Deferoxamine has the Potential to Improve the COVID-19-Related Inflammatory Response in Diabetic Patients.

The clinical state of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been considered a pandemic disease (COVID-19) that is rapidly spreading worldwide. Despite all global efforts, the only treatment for COVID-19 is supportive care and there has been no efficient treatment to fight this plague. It is confirmed that patients with chronic diseases such as cardiovascular disorder and diabetes; are more vulnerable to COVID-19. In the severe type of COVID-19, laboratory findings showed a remarkably enhanced C-reactive protein, IL-6 serum, Iron, and ferritin, which suggest an inflammatory response. Inflammation results in iron homeostasis imbalance and causes iron overload, exacerbating the SARSCOV2 infection. More importantly, recent studies have established that SARS-CoV-2 needs iron for viral replication and also activation. As a result, managing iron overload in diabetic patients with COVID-19 could be an early therapeutic approach to limit the lethal inflammatory response of COVID-19. In this review, Deferoxamine (DFO) has been proposed as an effective iron chelator agent.

Apelin-13 attenuates cerebral ischemia/reperfusion injury through regulating inflammation and targeting the JAK2/STAT3 signaling pathway.

BACKGROUND: The precise mechanisms whereby apelin-13 acts against ischemic stroke have remained in the dark. Hence, this study aims to examine the effects of apelin-13 on hypothalamic-pituitary-adrenal (HPA) axis over activation, Jak2-STAT3 signaling pathway, and inflammation following ischemic stroke. METHODS: Middle cerebral artery occlusion (MCAO) was used to induce the cerebral ischemic/reperfusion injury (I/RI). Thirty-five male Wistar rats (250-300 g, 8 weeks old) were randomly divided into sham, MCAO, and intravenous (IV) apelin-13 treated groups which received 10, 20, and 40 µg/kg 5 min before reperfusion (n = 7). Neurological status (modified Longa scoring scale), infarct volume, serum levels of malondialdehyde (MDA), total antioxidant capacity (TAC), interleukin 6 (IL-6), corticosterone, and the expressions of the Jak2/STAT3 were assessed. RESULTS: Our results confirm that IV administration of all three doses of apelin-13 significantly improved neurological defects and reduced infarct volume following cerebral I/RI. Furthermore, we observed that acute stroke caused a rise in the expression of the Jak2/STAT3, IL-6, corticosterone, and MDA content, while apelin-13 could reduce the expression of the Jak2/STAT3 and the serum indices in a dose-dependent manner. The 40 µg/kg dose of apelin-13 was also more effective in reducing the infarct volume and improving TAC. CONCLUSION: Our findings suggest that apelin-13 has protective effects against cerebral I/RI-related inflammation and also could attenuate the HPA axis over activation.

Simvastatin-loaded nano-niosomes efficiently downregulates the MAPK-NF-κB pathway during the acute phase of myocardial ischemia-reperfusion injury.

BACKGROUND: Simvastatin can potentially mitigate acute inflammatory phase of myocardial ischemia-reperfusion injury. However, these effects negatively influenced by its poor bioavailability, low water solubility and high metabolism. Here, we investigated the effects of SIM-loaded nano-niosomes on a rat model of MI/R injury to find a drug delivery method to tackle the barriers. METHODS: Nano-niosomes' characteristics were identified using dynamic light scattering and transmission electron microscopy. Fifty male Wistar rats were divided into five groups: Sham; MI/R; MI/R + nano-niosome; MI/R + SIM; MI/R + SIM-loaded nano-niosomes. Left anterior descending artery was ligated for 45 min, and 3 mg/kg SIM, nano-niosomes, or SIM-loaded nano-niosomes was intramyocardially injected ten min before the onset of reperfusion. ELISA assay was used to assess cardiac injury markers (cTnI, CK-MB) and inflammatory cytokines (TNF-α, IL-6, TGF-ß, MPC-1). Expression level of MAPK-NF-κB and histopathological changes were evaluated by western blot and hematoxylin & eosin staining, respectively. RESULTS: the size of nano-niosome was 137 nm, reached to 163 nm when simvastatin was loaded. To achieve optimized niosomes span 80, a drug/cholesterol ratio of 0.4 and seven min of sonication time was applied. Optimized entrapment efficiency of SIM-loaded nano-niosomes was 98.21%. Inflammatory cytokines and the expression level of MAPK and NF-κB were reduced in rats receiving SIM-loaded nano-niosomes compared to MI/R + SIM and MI/R + SIM-loaded nano-niosomes. CONCLUSION: Our results showed that SIM-loaded nano-niosomes could act more efficiently than SIM in alleviating the acute inflammatory response of reperfusion injury via downregulating the activation of MAPK-NF-κB.

ERK/HIF-1α/VEGF pathway: a molecular target of ELABELA (ELA) peptide for attenuating cardiac ischemia-reperfusion injury in rats by promoting angiogenesis.

BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury is caused by a chain of events such as endothelial dysfunction. This study was conducted to investigate protective effects of ELABELA against myocardial I/R in Wistar rats and clarify its possible mechanisms. METHODS AND RESULTS: MI model was established based on the left anterior descending coronary artery ligation for 30 min. Then, 5 µg/kg of ELA peptide was intraperitoneally infused in rats once per day for 4 days. Western blot assay was used to assay the expression of t-ERK1/2, and p-ERK1/2 in different groups. The amount of myocardial capillary density, the expression levels of VEGF and HIF-1α were evaluated using immunohistochemistry assay. Masson's trichrome staining was utilized to assay cardiac interstitial fibrosis. The results showed that establishment of MI significantly enhanced cardiac interstitial fibrosis and changed p-ERK1/2/ t-ERK1/2 ratio. Likewise, ELA post-treatment markedly increased myocardial capillary density, the expression of several angiogenic factors (VEGF-A, HIF-1α), and reduced cardiac interstitial fibrosis by activation of ERK1/2 signaling pathways. CONCLUSION: Collectively, ELA peptide has ability to reduce myocardial I/R injury by promoting angiogenesis and reducing cardiac interstitial fibrosis through activating ERK/HIF-1α/VEGF pathway.

Propolis add-on therapy alleviates depressive symptoms; A randomized placebo-controlled clinical trial.

Almost half of the treatments with common antidepressants are failed or result in a relapse of symptoms after cessation. Moreover, the antidepressants side effects rationalize the use of complementary medicine as an adjunctive therapy. This study aimed to evaluate the efficacy and safety of propolis in complementary therapy of depressive disorder. Chromatography technics were used to detect propolis components. A double-blind, randomized, placebo-controlled trial was designed, and 54 participants were randomly assigned to receive either propolis or Placebo for 6 weeks. Treatment was defined as a decrease in 17-item Hamilton Depression Scale (HAMD-17) and Beck depression inventory (BDI). On D42, there was a significant reduction in HAMD score in the propolis group compared with the placebo group (p < .0001). HAMD score significantly decreased in the propolis group from 20.92 ± 3.77 on D0 to 10.03 ± 5.55 on D42, and BDI score was improved from 29.25 ± 3.06 on D0 to 14.17 ± 4.86 on D42. Our findings confirmed that complementary treatment of propolis with SSRIs could safely attenuate symptoms of moderate-severe MDD. These antidepressant effects might result from the rich phenolic acids and flavonoids content of Azerbaijan propolis.

Simvastatin-loaded nano-niosomes confer cardioprotection against myocardial ischemia/reperfusion injury.

Although simvastatin (SIM) has been proven to be a powerful agent against myocardial ischemia/reperfusion (MI/R) injury, poor water solubility, short half-life, and low bioavailability have made it futile while using conventional drug delivery system. Hence, this study aims to investigate therapeutic efficacy of SIM-loaded nano-niosomes on MI/R injury. Surface active agent film hydration method was used to synthesize nano-niosomes. The physicochemical properties of nano-niosomes were characterized using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Moreover, niosomes were characterized in entrapment efficiency (EE) and releasing pattern. Male Wistar rats were assigned into five groups (sham, MI/R, SIM, nano-niosomes, and SIM-loaded nano-niosomes). To induce MI/R, left thoracotomy was performed along mid-axillary line. The LAD ligation lasted for 45 min. A single dose (3 mg/kg) of drug formulations was injected into myocardial. Echocardiography was performed to evaluate cardiac function. The expression of the necroptosis markers was evaluated using western blot assay. Particle size of only nano-niosomes was about 137 nm, whereas a shift to 163 nm was observed in nano-niosomes containing SIM. Optimized niosomes were achieved by span 80, drug to cholesterol ratio of 0.4 with 7-min sonication time. EE of optimized nano-niosomes containing SIM was 98.21%. The effects of nano-niosomes containing on improving cardiac function and inhibiting necroptosis pathway was more efficient than the SIM group. Our findings have suggested that nano-niosomes can be applied as a notable drug delivery method to augment stability, bioavailability, and therapeutic efficacy of SIM, when it used against myocardial I/R injury.

Human mesenchymal stem cells derived from amniotic membrane attenuate isoproterenol (ISO)-induced myocardial injury by targeting apoptosis.

Background: Currently, stem cell therapy has been proposed as an efficient strategy to prevent or treat myocardial injuries. The current study was conducted to examine cardioprotective effects of human mesenchymal stem cells derived from amniotic membrane (hAMSCs) against isoproterenol (ISO)-induced myocardial injury and explore its potential mechanisms. Methods: The hAMSCs were injected intramyocardially in male Wistar rats 28 days after last injection of ISO (170 mg/kg body weight for 4 consecutive days). The echocardiography was performed to confirm induction of myocardial damage and cardiac function 28 days after last injection of ISO and 4 weeks hAMSCs transplantation after HF induction. The expression of apoptotic markers such as Bcl-2, Bax and P53 was evaluated using Western blotting assay. Masson's trichrome staining was used to determine fibrosis. The cytoarchitecture of myocardial wall and morphology of cells were investigated using hematoxylin and eosin (H&E) staining. Results: As compared to ISO group, hAMSCs transplantation after heart failure (HF) induction significantly blunted the increasing of cardiac dimensions and restored ejection fraction (EF) and fractional shortening (FS) parameters (p<0.05). Moreover, hAMSCs transplantation after HF induction increased the expression of antiapoptotic markers such as Bcl-2 and decreased the expression of pro-apoptotic markers such as P53 and Bax (p<0.05). As compared to ISO group, hAMSCs transplantation after HF induction markedly reduced interstitial myocardial fibrosis and contributed to maintain of normal cytoarchitecture of myocardial wall and morphology of cells. Conclusion: Collectively, the results of current study suggest that transplantation of hAMSCs confers cardioprotection by targeting ISO-induced mitochondria-dependent (intrinsic) pathway of apoptosis.

Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model.

Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia-reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. These findings have shown that nesfatin-1 can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK1-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway.

FoxO1 and Wnt/ß-catenin signaling pathway: Molecular targets of human amniotic mesenchymal stem cells-derived conditioned medium (hAMSC-CM) in protection against cerebral ischemia/reperfusion injury.

Ischemia-reperfusion (I/R) injury has weakened the effects of available treatment options for ischemic stroke. Although conditioned medium obtained from human amniotic mesenchymal stem cells (hAMSC-CM) has been reported to exert protective effect against stroke, detailed knowledge about its possible molecular mechanisms is not still completely available. The present study was designed to investigate whether hAMSC-CM can modulate FoxO1 and Wnt/ß-catenin signaling pathway after ischemic stroke to create neuroprotective effects. Middle cerebral artery occlusion (MCAO) model with male Wistar rats was used to evaluate the effects of hAMSC-CM on activities of FoxO1, Wnt/ß-catenin signaling pathway, and endogenous antioxidant system and apoptotic cell death. The results demonstrated that induction of MCAO significantly reduced activities of FoxO1, Wnt/ß-catenin signaling pathway, and endogenous antioxidant system and enhanced apoptotic cell death (P < 0.05). In addition, treatment by hAMSC-CM immediately after cerebral reperfusion resulted in significantly reduced infarct size and increased activities of FoxO1, Wnt/ß-catenin signaling pathway, and restoring endogenous antioxidant system and suppressing apoptotic cell death (P < 0.05). Likewise, increased activity of Wnt/ß-catenin signaling pathway resulted in suppressing the neuroinflammation by inhibiting the expression of TNF-α and increasing the expression of IL-10. These findings demonstrate that hAMSC-CM can be considered as an excellent candidate in the treatment of acute ischemic stroke in clinical routine.