group (P < 0.001). 18F-FDG uptake was significantly reduced by SAMe in CHF-induced rats compared to DC rats for both doses (P < 0.001). SAMe showed significantly better values of both TNF-α and GSH than the DC group in both doses (P < 0.001). SAMe in both doses showed multifocal necrosis with scarring and minimal inflammatory cells. SAMe exerts a cardioprotective effect on ISO-induced CHF in rats because of its antioxidant and anti-inflammatory properties.

Cardiac Histopathology Alterations Induced by Subchronic Mangosteen Rind Extract in Wistar Rats

Mangosteen (Garcinia mangostana L.) is renowned for its potent antioxidant characteristics, including free radical scavenging, and its antibacterial, antifungal, anti-inflammatory, and antidiabetic properties. This study aims to assess the subchronic toxicity effects of ethanol extract from mangosteen rind on the cardiac histopathology of male and female Wistar rats. This research was a posttest-only control group design. Forty biological specimens from 40 Wistar rats were divided into four groups, a control group, and three treatment groups, which were given ethanol extract of mangosteen rind with doses of 250 mg/kg, 500 mg/kg, and 1,000 mg/kg for 28 days. Cardiac specimens were prepared and examined using hematoxylin-eosin (HE) staining at the Anatomical Pathology Laboratory of Universitas Jenderal Achmad Yani in December 2021. The findings indicated that prolonged ingestion of large amounts of ethanol extract from mangosteen rind can cause toxic effects characterized by an inflammatory response in cardiac tissue. No fibrosis or hypertrophy was detected; however, inflammatory changes such as the presence of inflammatory cells, vacuolar changes, and neovascularization were observed. The inflammation observed might be due to excessive antioxidant administration leading to oxidative stress. Inflammatory cells may trigger fibrotic remodeling in the heart. The difference in the quantity of inflammatory cells between male and female rats suggests that gender influences the inflammatory response. Overall, administration of ethanol extract from mangosteen rind at doses of 250 mg/kg, 500 mg/kg, and 1,000 mg/kg cause subchronic toxicity effects on the heart histopathology of Wistar rats, marked by inflammation.

Methanolic Extract of Phoenix Dactylifera Confers Protection against Experimental Diabetic Cardiomyopathy through Modulation of Glucolipid Metabolism and Cardiac Remodeling.

The incidence of cardiovascular disorders is continuously rising, and there are no effective drugs to treat diabetes-associated heart failure. Thus, there is an urgent need to explore alternate approaches, including natural plant extracts, which have been successfully exploited for therapeutic purposes. The current study aimed to explore the cardioprotective potential of Phoenix dactylifera (PD) extract in experimental diabetic cardiomyopathy (DCM). Following in vitro phytochemical analyses, Wistar albino rats (N = 16, male; age 2-3 weeks) were fed with a high-fat or standard diet prior to injection of streptozotocin (35 mg/kg i.p.) after 2 months and separation into the following four treatment groups: healthy control, DCM control, DCM metformin (200 mg/kg/day, as the reference control), and DCM PD treatment (5 mg/kg/day). After 25 days, glucolipid and myocardial blood and serum markers were assessed along with histopathology and gene expression of both heart and pancreatic tissues. The PD treatment improved glucolipid balance (FBG 110 ± 5.5 mg/dL; insulin 17 ± 3.4 ng/mL; total cholesterol 75 ± 8.5 mg/dL) and oxidative stress (TOS 50 ± 7.8 H2O2equiv./L) in the DCM rats, which was associated with preserved structural integrity of both the pancreas and heart compared to the DCM control (FBG 301 ± 10 mg/dL; insulin 27 ± 3.4 ng/mL; total cholesterol 126 ± 10 mg/dL; TOS 165 ± 12 H2O2equiv./L). Gene expression analyses revealed that PD treatment upregulated the expression of insulin signaling genes in pancreatic tissue (INS-I 1.69 ± 0.02; INS-II 1.3 ± 0.02) and downregulated profibrotic gene expression in ventricular tissue (TGF-β 1.49 ± 0.04) compared to the DCM control (INS-I 0.6 ± 0.02; INS-II 0.49 ± 0.03; TGF-β 5.7 ± 0.34). Taken together, these data indicate that Phoenix dactylifera may offer cardioprotection in DCM by regulating glucolipid balance and metabolic signaling.

Biochemical properties and biological potential of Syzygium heyneanum with antiparkinson's activity in paraquat induced rodent model.

Syzygium heyneanum is a valuable source of flavonoids and phenols, known for their antioxidant and neuroprotective properties. This research aimed to explore the potential of Syzygium heyneanum ethanol extract (SHE) in countering Parkinson's disease. The presence of phenols and flavonoids results in SHE displaying an IC50 value of 42.13 when assessed in the DPPH scavenging assay. Rats' vital organs (lungs, heart, spleen, liver, and kidney) histopathology reveals little or almost no harmful effect. The study hypothesized that SHE possesses antioxidants that could mitigate Parkinson's symptoms by influencing α-synuclein, acetylcholinesterase (AChE), TNF-α, and IL-1β. Both in silico and in vivo investigations were conducted. The Parkinson's rat model was established using paraquat (1 mg/kg, i.p.), with rats divided into control, disease control, standard, and SHE-treated groups (150, 300, and 600 mg/kg) for 21 days. According to the ELISA statistics, the SHE treated group had lowers levels of IL-6 and TNF-α than the disease control group, which is a sign of neuroprotection. Behavioral and biochemical assessments were performed, alongside mRNA expression analyses using RT-PCR to assess SHE's impact on α-synuclein, AChE, TNF-α, and interleukins in brain homogenates. Behavioral observations demonstrated dose-dependent improvements in rats treated with SHE (600 > 300 > 150 mg/kg). Antioxidant enzyme levels (catalase, superoxide dismutase, glutathione) were significantly restored, particularly at a high dose, with notable reduction in malondialdehyde. The high dose of SHE notably lowered acetylcholinesterase levels. qRT-PCR results indicated reduced mRNA expression of IL-1β, α-synuclein, TNF-α, and AChE in SHE-treated groups compared to disease controls, suggesting neuroprotection. In conclusion, this study highlights Syzygium heyneanum potential to alleviate Parkinson's disease symptoms through its antioxidant and modulatory effects on relevant biomarkers.

C-terminal fragment of fibroblast growth factor 23 improves heart function in murine models of high intact fibroblast growth factor 23.

Cardiovascular disease (CVD) is the major cause of death in chronic kidney disease (CKD) and is associated with high circulating fibroblast growth factor (FGF)23 levels. It is unresolved whether high circulating FGF23 is a mere biomarker or pathogenically contributes to cardiomyopathy. It is also unknown whether the C-terminal FGF23 peptide (cFGF23), a natural FGF23 antagonist proteolyzed from intact FGF23 (iFGF23), retards CKD progression and improves cardiomyopathy. We addressed these questions in three murine models with high endogenous FGF23 and cardiomyopathy. First, we examined wild-type (WT) mice with CKD induced by unilateral ischemia-reperfusion and contralateral nephrectomy followed by a high-phosphate diet. These mice were continuously treated with intraperitoneal implanted osmotic minipumps containing either iFGF23 protein to further escalate FGF23 bioactivity, cFGF23 peptide to block FGF23 signaling, vehicle, or scrambled peptide as negative controls. Exogenous iFGF23 protein given to CKD mice exacerbated pathological cardiac remodeling and CKD progression, whereas cFGF23 treatment improved heart and kidney function, attenuated fibrosis, and increased circulating soluble Klotho. WT mice without renal insult placed on a high-phosphate diet and homozygous Klotho hypomorphic mice, both of whom develop moderate CKD and clear cardiomyopathy, were treated with cFGF23 or vehicle. Mice treated with cFGF23 in both models had improved heart and kidney function and histopathology. Taken together, these data indicate high endogenous iFGF23 is not just a mere biomarker but pathogenically deleterious in CKD and cardiomyopathy. Furthermore, attenuation of FGF23 bioactivity by cFGF23 peptide is a promising therapeutic strategy to protect the kidney and heart from high FGF23 activity.NEW & NOTEWORTHY There is a strong correlation between cardiovascular morbidity and high circulating fibroblast growth factor 23 (FGF23) levels, but causality was never proven. We used a murine chronic kidney disease (CKD) model to show that intact FGF23 (iFGF23) is pathogenic and contributes to both CKD progression and cardiomyopathy. Blockade of FGF23 signaling with a natural proteolytic product of iFGF23, C-terminal FGF23, alleviated kidney and cardiac histology, and function in three separate murine models of high endogenous FGF23.

Semiautomated pipeline for quantitative analysis of heart histopathology

BackgroundHeart diseases are among the leading causes of death worldwide, many of which lead to pathological cardiomyocyte hypertrophy and capillary rarefaction in both patients and animal models, the quantification of which is both technically challenging and highly time-consuming. Here we developed a semiautomated pipeline for quantification of the size of cardiomyocytes and capillary density in cardiac histology, termed HeartJ, by generating macros in ImageJ, a broadly used, open-source, Java-based software.MethodsWe have used modified Gomori silver staining, which is easy to perform and digitize in high throughput, or Fluorescein-labeled lectin staining. The latter can be easily combined with other stainings, allowing additional quantitative analysis on the same section, e.g., the size of cardiomyocyte nuclei, capillary density, or single-cardiomyocyte protein expression. We validated the pipeline in a mouse model of cardiac hypertrophy induced by transverse aortic constriction, and in autopsy samples of patients with and without aortic stenosis.ResultsIn both animals and humans, HeartJ-based histology quantification revealed significant hypertrophy of cardiomyocytes reflecting other parameters of hypertrophy and rarefaction of microvasculature and enabling the analysis of protein expression in individual cardiomyocytes. The analysis also revealed that murine and human cardiomyocytes had similar diameters in health and extent of hypertrophy in disease confirming the translatability of our murine cardiac hypertrophy model. HeartJ enables a rapid analysis that would not be feasible by manual methods. The pipeline has little hardware requirements and is freely available.ConclusionsIn summary, our analysis pipeline can facilitate effective and objective quantitative histological analyses in preclinical and clinical heart samples.

Euterpe oleracea extract (açaí) exhibits cardioprotective effects after chemotherapy treatment in a breast cancer model.

Açaí, a Brazilian native fruit, has already been demonstrated to play a role in the progress of breast cancer and cardiotoxicity promoted by chemotherapy agents. Thus, the present study aimed to evaluate the combined use of açaí and the FAC-D chemotherapy protocol in a breast cancer model in vivo. Mammary carcinogenesis was induced in thirty female Wistar rats by subcutaneous injection of 25mg/kg 7,12-dimethylbenzanthracene (DMBA) in the mammary gland. After sixty days, the rats were randomized into two groups: treated with 200mg/kg of either açaí extract or vehicle, via gastric tube for 45 consecutive days. The FAC-D protocol was initiated after 90 days of induction by intraperitoneal injection for 3 cycles with a 7-day break each. After treatment, blood was collected for haematological and biochemical analyses, and tumours were collected for macroscopic and histological analyses. In the same way, heart, liver, and kidney samples were also collected for macroscopic and histological analyses. Breast cancer was found as a cystic mass with a fibrotic pattern in the mammary gland. The histological analysis showed an invasive carcinoma area in both groups; however, in the saline group, there was a higher presence of inflammatory clusters. No difference was observed regarding body weight, glycaemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and urea in either group. However, açaí treatment decreased creatine kinase (CK), creatine kinase MB (CKMB), troponin I and C-reactive protein levels and increased the number of neutrophils and monocytes. Heart histopathology showed normal myocardium in the açaí treatment, while the saline group presented higher toxicity effects with loss of architecture of cardiac tissue. Furthermore, the açaí treatment presented greater collagen distribution, increased hydroxyproline concentration and lower H2AX immunostaining in the heart samples. Açaí decreased the number of inflammatory cells in the tumor environment and exhibited protection against chemotherapy drug cardiotoxicity with an increased immune response in animals. Thus, açaí can be considered a promising low-cost therapeutic treatment that can be used in association with chemotherapy agents to avoid heart damage.

Rifampicin efficacy against doxorubicin-induced cardiotoxicity in mice

BackgroundThe toxic effect of doxorubicin on the heart limits its clinical usage in cancer therapy. This work intended to investigate, for the first time, the efficacy of rifampicin administration against doxorubicin-induction of cardiotoxicity in mice. Forty adult male albino mice were distributed into four sets: Control, Doxorubicin, Doxorubicin + Rifampicin 0.107, and Doxorubicin + Rifampicin 0.214, with n = 10 for each. Heart histopathology and biochemical assays for heart function tests [creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), cardiac troponin I (cTnI), atrial natriuretic peptide (ANP), and vascular endothelial growth factor (VEGF)], oxidative stress [malondialdehyde (MDA) and superoxide dismutase (SOD)], and minerals [phosphorus, sodium, potassium, and calcium] were done.ResultsDoxorubicin-induced cardiotoxicity using a total dose of 15 mg/kg was confirmed histologically. Cardiomyocytes showed congestion, necrosis, edema, and inflammatory cell infiltration. Biochemically, elevations in LDH, CK, and AST activities, p < 0.001, as well as increases in cTnI and ANP levels, p < 0.001, increased oxidative stress (MDA, p < 0.001), high minerals (Na, K, p < 0.001, P, p < 0.01, and Ca, p < 0.05), with reduced VEGF concentration, p < 0.001, and low antioxidant (SOD, p < 0.001) were observed in the Doxorubicin group compared to control. Co-treatment with rifampicin significantly (p < 0.001) reduced the increased oxidative stress, high Na and K, increased LDH, CK, AST, cTnI, and ANP, and elevated the low SOD toward the normal ranges. Our histological data supported our biochemical data; rifampicin dose 0.214 mg/kg showed better improvements than dose 0107.ConclusionsOur results demonstrated that rifampicin could help protect the body against doxorubicin-induced cardiotoxicity through its antioxidative effect.

Doxorubicin loaded zinc oxide nanoflowers – Surmounting drug-induced toxicity

Doxorubicin (DOX) induces cardiotoxicity, hepatotoxicity and nephrotoxicity, through multiplicity of mechanisms involving the production of free radicals causing oxidative stress and apoptosis. Zinc oxide (ZnO) nanomaterials, besides biocompatibility and biodegradability, also show the protective effect on cells and organs. The current study aspires to delve into the protective effects of ZnO in DOX-loaded ZnO nanoflowers (DOX-ZnO-NFs). Comparative in-vitro toxicities of DOX, blank zinc oxide nanoflowers (ZnO-NFs) and DOX-ZnO-NFs were examined against in-vitro normal Henrietta Lacks (HeLa) cell line and in-vivo in the Wistar rats. The change in body weight, hematological parameters and biochemical biomarkers of heart, kidney and liver and histopathology of tissues were examined at 24 h and after 14 days post dosing of the test moieties. DOX-ZnO-NFs portrayed biocompatibility and safety in the HeLa cells and the kidneys, liver and heart of Wistar rats. At 30 μg/ml, DOX-ZnO-NFs showed 72.53 ± 0.39% cell survival rate, relative to 80.59 ± 0.99% by ZnO-NFs and 13.8 ± 0.22%, by DOX. DOX-ZnO-NFs and ZnO-NFs caused slight change in organ's weight, minimum haemolysis, little effect on liver and kidney enzymes, improved activity of antioxidant enzymes and maintained tissues' architecture relative to the bare DOX. The drug-free ZnO-NFs with the maximum safety supported the protective effect of ZnO and, thus DOX-ZnO-NFs surmounted the DOX-induced systemic toxicity.

1621-P: Commercially Available Stevia-Based Sweetener, Antidiabetic or Toxic—An Ad Libitum Feeding Study in a Type 2 Diabetes Model of Rat

The use of non-nutritive sweeteners as sugar substitutes by overweight, obese and diabetic individuals has been increased rapidly in recent years, when Stevia is the most popular one not only due to its natural source of origin but also for it antidiabetic potential. However, the effects commercially available stevia-based NNS are not investigated at all. The present study was conducted to investigate the effects of ad libitum consumption of commercially available stevia-based non-nutritive sweetener (NNS) in an experimentally-induced rat model of type 2 diabetes (T2D). Seven-week-old male Sprague-Dawley rats were randomly divided into three groups, namely: Normal Control (NC), Diabetic Control (DBC) and Diabetic Stevia (DSTV). T2D was induced in the DBC and DSTV groups only. The control groups were received normal drinking water, whilst rats in the DSTV group were administered with stevia-containing NNS solution, at a concentration equivalent to the sweetness of 10% sucrose. After 13 week intervention, although food and fluid intake, body weight, weekly blood glucose, glucose tolerance, serum insulin, fructosamine, ALT, ALP, creatinine and brain, liver and pancreatic histopathology were not significantly affected; serum AST, LDH and CK-MB as well as heart and kidney histopathology were significantly deteriorated in stevia-based NNS consuming group compared to the DBC group. The data of this study suggest that uncontrolled consumption of stevia-based NNS has no significant antidiabetic effect but have some toxicological effects in an animal model of T2D. Hence, diabetic patients consuming stevia-based NNS should limit their daily intake. Disclosure S. Islam: None. S.N. Dlamini: None. Funding South African Sugar Association (Project 233)

Carvacrol enhances anti-tumor activity and mitigates cardiotoxicity of sorafenib in thioacetamide-induced hepatocellular carcinoma model through inhibiting TRPM7

AimsSorafenib (Sora) represents one of the few effective drugs for the treatment of advanced hepatocellular carcinoma (HCC), while resistance and cardiotoxicity limit its therapeutic efficacy. This study investigated the effect of transient receptor potential melastatin 7 (TRPM7) inhibitor, carvacrol (CARV), on overcoming Sora resistance and cardiotoxicity in thioacetamide (TAA) induced HCC in rats. Materials and methodsTAA (200 mg/kg/twice weekly, intraperitoneal) was administered for 16 weeks to induce HCC. Rats were treated with Sora (10 mg/Kg/day; orally) and CARV (15 mg/kg/day; orally) alone or in combination, for six weeks after HCC induction. Liver and heart functions, antioxidant capacity, and histopathology were performed. Apoptosis, proliferation, angiogenesis, metastasis, and drug resistance were assessed by quantitative real time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry. Key findingsCARV/Sora combination significantly improved survival rate, and liver functions, reduced Alpha-Fetoprotein level, and attenuated HCC progression compared with Sora group. CARV coadministration almost obviated Sora-induced changes in cardiac and hepatic tissues. The CARV/Sora combination suppressed drug resistance and stemness by downregulating ATP-binding cassette subfamily G member 2, NOTCH1, Spalt like transcription factor 4, and CD133. CARV boosted Sora antiproliferative and apoptotic activities by decreasing cyclin D1 and B-cell leukemia/lymphoma 2 and increasing BCL2-Associated X and caspase-3. SignificanceCARV/Sora is a promising combination for tumor suppression and overcoming Sora resistance and cardiotoxicity in HCC by modulating TRPM7. To our best knowledge, this study represents the first study to investigate the efficiency of CARV/ Sora on the HCC rat model. Moreover, no previous studies have reported the effect of inhibiting TRPM7 on HCC.

Kleinhovia Hospita Leaf Extract Protects the Heart Against Infarction by Isoproterenol

Background: Isoproterenol, a β-adrenergic agonist, may induce myocardial infarction when used in high dosage in rats. This study was conducted to evaluate the effect of the ethanol extract of Kleinhovia hospita leaves on cardiac biomarkers and myocardial structures of rats induced by isoproterenol. Methods: Male rats (n=30) were assigned as a normal controls or treatment groups. The treatment groups received pretreatments, either placebo or the extract at doses of 250, 500, or 750 mg/kg for 14 days, followed by two isoproterenol injections at 100 mg/kg. After 24 hours, blood samples were taken and the hearts dissected. The tested cardiac biomarkers were creatinine kinase myocardial band (CKMB) and lactate dehydrogenase (LDH). Heart histopathology analysis was performed followed by staining of samples with hematoxylin and eosin. Results: The isoproterenol injections significantly increased CKMB and LDH levels in the placebo group compared to those in normal controls. Pretreatment with the extract at doses of 500 and 750 mg/kg significantly reduced the serum CKMB and LDH levels compared to those of the placebo. The histopathological examinations showed the presence of diffused necrosis and severe inflammation in the placebo group. Pretreatment with the extract at 500 or 750 mg/kg significantly reduced the myocardial tissue damages in rats. Conclusion: The K. hospita extract at doses of 500 or 750 mg/kg significantly reduced the infarctions in the rats’ heart tissue, shown by significantly low levels of CKMB and LDH, and reduced necrotic lesions and inflammation in the rat heart tissue samples induced by isoproterenol pretreatment.

Histopathological, biochemical and molecular studies on a model of systemic autoimmune disease induced by sodium silicate in non-genetically prone rats

Sodium silicate (Na2SiO3) is an inorganic silica salt used in many products. Few studies reported autoimmune diseases (AIDs) due to Na2SiO3 exposure. This study investigates the role of Na2SiO3 exposure by different routes and doses in AID development in rats. We assigned 40 female rats to four groups: G1 control group, G2 rats were subcutaneously injected with 5 mg Na2SiO3 suspension, and G3 and G4 rats were orally administered 5 mg and 7 mg Na2SiO3 suspension, respectively. Na2SiO3 was administered weekly for 20 weeks. Serum anti-nuclear antibodies (ANA) detection, histopathology of kidney, brain, lung, liver, and heart, oxidative stress biomarkers (MDA and GSH) in tissues, Matrix metalloproteinase activity in serum, TNF-α, and Bcl-2 expression in tissues were performed. ANA was significantly increased in silicate groups, especially G2. Creatinine was significantly increased in silicate groups. Histopathology revealed vasculitis and fibrinoid degeneration of blood vessels, a picture of immune-mediated glomerulonephritis in the kidneys, and chronic interstitial pneumonia with medial hypertrophy of pulmonary blood vessels. The activity of gelatinases (MMP-2 and MMP-9) and collagenase (MMP-13), which play role in inflammation, remodeling, and immune complex degradation, were significantly increased in the silicate-exposed groups. Bcl-2 was significantly decreased, indicating apoptosis. Therefore, oral administration and subcutaneous injection of Na2SiO3 induced immune-mediated glomerulonephritis with elevated ANA levels and overexpression of TNF-α in rats.

Trypanosoma cruzi: Does the intake of nanoencapsulated benznidazole control acute infections?

Chagas Disease (CD) affects around eight million people worldwide. It is considered a neglected disease that presents few treatment options with efficacy only in the acute phase. Nanoparticles have many positive qualities for treating parasite infections and may be effectively and widely employed in clinical medicine. This research aimed to evaluate the nanoencapsulated benznidazole treatment in animals experimentally infected with Trypanosoma cruzi. To analyze the treatment efficacy, we evaluated survival during thirty days, parasitemia, genotoxicity, and heart and liver histopathology. Thirty-five female Swiss mice were organized into seven groups characterizing a dose curve: A – Negative control (uninfected animals), B – Positive control (infected animals), C – Benznidazole (BNZ) 100 mg/kg (infected animals), D – 5 mg/kg Benznidazole nanocapsules (NBNZ) (infected animals), E − 10 mg/kg Benznidazole nanocapsules (infected animals), F – 15 mg/kg Benznidazole nanocapsules (infected animals), G – 20 mg/kg Benznidazole nanocapsules (infected animals). The animals were infected with the Y strain of T. cruzi intraperitoneally. The treatment was administered for eight days by oral gavage. It was possible to observe that the treatment with the highest NBNZ dose presented efficacy similar to the standard benznidazole drug. The 20 mg/kg NBNZ dose was able to reduce parasitemia, increase survival, and drastically reduce heart and liver tissue damage compared to the 100 mg/kg BNZ dose. Moreover, it showed a lower DNA damage index than the BNZ treatment. In conclusion, the nanoencapsulation of BNZ promotes an improvement in parasite proliferation control with a five times smaller dose relative to the standard dose of free BNZ, thus demonstrating to be a potential innovative therapy for CD.

Metformin pretreatment potentiates the antiproliferative action of doxorubicin against breast cancer

The present study aimed to evaluate the effect of metformin pretreatment on the potentiation of antiproliferative action of doxorubicin against breast cancer. Female Wistar rats were administered with 7,12-Dimethylbenz(a)anthracene (DMBA) (35 mg) in 1 ml olive oil subcutaneously beneath the mammary gland. Animals were pretreated with metformin (Met) 200 mg/kg two weeks before DMBA administration. DMBA control groups received doxorubicin (Dox) (4 mg/kg and 2 mg/kg), Met (200 mg/kg) alone and in combination with Dox (4 mg/kg). Met pre-treated DMBA control groups received Dox 4 mg/kg and 2 mg/kg. Met pre-treated groups treated with Dox exhibited a decrease in tumor incidence, tumor volume and increased survival rate than the DMBA group. Organ-to-body weight ratios and histopathology of heart, liver and lungs of Met pre-treated groups treated with Dox showed lesser toxicity than Dox treated DMBA control groups. There was a noteworthy decrease in malondialdehyde levels and a substantial increase in the levels of reduced glutathione together with a significant decrease in the levels of inflammatory markers like IL-6, IL-1β and NF-κB in Met pre-treated groups treated with Dox. Histopathology of breast tumors revealed better control of tumors in Met pre-treated groups treated with Dox than DMBA control group. Immunohistochemistry and real-time PCR data revealed a significant reduction in Ki67 expression in Met pre-treated groups treated with Dox as compared to the DMBA control group. The present study suggests that metformin pretreatment potentiates the antiproliferative action of doxorubicin against breast cancer.

Natural sea salt in diet ameliorates better protection compared to table salt in the doxorubicin-induced cardiac remodeling

Cardiac dysfunction can be prevented by addressing risk factors including unhealthy diet with other lifestyle modifications. The present study demonstrates the effect of diet mixed with sea and table salts on cardiac remodeling with respect to CKMB, renin, angiotensin II, interleukin-6 and 10. Animals divided into six groups. Normal control, Table salt (0.3%), Natural sea salt (0.3%), Doxorubicin-induced cardiac remodeling control (2 mg/kg), + Normal table salt (0.3%) and Doxorubicin + Natural sea salt (0.3%) . Serum analysis and histopathology of heart, liver and kidney was performed. Significant variation (P < .05) observed in in CKMB for Natural sea salt group compared to Normal. Significant (P < .05) variation in renin for Normal table salt group compared to Normal. Variation in interleukin-6, 10, renin and angiotensin II give new insight in these parameters with marked variation in cellular architecture of the heart, liver and kidney. Observations suggest diet with natural sea salt demonstrated significant beneficial effect on cardiac dysfunction.

Abstract A079: The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses

Abstract The human genome contains multiple sites of quadruplex (G4) arrangements, with over-representation in promoter regions of many oncogenes. Small molecule G4 stabilization down-regulates the transcription of these genes, leading to selective inhibition of cancer cell growth and anti-tumor activity. We have developed a number of novel G4-binding small molecules. QN-302, the most potent, has significant in vivo activity in animal models for pancreatic cancer and is currently in pre-clinical development with Qualigen Therapeutics. The effects of QN-302 have been examined on (1) a panel of cardiac function receptors, (2) heart rate in vivo, and (3) on the histopathology of organs from treated animals. QN-302 was initially screened in a series of in vitro industry-standard CEREP receptor binding assays. The few apparent indications of significant receptor binding were examined in vivo by means of ELISA assays. Cardiac function was examined using a cardiac heart-beat monitor attached to animals treated with QN-302 and compared to animals dosed with a vehicle control. QN-302 gave negative results in CEREP assays, apart from micromolar inhibition of acetylcholinesterase (ACE) and muscarinic (MUSC) receptors. There was no significant hERG receptor inhibition. There was no significant inhibition of ACE and MUSC receptors in vivo. Heart rate experiments, run at both the proposed therapeutic dose of 1mg/kg and at elevated levels, did not show significant deviations from values for the vehicle control arm. Histopathology of heart, liver and brain tissues from QN-302 treated animals, did not show any deleterious effects from the drug. The lack of effects on ACE and MUSC receptors in vivo, together with the absence of effects on heart, liver and brain tissue from treated animals and the normality of heart rate during treatment, demonstrate that treatment of MIA-Paca2 tumor-bearing mice with QN-302 does not have a cardio-, nephro- or neurotoxic burden at therapeutic doses. QN-302 is bio-available at therapeutic doses and is currently in pre-clinical development with Qualigen Therapeutics Inc Citation Format: Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A079.