The effectiveness of cancer immunotherapy is impaired by the dysfunctional vasculature of tumors. Created hypoxia zones and limited delivery of cytotoxic immune cells help to have immune resistance ...in tumor tissue. Structural and functional normalization of abnormal tumor vasculature provide vessels for more perfusion efficiency and drug delivery that result in alleviating the hypoxia in the tumor site and increasing infiltration of antitumor T cells. Taking advantage of peptide amphiphiles, herein, a novel peptide amphiphile nanoparticle composed of an antiangiogenic peptide (FSEC) and an immune checkpoint blocking peptide (DPPA) is designed and characterized. FSEC peptide is known to be involved in vessel normalization of tumors in vivo. DPPA is an inhibitory peptide of the PD‐1/PD‐L1 immune checkpoint pathway. The peptide amphiphile nanoparticle sets out to test whether simultaneous modulation of tumor vasculature and immune systems in the tumor microenvironment has a synergistic effect on tumor suppression. Increased intratumoral infiltration of immune cells following vascular normalization, and simultaneously blocking the immune checkpoint function of PD‐L1 reactivates effective immune responses to the tumors. In summary, the current study provides a new perspective on the regulation of tumor vessel normalization and immunotherapy based on functional peptide nanoparticles as nanomedicine for improved therapeutic purposes.
The current study provides a new perspective on the combination of tumor vessel normalization and immunotherapy using a bifunctional peptide nanoparticle as nanomedicine to improve the therapeutic outcomes. The manipulation of the vasculature network is a promising new strategy that in combination with immune checkpoint inhibitors enhances the immunotherapy of solid tumors.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Hypoxia is a common phenomenon among most solid tumors that significantly influences tumor response toward chemo- and radiotherapy. Understanding the distribution and extent of tumor hypoxia in ...patients will be very important to provide personalized therapies in the clinic. Without sufficient vessels, however, traditional contrast agents for clinical imaging techniques will have difficulty in accumulating in the hypoxic region of solid tumors, thus challenging the detection of hypoxia in vivo. To overcome this problem, herein we develop a novel hypoxia imaging probe, consisting of a hypoxia-triggered self-assembling ultrasmall iron oxide (UIO) nanoparticle and assembly-responding fluorescence dyes (NBD), to provide dual-mode imaging in vivo. In this strategy, we have employed nitroimidazole derivatives as the hypoxia-sensitive moiety to construct intermolecular cross-linking of UIO nanoparticles under hypoxia, which irreversibly form larger nanoparticle assemblies. The hypoxia-triggered performance of UIO self-assembly not only amplifies its T 2-weighted MRI signal but also promotes the fluorescence intensity of NBD through its emerging hydrophobic environment incorporated into self-assemblies. In vivo results further confirm that our hypoxic imaging probe can display a prompt MRI signal for the tumor interior region, and its signal enhancement performs a long-term effective feature and gradually reaches 3.69 times amplification. Simultaneously, this probe also exhibits obvious green fluorescence in the hypoxic region of tumor sections. Accordingly, we also have developed a MRI difference value method to visualize the 3D distribution and describe the extent of the hypoxic tumor region within the whole bodies of mice. Due to its notable efficiency of penetration and accumulation inside a hypoxic tumor, our hypoxia imaging probe could also be considered as a potential candidate as a versatile platform for hypoxia-targeted drug delivery, and meanwhile its hypoxia-related therapeutic efficacy can be monitored.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Type 2 diabetes (T2D) is a major risk factor for cardiovascular disorders (CVD), characterized by pathological diastolic as well as systolic dysfunction, ventricular dilation, and cardiomyocyte ...hypertrophy. CVD is the main cause of death in postmenopausal women. Estradiol (E2) has protective effects on cardiovascular function. The biological effects of E2 are mainly mediated by classical estrogen receptors (ERs). The present study aimed to investigate the cardioprotective effects of classical ERs in ovariectomized (OVX) diabetic female rats.
T2D was induced in female rats by high-fat diet feeding along with a low dose of streptozotocin. Then diabetic animals were divided into eight groups: Sham-control, OVX, OVX + Vehicle (Veh), OVX + E2, OVX + E2 + MPP (ERα antagonist), OVX + E2 + PHTPP (ERβ antagonist), OVX + E2 + Veh, OVX + E2 + MPP + PHTPP. Animals received E2, MPP, and PHTPP every four days for 28 days. At the end blood was collected, serum separated, and used for biochemical parameters. Heart tissue was used for cardiac angiotensin II and cytokines measurement.
E2 treatment improved the metabolic disorders caused by T2D, and its receptor antagonists intensified the effects of T2D on the metabolic status. Also, E2 therapy decreased cardiac inflammatory cytokines, and MPP and PHTPP increased cardiac inflammation by increasing TNF-α and IL-6 and decreasing IL-10.
Classical ERs have protective effects on diabetic hearts by improving the metabolic status and inflammatory balance.
Diabetic cardiomyopathy is the most common chronic disease in postmenopausal women, but the mechanism(s) is unclear. G-protein coupled receptor 30 (GPR30) is one of the receptors that binds to 17-β ...Estradiol (E2). To date, there is little information on GPR30 and its expression in postmenopausal type 2 diabetes (T2D) in the heart. The current study hypothesized that GPR30 mediated cardioprotective effects of E2 in ovariectomized diabetic rats. Female ovariectomized diabetic rats were divided in nine groups: Control, Vehicle, Diabetes, Proestrous, Non-proestrous, E2, E2+Vehicle, E2+G15, and G1. G15 is a GPR30 antagonist, while G1 is an agonist of GPR30. T2D was induced by high fat diet and streptozotocin. E2, G1 and G15 were administrated for four weeks after establishment of T2D. Results showed that mean arterial pressure, fasting blood glucose and HOMA-IR in diabetic and vehicle groups were alleviated by E2 and G1, while salutary effects of E2 were inhibited by G15. Furthermore, E2 and G1 improved cardiac weight, atherogenic and cardiovascular risk indices; meanwhile G15 exacerbated cardiac weight and atherogenic indices. Also, diabetes increased cardiac levels of tumor necrosis factor-alpha and interleukin 6 and E2 only decreased interleukin 6. Significant decrement in the level of interleukin 10, and GPR30 protein were observed in diabetic group, whereas E2 and G1 increased the cardiac levels of interleukin 10, and GPR30 protein. Our study suggested that beneficial and anti-inflammatory effects of E2 on diabetic cardiomyopathy are probably mediated via non-genomic E2 pathways.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•High Fat Diet led to obesity in young ovariectomized compared to aged and young sham animals.•Estrogen led to weight loss in young ovariectomized compared to aged animals.•Estrogen increased leptin ...sensitivity in young animals, but not in aged.•Estrogen modified the effects of HFD on brain levels of TNF-α and IL-10 in young ovariectomized and aged animals.•Estrogen prevented the reduction of ERα caused by ovariectomy in ARC of young ovariectomized animals, but not in aged ones.
Aging causes changes in body composition and energy balance. Estrogen plays an important role in body’s metabolism. The aim of this study was to determine whether estrogen has beneficial effects on leptin responsiveness in aged mice. Young 4 months and aged 19–21 female mice fed High Fat Diet (HFD) or Standard Diet (SD) for 12 weeks and following received estrogen for 4 weeks. Responsiveness to leptin was compared by measuring energy balance parameters. Results showed that HFD caused weight gain compared to SD in young, but had no effect on aged animals. Estrogen reduced body weight, energy intake and visceral fat in young, while none of these parameters was affected in aged animals. Although there was leptin sensitivity in aged compared to ovariectomized animals, estrogen only improved the sensitivity of young to leptin. Estrogen prevented increase in TNF-α and a decrease in IL-10 in HFD young and aged animals. Response to estrogen depended on age, and estrogen increased leptin sensitivity only in young animals. Determining the exact mechanism of this action is suggested in future studies.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aging effects in energy balance in all tissues and organs, including the cardiovascular. The risk of cardiovascular disease is drastically higher in postmenopausal women than in premenopausal women. ...Estrogen plays an important role in the cardiac function and body's metabolism. The aim of this study was to determine whether 17β-estradiol (E2) has beneficial effects on insulin resistance and some key stages of the insulin signalling pathway in the aged hearts. Young and aged female Wistar rats were ovariectomized and were randomly divided into three groups: young (YS) and aged (AS) sham, young (YV) and aged (AV) vehicle, and young (YE2) and aged (AE2) E2 treatment groups. E2 (1 mg/kg) was administrated every four days for four weeks. Results showed that ovariectomy increased fasting blood glucose, insulin, and HOMAIR in young, while none of these parameters was affected in aged animals. On the other hand, aging itself increased these variables. Furthermore, E2 therapy alleviated these changes in both young and aged animals. Moreover, aging also decreased the p-IRS1, p-Akt level, and translocation of GLUT4 to the plasma membrane. E2 reduced the negative impact of menopause and aging on insulin sensitivity by favoring increase in the level of IL-10 and decrease in the levels of TNF-α and IL-1β. Our results indicated that the heart response to E2 depended on age, and E2 increased insulin sensitivity in the heart of both young and aged animals by altering inflammatory conditions. Determining the exact mechanism of this action is suggested in future studies.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Postmenopausal diabetic women are at higher risk to develop cardiovascular diseases (CVD) compared with nondiabetic women. Alterations in cardiac cellular metabolism caused by changes in sirtuins are ...one of the main causes of CVD in postmenopausal diabetic women. Several studies have demonstrated the beneficial actions of the G protein-coupled estrogen receptor (GPER) in postmenopausal diabetic CVD. However, the molecular mechanisms by which GPER has a cardioprotective effect are still not well understood. In this study, we used an ovariectomized (OVX) type-two diabetic (T2D) rat model induced by high-fat diet/streptozotocin to investigate the effect of G-1 (GPER-agonist) on sirtuins, and their downstream pathways involved in regulation of cardiac metabolism and function. Animals were divided into five groups: Sham-Control, T2D, OVX+T2D, OVX+T2D+Vehicle, and OVX+T2D+G-1. G-1 was administrated for six weeks. At the end, hemodynamic factors were measured, and protein levels of sirtuins, AMP-activated protein kinase (AMPK), and uncoupling protein 2 (UCP2) were determined by Western blot analysis. In addition, cardiac levels of oxidative stress biomarkers were measured. The findings showed that T2D led to left ventricular dysfunction and signs of oxidative stress in the myocardium, which were accompanied by decreased protein levels of Sirt1/2/3/6, p-AMPK, and UCP2 in the heart. Moreover, the induction of the menopausal state exacerbated these changes. In contrast, treatment with G-1 ameliorated the hemodynamic changes associated with ovariectomy by increasing Sirt1/3, p-AMPK, UCP2, and improving oxidative status. The results provide evidence of the cardioprotective effects of GPER operating through Sirt1/3, p-AMPK, and UCP2, thereby improving cardiac function. Our results suggest that increasing Sirt1/3 levels may offer new therapeutic approaches for postmenopausal diabetic CVD.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Obesity is characterized by an increase in food intake and a decrease in energy expenditure, which causes the accumulation of fat in the body, resulting in various disorders such as type 2 diabetes ...and cancer. Adipocytes secrete the hormone leptin, and leptin signaling plays an essential role in regulating energy balance. Leptin reduces food intake and increases energy expenditure by binding to its receptors in the hypothalamus and regulating appetite-regulating neurons. Accumulation of excess fat along with increased blood levels of leptin impairs the passage of leptin across the blood-brain barrier and induces leptin resistance. Estrogen also plays an important role in regulating energy balance due to the expression of its receptors in the hypothalamus, and its deficiency is associated with increased food intake and body weight, and estrogen therapy is able to partially mimic the effects of leptin. In this review, we get familiar with the concept of leptin resistance and its mechanisms, and finally, we examine the role of estrogen by emphasizing the mechanisms of energy balance regulation.
•Increased inflammation and high levels of leptin in obesity lead to leptin resistance.•Estrogen via ERα increases p-STAT3 signaling in the ARC of hypothalamus and reduces leptin resistance.•Estrogen via ERα reduces inflammation, NPY, and AgRP levels and increases α-MSH.•Tamoxifen as a SERM, reduces leptin resistance by reducing inflammation and modulating brain neuropeptides.•Aging is an influential factor contributing to leptin responsiveness in presence of estrogen, which reduces the effects of estrogen.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Type 2 diabetes mellitus (T2DM) is associated with cardiometabolic changes, and menopause exacerbates these conditions, leading to a greater risk of cardiovascular diseases (CVDs). The G ...protein-coupled estrogen receptor (GPER), which mediates the rapid effects of estrogen, has beneficial cardiac effects in both T2DM and menopause, but its mechanism of action is not well understood. Objectives: This study aimed to determine whether G1 as a selective GPER-agonist has beneficial effects on cardiac lipid metabolism in ovariectomized rats with T2DM. Methods: Female Wistar rats were divided into 5 groups (n = 7 in each group): Sham-control (Sh-Ctl), T2DM, ovariectomized-T2DM (OVX-T2DM), OVX-T2DM-G1 (GPER-agonist), and OVX-T2DM-vehicle (OVX-T2DM-Veh). After stabilization of T2DM, G1 (200 μg/Kg) was administrated for 6 weeks. Then, the levels of free fatty acids (FFAs), CD36, peroxisome proliferator-activated receptor α (PPARα), and lipid accumulation in the cardiac tissue were determined. Results: Compared with the Sh-Ctl group, cardiac FFAs (P < 0.001), CD36 (P < 0.05), and lipid accumulation (P < 0.001) increased, and cardiac PPARα (P < 0.01) decreased in T2DM animals; ovariectomy intensified these changes. Also, cardiac FFAs, PPARα, and lipid accumulation (P < 0.05) significantly decreased in the OVX-T2DM-G1 group compared to the OVX-T2DM-Veh group. However, cardiac CD36 levels did not change. Conclusions: G1 as a selective GPER-agonist affects lipid metabolism in T2DM animals. It also plays a vital role in improving cardiac metabolism during postmenopausal diabetic conditions.
PDF
