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Ischemic heart diseases such as myocardial infarction (MI) are a global health problem and a leading cause of mortality worldwide. Angiogenesis is an important approach for myocardial healing following ischemia. Thus, this study aimed to explore the potential cardiac angiogenic effects of selenium (Se), alone and in combination with the tumor necrosis factor-alpha inhibitor, pentoxifylline (PTXF), via Akt/HIF-1α signaling. MI was induced in rats using two subcutaneous doses of isoprenaline (ISP) at a 24-h interval (150 mg/kg). One week later, rats were orally given Se (150 µg/kg/day), PTXF (50 mg/kg/day), or Se/PTXF combination. ISP-induced myocardial damage was evident by increased HW/TL ratios, ST segment elevation, and increased serum levels of CK-MB, LDH, and troponin-I. ISP increased the cardiac levels of the lipid peroxidation marker MDA; the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the pro-apoptotic protein Bax and caspase-3. In contrast, the cardiac levels of the antioxidant markers GSH and SOD and the anti-apoptotic marker Bcl-2 were reduced. Furthermore, ISP markedly increased the cardiac levels of p-Akt and HIF-1α proteins and the cardiac gene expression of ANGPT-1, VEGF, and FGF-2. Treatment with Se both alone and in combination with PTXF ameliorated the ISP-induced myocardial damage and further increased cardiac angiogenesis via Akt/HIF-1α signaling. Se/PTXF combined therapy was more beneficial than individual treatments. Our study revealed for the first time the cardiac angiogenic effects of Se both alone and in combination with PTXF in myocardial infarction, suggesting that both may be promising candidates for clinical studies., (© 2023. The Author(s).)

Exploitation of nanocarriers provides a compartment for enclosing drugs to protect them from degradation and potentiate their therapeutic efficiency. In the current study, amitriptyline- and liraglutide-loaded proniosomes were constructed for management of diabetic neuropathy, a serious complication associated with diabetes, that triggers spontaneous pain in patients and results in impaired quality of life. The developed therapeutic proniosomes were extensively characterized via dynamic light scattering, scanning electron microscopy, transmission electron microscopy, and Fourier transform-infrared spectroscopy. High entrapment efficiency could be attained for both drugs in the proniosomes, and the reconstituted amitriptyline- and liraglutide-loaded niosomes possessed spherical morphology and particle sizes of 585.3 nm and 864.4 nm, respectively. In a diabetic neuropathy rat model, oral administration of the developed amitriptyline- and liraglutide-loaded proniosomes significantly controlled blood glucose levels, reduced neuropathic pain, oxidative stress and inflammatory markers, and improved histological structure of the sciatic nerve as compared to the oral and subcutaneous administration of amitriptyline and liraglutide, respectively. Loading of the tricyclic antidepressant amitriptyline and the antidiabetic peptide liraglutide into proniosomes resulted in exceptional control over hyperglycemia and neuropathic pain, and thus could provide an auspicious delivery system for management of neuropathic pain and control of blood glucose levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To compare the therapeutic potential of rat bone marrow-derived mesenchymal stem cells (BM-MSCs) preconditioned ex-vivo with resveratrol (MCR) and BM-MSCs isolated from resveratrol-pre-treated rats (MTR) in type-1 diabetic rats., Methods: Type-1 diabetes was induced by a single streptozotocin injection (50 mg/kg; ip) in 24 rats. Following the confirmation of T1DM, diabetic rats were randomly divided into four groups: diabetic control (DC), diabetic rats treated with insulin subcutaneous (7.5 IU/kg/day), diabetic rats treated with MCR cells (3 × 106cells/rat, intravenous) and diabetic rats treated with MTR cells (3 × 106cells/rat, intravenous). Rats were sacrificed 4 weeks following cellular transplantation., Key Findings: Untreated diabetic rats suffered from pancreatic cell damage, had high blood glucose levels, increased apoptotic, fibrosis, and oxidative stress markers and decreased survival and pancreatic regeneration parameters. Both MSCs preconditioned ex-vivo with RES and MSCs isolated from rats pre-treated with RES homed successfully in injured pancreas and showed therapeutic potential in the treatment of STZ-induced T1DM. MCR cells showed better efficiency than MTR cells., Conclusions: The pre-conditioning of BM-MSCs with resveratrol may be a promising therapeutic possibility in T1DM. Resveratrol-preconditioned BM-MSCs encouraged effects almost comparable to that of exogenous insulin with the advantages of cured pancreas and restored islets not attained by insulin., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Trichinellosis is a serious foodborne zoonosis. It poses a serious risk to public health worldwide. Early serological diagnosis of trichinellosis is influenced by an immunological 'silent' phase following infection. This highlights the necessity for developing sensitive diagnostic approaches to be employed when antibodies cannot be detected. In this work, the validity of traditional ELISA, Nano-ELISA and real time polymerase chain reaction (PCR) were evaluated in early diagnosis of Trichinella spiralis. Swiss albino mice were orally infected with 100 and 300 muscle larvae/mouse. Mice were sacrificed 4, 6, 8, 10, 15, and 28 days post-infection (dpi). Blood samples were tested for circulating antigen by traditional ELISA and Nano-ELISA using anti-rabbit polyclonal IgG conjugated with AgNPs and for Rep gene by SYBR green real-time PCR. Rep gene detection by SYBR green real-time PCR could detect T. spiralis with 100% sensitivity in the mild infection group at 8 dpi, while in the severe infection group it reached 100% sensitivity at 4 dpi. Nano-ELISA could detect T. spiralis circulating antigen from 4 dpi in both mild and severe infection and reached 100% sensitivity at 8 dpi and 6 dpi in mild and severe infection, respectively. However, traditional ELISA could detect T. spiralis circulating antigen from 6 dpi and reached maximum sensitivity at 15 dpi in the mild infection group, while in the severe infection group detection began at 4 dpi and reached 100% sensitivity at 8 dpi. Nano-ELISA and real time PCR, using Rep gene, are useful tools for the detection of early T. spiralis infection even in its mild infection state.

Myocardial infarction (MI) is a major health problem associated with high morbidity and mortality. Recently, angiogenesis has emerged as a novel therapeutic approach against ischemic diseases including MI. Therefore, we aimed to investigate the potential angiogenic effects of vanillin (Van) both alone and in combination with pentoxifylline (PTX), and to examine the molecular mechanisms through which Van and PTX may ameliorate cardiac injury induced in rats including their effects on oxidative stress, inflammation and apoptosis which play a key role in MI pathogenesis. MI was induced in rats using isoproterenol (ISO) (150 mg kg -1 , SC, twice at a 24 h interval). Then, rats were treated orally with Van (150 mg kg -1 day -1 ), PTX (50 mg kg -1 day -1 ) or Van + PTX combination. ISO-induced cardiac injury was characterized by cardiac hypertrophy, ST-segment elevation and elevated serum levels of troponin-I, creatine kinase-MB and lactate dehydrogenase. Cardiac levels of the antioxidant markers GSH and SOD and the antiapoptotic protein Bcl-2 were decreased. On the other hand, cardiac levels of the oxidative stress marker malonaldehyde, the inflammatory cytokines TNF-α, IL-6 and IL-1β, the proapoptotic protein Bax, and caspase-3 were increased. Moreover, the cardiac levels of p-Akt and HIF-1α and the mRNA expression levels of the angiogenic genes VEGF , FGF-2 and ANGPT-1 were increased. Treatment with either Van or PTX ameliorated ISO-induced changes and further upregulated Akt/HIF-1α/VEGF signaling. Furthermore, Van + PTX combination was more effective than monotherapy. These findings suggest a novel therapeutic potential of Van and PTX in ameliorating MI through enhancing cardiac angiogenesis and modulating oxidative stress, inflammation and apoptosis.

Context: Myocardial cell death occurs within hours following the onset of myocardial ischaemia and its chief cause is atherosclerosis. There is a link between vitamin D3 deficiency and many cardiovascular risk factors., Objective: This study compared the effect of vitamin D3 on early biomarkers of myocardial injury, to that of atorvastatin., Methods: Diabetic hyperlipidaemia was induced in Wistar rats, which were divided into 3 groups: diabetic hyperlipidaemic control, diabetic hyperlipidaemic rats treated with atorvastatin and diabetic hyperlipidaemic rats treated with vitamin D3. Blood glucose, glycated haemoglobin and lipid profile were evaluated. Markers of myocardial injury were examined including cardiac troponin, heart fatty acid binding protein (HFABP) and C-terminal pro-endothelin-1 (CT-pro-ET-1)., Results: Vitamin D3 and atorvastatin intake improved lipid profile and glucose homeostasis, and reduced levels of predictive biomarkers of myocardial injury., Conclusion: Vitamin D3 can be used in a suitable dose as a safe and protective candidate against myocardial injury.

Background: The regenerative capacity of the heart after myocardial infarction is limited. Our previous study showed that ectopic introduction of 4 cell cycle factors (4F; CDK1 [cyclin-dependent kinase 1], CDK4 [cyclin-dependent kinase 4], CCNB [cyclin B1], and CCND [cyclin D1]) promotes cardiomyocyte proliferation in 15% to 20% of infected cardiomyocytes in vitro and in vivo and improves cardiac function after myocardial infarction in mice., Methods: Using temporal single-cell RNA sequencing, we aimed to identify the necessary reprogramming stages during the forced cardiomyocyte proliferation with 4F on a single cell basis. Using rat and pig models of ischemic heart failure, we aimed to start the first preclinical testing to introduce 4F gene therapy as a candidate for the treatment of ischemia-induced heart failure., Results: Temporal bulk and single-cell RNA sequencing and further biochemical validations of mature human induced pluripotent stem cell-derived cardiomyocytes treated with either LacZ or 4F adenoviruses revealed full cell cycle reprogramming in 15% of the cardiomyocyte population at 48 hours after infection with 4F, which was associated mainly with sarcomere disassembly and metabolic reprogramming (n=3/time point/group). Transient overexpression of 4F, specifically in cardiomyocytes, was achieved using a polycistronic nonintegrating lentivirus (NIL) encoding 4F; each is driven by a TNNT2 (cardiac troponin T isoform 2) promoter (TNNT2-4Fpolycistronic-NIL). TNNT2-4Fpolycistronic-NIL or control virus was injected intramyocardially 1 week after myocardial infarction in rats (n=10/group) or pigs (n=6-7/group). Four weeks after injection, TNNT2-4Fpolycistronic-NIL-treated animals showed significant improvement in left ventricular ejection fraction and scar size compared with the control virus-treated animals. At 4 months after treatment, rats that received TNNT2-4Fpolycistronic-NIL still showed a sustained improvement in cardiac function and no obvious development of cardiac arrhythmias or systemic tumorigenesis (n=10/group)., Conclusions: This study provides mechanistic insights into the process of forced cardiomyocyte proliferation and advances the clinical feasibility of this approach by minimizing the oncogenic potential of the cell cycle factors owing to the use of a novel transient and cardiomyocyte-specific viral construct.

Trichinellosis is a re-emerging zoonotic disease that has become a public health concern since its reported human outbreaks in many countries. The traditional therapy has many adverse effects in addition to the developing resistance. So, this necessitates finding effective natural alternatives. The current study targeted to assess the potential therapeutic effects of Zingiber officinale and Cinnamomum zeylanicum in comparison to albendazole, a conventional therapy for treatment of trichinosis . Sixty mice were classified into five groups (12 mice each), non-infected control, infected control, combined albendazole and prednisolone, Zingiber officinale , and Cinnamomum zeylanicum treated groups. Mice sacrifice was performed on the 7th and 35th days post infection for intestinal and muscular phases respectively. Efficiency of the used preparations was assessed by parasitological, histopathological, immunohistochemical, biochemical studies in addition to ultrastructural evaluation using transmission electron microscopy. A significant reduction in the mean number of T. spiralis adult worms and larvae was observed in Zingiber officinale and Cinnamomum zeylanicum treated groups, (64.5%, 50.8%) and (68%, 54.6%) respectively. Also, both extracts showed moderate cytoplasmic reactivity for TGF-β1, (69.3% & 67.8%) respectively. The highest reduction in serum TNF- α level was observed in Zingiber officinale treated group during the muscle phase (58.4%) while in the intestinal phase was 50%. The ultrastructural study revealed degenerative effects on both adults and larvae in addition to obvious improvement of the histopathological changes in the small intestine and muscles. We concluded that these herbal extracts especially Zingiber officinale can be considered a practical and successful alternative for the treatment of trichinellosis., Competing Interests: Conflict of interestThe authors declared that they have no conflict of interest., (© Indian Society for Parasitology 2021.)

Objectives: Chronic kidney disease (CKD) is a major public health problem associated with high mortality. The therapeutic effects of pachymic in CKD management and its underlying mechanisms have not been studied. Therefore, we aimed to investigate the possible inhibitory effect of PA on renal Wnt/β-catenin signalling in CKD., Methods: CKD was induced in rats by doxorubicin (DOX; 3.5 mg/kg i.p., twice weekly for 3 weeks). Rats were treated orally with PA (10 mg/kg/day), LOS (10 mg/kg/day) or their combination (PA + LOS) for 4 weeks starting after the last dose of DOX., Key Findings: DOX-induced renal injury was characterized by high serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho were decreased. Tumour necrosis factor-α, interleukin-6, interleukin-1β, Wnt1, active β-catenin/total β-catenin ratio and fibronectin along with mRNA expression of RENIN, ACE and AT1 were increased in renal tissues. Treatment with either PA or LOS ameliorated all DOX-induced changes. The combined treatment was more effective in improving all changes than monotherapy., Conclusions: These results suggest a new therapeutic benefit of PA in ameliorating CKD in rats through its up-regulatory effect on renal klotho thereby preventing Wnt/β-catenin reactivation and RAS gene expression. PA/LOS combination provided an additional inhibition of Wnt/β-catenin signalling and its downstream targets., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: The coordinated gene and metabolic programs that facilitate cardiomyocyte entry and progression in the cell cycle are poorly understood. The purpose of this study was to identify the metabolic changes that influence myocyte proliferation., Methods and Results: In adult mouse cardiomyocytes and human induced pluripotent stem cell cardiomyocytes (hiPS-CMs), cell cycle initiation by ectopic expression of Cyclin B1, Cyclin D1, CDK1, and CDK4 (termed 4F) downregulated oxidative phosphorylation genes and upregulated genes that regulate ancillary biosynthetic pathways of glucose metabolism. Results from metabolic analyses and stable isotope tracing experiments indicate that 4F-mediated cell cycle induction in hiPS-CMs decreases glucose oxidation and oxidative phosphorylation and augments NAD + , glycogen, hexosamine, phospholipid, and serine biosynthetic pathway activity. Interventions that diminish NAD + synthesis, serine synthesis, or protein O-GlcNAcylation decreased 4F-mediated cell cycle entry. In a gain of function approach, we overexpressed phosphoenolpyruvate carboxykinase 2 (PCK2), which can drive carbon from the Krebs cycle to the glycolytic intermediate pool, and found that PCK2 augments 4F-mediated cell cycle entry., Conclusions: These findings suggest that a metabolic shift from catabolic to anabolic activity is a critical step for cardiomyocyte cell cycle entry and is required to facilitate proliferation., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Postmenopausal women are at an increased risk of vascular calcification which is defined as the pathological deposition of minerals in the vasculature, and is strongly linked with increased cardiovascular disease risk. Since estrogen-replacement therapy is associated with increased cancer risk, there is a strong need for safer therapeutic approaches. In this study we aimed to investigate the protective and therapeutic effects of the phytoestrogen resveratrol against vascular calcification in ovariectomized rats, a preclinical model of postmenopause. Furthermore, we aimed to compare the effects of resveratrol to those of estrogen and to explore the mechanisms underpinning those effects. Treatment with resveratrol or estrogen ameliorated aortic calcification in ovariectomized rats, as shown by reduced calcium deposition in the arterial wall. Mechanistically, the effects of resveratrol and estrogen were mediated via the activation of SIRT1 signaling. SIRT1 protein expression was downregulated in the aortas of ovariectomized rats, and upregulated in rats treated with resveratrol or estrogen. Moreover, resveratrol and estrogen reduced the levels of the osteogenic markers: runt-related transcription factor 2 (RUNX2), osteocalcin and alkaline phosphatase (ALP) which have been shown to play a role during vascular calcification. Additionally, the senescence markers (p53, p16 and p21) which were also reported to play a role in the pathogenesis of vascular calcification, were reduced upon treatment with resveratrol and estrogen. In conclusion, the phytoestrogen resveratrol may be a safer alternative to estrogen, as a therapeutic approach against the progression of vascular calcification during postmenopause.

Osteoporosis is a skeletal disorder that is common in postmenopausal women. It is characterized by deteriorated bone mass and microarchitecture. In this study, we aimed to explore the effects and molecular mechanisms of resveratrol and mesenchymal stem cell (MSC) individual and combined treatment in management of osteoporosis in ovariectomized rats. Our results demonstrated that treatment of ovariectomized rats with resveratrol or MSCs improved bone mass and microstructure as indicated by increased bone mineral content and density. Moreover, resveratrol and MSCs stimulated osteogenesis as shown by increased levels of osteogenic markers such as runt-related transcription factor 2 (RUNX2). In addition, resveratrol and MSCs inhibited adipogenesis and osteoclastogenesis as indicated by the suppression of the adipogenic marker, peroxisome proliferator-activated receptor gamma (PPARγ) and the osteoclastogenesis marker, receptor activator of nuclear factor-κB ligand (RANKL). Mechanistically, our results showed that management of osteoporosis in resveratrol or MSC treated rats was achieved by activating two signaling pathways, sirtuin 1 (SIRT1) and wingless-related MMTV integration site (Wnt). Finally, the combination of resveratrol and MSCs was more effective in increasing bone mass and improving osteoporosis than individual treatments., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Trichinellosis is a zoonotic disease that endangers human health and can lead to death. Restricted absorption and poor results of conventional therapies demand new effective natural remedies to treat both enteral and parenteral trichinellosis. This study assessed the antiparasitic and anti-inflammatory effects of Citrus limon and Capsicum frutescens on murine trichinellosis and compared them with those of albendazole and prednisolone, which are conventionally used to treat trichinellosis. Overall, 50 Swiss albino male mice were divided into five groups, with ten mice in each group: negative control, positive control, albendazole combined with prednisolone, C. limon, and C. frutescens. Mice were sacrificed 7 and 35 days after infection, for intestinal and muscular phase analyses. Drug efficacies were parasitologically, biochemically, histopathologically and ultrastructurally assessed. Our results demonstrated the efficacy of C. frutescens and C. limon extracts as antiparasitic agents, showing a substantial decrease in adult and larval counts. Moreover, both extracts had the ability to decrease serum tumour necrosis factor-α levels during the intestinal and muscular phases. In addition to the improved histopathological changes in the small intestine and muscles, the destructive effects on adults and larvae were ultrastructurally evident on transmission electron microscopy. In conclusion, C. frutescens and C. limon extracts are promising remedies for the treatment of experimental trichinellosis, particularly, the C. frutescens extract.

Infliximab (IFX), a chimeric monoclonal antibody against tumor necrosis factor-α (TNF-α), is widely used to treat autoimmune diseases and chronic diseases associated with inflammation. TNF-α was reported to inhibit klotho, reactivate β-catenin and cause tubular cell injury in vitro. Whether the inhibition of TNF-α can regulate Wnt/β-catenin pathway via klotho in CKD in vivo is not studied yet. We aimed to investigate the impact of IFX on Wnt/β-catenin pathway in doxorubicin (DOX)-induced nephropathy. Doxorubicin (3.5 mg/kg; i.p., twice weekly for 3 weeks) increased serum cystatin-C, urine albumin/creatinine ratio (UACR), but depleted renal podocin. It markedly increased renal contents of TNF-α, interleukin-6 (IL-6), interleukin-1β (IL1β). DOX decreased the renal expression of klotho which in turn increased Wnt1, active β-catenin/total β-catenin ratio in renal tissue. Significant increase in renal gene expression of RENIN, ACE, and AT1 was observed. Moreover, renal fibronectin and collagen deposition increased in renal tissue. Treatment with either IFX (5 mg/kg, once; i.p.), losartan (LOS, 10 mg/kg/day, orally) or their combination significantly improved renal function, inhibited inflammatory cytokines and fibrosis. Renal TNF-α was negatively correlated with renal klotho. On the hand, it was positively correlated with renal Wnt1 and active β-catenin/total β-catenin ratio. The combined IFX and LOS treatment was the most effective in improving all studied parameters. In conclusion, this study proved, for the first time, the inhibitory effect of IFX on renal Wnt/β-catenin signaling in DOX-induced nephropathy in vivo by up-regulating renal klotho. Therefore, these results suggest a new role for IFX in chronic kidney disease via targeting renal Wnt/β-catenin/renin angiotensin axis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Impact Statement: Hyperlipidemia represents a major risk factor for cardiovascular diseases leading to myocardial injury (MI). The present study aimed to illustrate the pattern of myocardial injury induced in diabetic hyperlipidemic rat model and the effect of vitamin D3, 10-dehydrogingerdione (10-DHGD) intake either individually or in combination form.

Hypertension is a well-established risk factor for adverse cardiovascular events, and older age is a risk factor for the development of hypertension. Genomewide association studies have linked ATP2B1, the gene for the plasma membrane calcium ATPase 1 (PMCA1), to blood pressure (BP) and hypertension. Here, we present the effects of reduction in the expression of PMCA1 on BP and small artery structure and function when combined with advancing age. Heterozygous PMCA1 null mice (PMCA1 Ht ) were generated and conscious BP was measured at 6 to 18 months of age. Passive and active properties of isolated small mesenteric arteries were examined by pressure myography. PMCA1 Ht mice exhibited normal BP at 6 and 9 months of age but developed significantly elevated BP when compared to age-matched wild-type controls at ≥12 months of age. Decreased lumen diameter, increased wall thickness and increased wall:lumen ratio were observed in small mesenteric arteries from animals 9 months of age and older, indicative of eutrophic remodelling. Increases in mesenteric artery intrinsic tone and global intracellular calcium were evident in animals at both 6 and 18 months of age. Thus, decreased expression of PMCA1 is associated with increased BP when combined with advancing age. Changes in arterial structure precede the elevation of BP. Pathways involving PMCA1 may be a novel target for BP regulation in the elderly., (© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)