Showing papers in "Naunyn-schmiedebergs Archives of Pharmacology in 2021"

The SARS-CoV-2 main protease M-pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

Abstract: Several lines of evidence suggest that neurological symptoms in COVID-19 patients are partially due to damage to small vessels. However, the potential mechanisms are unclear. Here, we show that brain endothelial cells express SARS-CoV-2 receptors. The main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of NF-κB signaling. By ablating NEMO, Mpro induces the death of human brain endothelial cells and a microvascular pathology in mice that is similar to what we find in the brain of COVID-19 patients. Importantly, the inhibition of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Our data suggest RIPK as a therapeutic target to treat the neuropathology of COVID-19.

Ferroptosis occurs in phase of reperfusion but not ischemia in rat heart following ischemia or ischemia/reperfusion

Abstract: Ferroptosis is an iron-dependent regulated necrosis This study aims to evaluate the contribution of ferroptosis to ischemia or reperfusion injury, and lay a basis for precise therapy of myocardial infarction The Sprague-Dawley (SD) rat hearts were subjected to ischemia for different duration or the hearts were treated with 1 h-ischemia plus different duration of reperfusion The myocardial injury was assessed by biochemical assays and hematoxylin & eosin (HE) staining The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), iron, and malondialdehyde Iron chelator (deferoxamine) was applied to verify the contribution of ferroptosis to ischemia and reperfusion injury The results showed that ischemic injury (infarction and CK release) was getting worse with the extension of ischemia, but no significant changes in ferroptosis indexes (ACSL4, GPX4, iron, and malondialdehyde) in cardiac tissues were observed Differently, the levels of ACSL4, iron, and malondialdehyde were gradually elevated with the extension of reperfusion concomitant with a decrease of GPX4 level In the ischemia-treated rat hearts, no significant changes in myocardial injury were observed in the presence of deferoxamine, while in the ischemia/reperfusion-treated rat hearts, myocardial injury was markedly attenuated in the presence of deferoxamine concomitant with a reduction of ferroptosis Based on these observations, we conclude that ferroptosis occurs mainly in the phase of myocardial reperfusion but not ischemia Thus, intervention of ferroptosis exerts beneficial effects on reperfusion injury but not ischemic injury, laying a basis for precise therapy for patients with myocardial infarction

NF-κB signalling as a pharmacological target in COVID-19: potential roles for IKKβ inhibitors

Abstract: Coronavirus disease 2019 (COVID-19) has been characterized by lymphopenia as well as a proinflammatory cytokine storm, which are responsible for the poor prognosis and multiorgan defects. The transcription factor nuclear factor-κB (NF-κB) modulates the functions of the immune cells and alters the gene expression profile of different cytokines in response to various pathogenic stimuli, while many proinflammatory factors have been known to induce NF-κB signalling cascade. Besides, NF-κB has been known to potentiate the production of reactive oxygen species (ROS) leading to apoptosis in various tissues in many diseases and viral infections. Though the reports on the involvement of the NF-κB signalling pathway in COVID-19 are limited, the therapeutic benefits of NF-κB inhibitors including dexamethasone, a synthetic form of glucocorticoid, have increasingly been realized. Considering the fact, the abnormal activation of the NF-κB resulting from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection might be associated with the pathogenic profile of immune cells, cytokine storm and multiorgan defects. Thus, the pharmacological inactivation of the NF-κB signalling pathway can strongly represent a potential therapeutic target to treat the symptomatology of COVID-19. This article signifies pharmacological blockade of the phosphorylation of inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ), a key downstream effector of NF-κB signalling, for a therapeutic consideration to attenuate COVID-19.

Gallic acid exerts anti-inflammatory, anti-oxidative stress, and nephroprotective effects against paraquat-induced renal injury in male rats

Abstract: Paraquat (PRQ) is a toxic chemical compound that is very noxious to animals and humans. Gallic acid is a phenolic compound that has antioxidant properties. In this study, we evaluated the ameliorative effect of gallic acid against PRQ-induced renal injury and oxidative stress. In this research, the rats were segregated into six groups. Group 1 is the control group; group 2 received paraquat only; group 3 received gallic acid only; and groups 4, 5, and 6 received paraquat plus gallic acid at doses of 25, 50, and 100 mg/kg bw respectively. Findings of this work displayed that the renal contents of the vitamin C, superoxide dismutase (SOD), and catalase (CAT) significantly reduced and the levels of the serum protein carbonyl, creatinine, serum glutamate pyruvate transaminase (sGPT), urea, serum glutamate oxaloacetate transaminase (sGOT), uric acid, MDA, serum IL-1β, and the kidney IL-1β gene expression were remarkably increased in the group receiving PRQ only compared with that in the control group. On the other hand, treatment with gallic acid after exposure to PRQ led to a significant elevation in renal vitamin C, SOD, and CAT levels plus a remarkable decrease in the serum protein carbonyl, creatinine, sGPT, urea, sGOT, uric acid, MDA, IL-1β, and renal gene expression of IL-1β in comparison with the PRQ-only-treated rats. Histological changes were also ameliorated by gallic acid administration. The data approve that gallic acid diminished the deleterious effects of PRQ exposure. In this regard, our results indicated that the administration of gallic acid could alleviate the noxious effects of PRQ on the antioxidant defense system and renal tissue.

Efficacy of synthetic glucocorticoids in COVID-19 endothelites.

Abstract: Since March 2020, the world has been fighting a global pandemic caused by a new coronavirus SARS-CoV-2 (COVID-19). SARS-CoV-2 is responsible for severe acute respiratory syndrome, an airway disease that can be severe and fatal in a percentage of cases. Patients with severe COVID-19 can develop extrapulmonary lesions, with renal, hepatic, cardiac, neurological, and tissue involvement that can cause further severe complications. On December 21, 2021, the European Medicines Agency (EMA) authorized the marketing of the first COVID-19 vaccine. However, several randomized trials are ongoing to find effective, safe, and widely available treatments. The most severe stages of COVID-19 infection are characterized by a multi-system inflammatory state induced by a cytokine storm causing multi-organ injury. Epidemiologic evidence has shown that glucocorticoids (GCs), particularly dexamethasone, are used in severe, hospitalized patients with COVID-19 with good therapeutic benefit. COVID-19 can also damage the endothelial system, causing microcirculatory disturbances and consequently leading to functional organ disorders. The combination of endothelial dysfunction with a generalized inflammatory state may contribute to the general pro-coagulative state described in patients with COVID-19 with increased risk of venous and arterial occlusions. The aim of this article is to describe the therapeutic utility of GCs in stabilizing the vascular endothelial barrier in COVID-19 infection. Indeed, we believe that the stabilization of the endothelial barrier and the anti-inflammatory effect of GCs could be the main effect underlying the therapeutic efficacy in COVID-19 patients.

Covid-19 and development of heart failure: mystery and truth.

Abstract: Coronavirus disease 2019 (Covid-19) is a novel worldwide pandemic caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During Covid-19 pandemic, socioeconomic deprivation, social isolation, and reduced physical activities may induce heart failure (HF), destabilization, and cause more complications. HF appears as a potential hazard due to SARS-CoV-2 infection, chiefly in elderly patients with underlying comorbidities. In reality, the expression of cardiac ACE2 is implicated as a target point for SARS-CoV-2-induced acute cardiac injury. In SARS-CoV-2 infection, like other febrile illnesses, high blood viscosity, exaggerated pro-inflammatory response, multisystem inflammatory syndrome, and endothelial dysfunction-induced coagulation disorders may increase risk of HF development. Hypoxic respiratory failure, as in pulmonary edema, severe acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) may affect heart hemodynamic stability due to the development of pulmonary hypertension. Indeed, Covid-19-induced HF could be through the development of cytokine storm, characterized by high proliferation pro-inflammatory cytokines. In cytokine storm-mediated cardiac dysfunction, there is a positive correlation between levels of pro-inflammatory cytokine and myocarditis-induced acute cardiac injury biomarkers. Therefore, Covid-19-induced HF is more complex and related from a molecular background in releasing pro-inflammatory cytokines to the neuro-metabolic derangements that together affect cardiomyocyte functions and development of HF. Anti-heart failure medications, mainly digoxin and carvedilol, have potent anti-SARS-CoV-2 and anti-inflammatory properties that may mitigate Covid-19 severity and development of HF. In conclusion, SARS-CoV-2 infection may lead to the development of HF due to direct acute cardiac injury or through the development of cytokine storms, which depress cardiomyocyte function and cardiac contractility. Anti-heart failure drugs, mainly digoxin and carvedilol, may attenuate severity of HF by reducing the infectivity of SARS-CoV-2 and prevent the development of cytokine storms in severely affected Covid-19 patients.

Interferon-beta offers promising avenues to COVID-19 treatment: a systematic review and meta-analysis of clinical trial studies.

Abstract: Severe acute respiratory syndrome coronavirus 2 principally weakens the hosts' innate immune system by impairing the interferon function and production. Type I interferons (IFNs) especially IFN-β are best known for their antiviral activities. IFNs accompanied by the standard care protocols have opened up unique opportunities for treating the coronavirus disease 2019 (COVID-19). The databases including PubMed, SCOPUS, EMBASE, and Google Scholar were searched up to October 30, 2020. The primary and secondary outcomes were considered discharge and mortality, respectively. The abovementioned outcomes of standard care protocol were compared with the standard care plus IFN-β in the confirmed COVID-19 patients. Out of 356 records identified, 12 randomized clinical trial studies were selected for full-text screening. Finally, 5 papers were included in the systematic review and 3 papers in the meta-analysis. The average mortality rate was reported as 6.195% and 18.02% in intervention and control groups, respectively. Likewise, the median days of hospitalization were lower in the intervention group (9 days) than the control group (12.25 days). According to meta-analysis, IFN-β was found to increase the overall discharge rate (RR = 3.05; 95% CI: 1.09-5.01). Our findings revealed that early administration of IFN-β in combination with antiviral drugs is a promising therapeutic strategy against COVID-19.

Emerging nanomaterials for antibacterial textile fabrication

Abstract: In recent times, the search for innovative material to fabricate smart textiles has been increasing to satisfy the expectation and needs of the consumers, as the textile material plays a key role in the evolution of human culture. Further, the textile materials provide an excellent environment for the microbes to grow, because of their large surface area and ability to retain moisture. In addition, the growth of harmful bacteria on the textile material not only damages them but also leads to intolerable foul odour and significant danger to public health. In particular, the pathogenic bacteria present in the fabric surface can cause severe skin infections such as skin allergy and irritation via direct human contact and even can lead to heart problems and pneumonia in certain cases. Recently, nanoparticles and nanomaterials play a significant role in textile industries for developing functional smart textiles with self-cleaning, UV-protection, insect repellent, waterproof, anti-static, flame-resistant and antimicrobial-resistant properties. Thus, this review is an overview of various textile fibres that favour bacterial growth and potential antibacterial nanoparticles that can inhibit the growth of bacteria on fabric surfaces. In addition, the probable antibacterial mechanism of nanoparticles and the significance of the fabric surface modification and fabric finishes in improving the long-term antibacterial efficacy of nanoparticle-coated fabrics were also discussed.

Selenium nanoparticles and metformin ameliorate streptozotocin-instigated brain oxidative-inflammatory stress and neurobehavioral alterations in rats

Abstract: Selenium nanoparticles (SeNPs) are well reported to exhibit pharmacological activities both in vitro and in vivo. However, literature is devoid of studies on the impact of SeNPs and/or metformin (M) against streptozotocin (STZ)-mediated oxidative brain injury and behavioral impairment. Consequently, to fill this gap, diabetes was induced in male Wistar rats by feeding with 10% fructose solution for 2 weeks, followed by a single dose intraperitoneal injection of STZ (40 mg/kg body weight [bwt]). After rats were confirmed diabetic, they were treated orally with 0.1 mg/kg bwt of SeNPs ± M (50 mg/kg bwt), and normal control (NC) received citrate buffer (2 mg/mL) for 5 weeks. In comparison with the diabetic control (DC), SeNPs, and/or M significantly (p < 0.05) lowered blood glucose levels, but increased insulin secretion and pancreatic β-cell function. An increase in locomotor and motor activities evidenced by improved spontaneous alternation, locomotor frequency, hinding, and increased mobility time were observed in treated groups. In addition, there was enhanced brain antioxidant status with a lower acetylcholinesterase (AChE) activity and oxidative-inflammatory stress biomarkers. A significant downregulation of caspase 3 and upregulation of parvalbumin and Nrf2 protein expressions was observed in treated groups. In some of the studied parameters, treated groups were statistically (p < 0.05) insignificant compared with the normal control (NC) group. Overall, co-treatment elicited more efficacy than that of the individual regimen.

Inhibition of NF-κB signaling and HSP70/HSP90 proteins by newly synthesized hydrazide derivatives in arthritis model.

Abstract: In the current study, the N-benzylidene-4-((2-hydroxynaphthalene-1-yl) diazenyl) hydrazides (NCHDH and NTHDH) were evaluated against the Carrageenan- and CFA-induced models. During the preliminary investigation, the NCHDH and NTHDH treatment showed marked anti-inflammatory and analgesic activity against the Carrageenan-induced acute model. Once the anti-inflammatory activity was established against acute Carrageenan model, the NCHDH and NTHDH were evaluated against the chronic CFA-induced arthritis model. The NCHDH and NTHDH treatment markedly attenuated the inflammatory and analgesic parameters compared to CFA-treated group. Furthermore, the increase in the oxidative stress and attenuation of antioxidant enzymes has been reported following CFA administration. However, NCHDH and NTHDH treatment significantly induced the antioxidants and attenuated the oxidative stress markers. The CFA administration showed marked tailing of DNA; however, the NCHDH- and NTHDH-treated group preserved DNA integrity. Furthermore, the histological studies showed marked alteration in the CFA-treated group; however, the NCHDH and NTHDH treatment markedly improved the histological features. The Western blot, immunohistology, and ELISA assay revealed marked increase in the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Jun N-terminal Kinase (JNK), TNF-α, and COX-2 levels; however, the NCHDH and NTHDH attenuated their expressions significantly. Similarly, the NCHDH and NTHDH significantly induced the mRNA expression levels of heat shock proteins. The computational analysis showed significant binding interaction with various protein targets via multiple hydrogens, and hydrophobic bonds. The in vivo pharmacokinetic study was also performed to assess the various pharmacokinetic parameters. In conclusion, the NCHDH and NTHDH treatment showed significant anti-arthritic activity against Carrageenan and CFA models.

Protective effects of apigenin on altered lipid peroxidation, inflammation, and antioxidant factors in methotrexate-induced hepatotoxicity.

Abstract: Methotrexate (MTX) is used as an effective chemotherapeutic agent against autoimmune diseases and tumors. Oxidative stress and inflammation are involved in the pathogenesis of MTX-induced damage. This study aimed at examining the ameliorating effects of apigenin (API) as a natural antioxidant on MTX-induced hepatotoxicity. The rats were classified into four groups: group I: normal saline-treated, group II: MTX-treated (20 mg/kg, ip, single dose at day 7), group III: MTX + API-treated (20 mg/kg, po), and group IV: API-treated. API was administrated for 9 days. Alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) were used as biochemical factors of MTX-induced hepatic injury. In hepatic tissues, the levels of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), and activities of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) as oxidative stress markers along with inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) were assessed. Our results showed that MTX administration significantly increased ALP, ASP, ALT, MDA, NO, TNF-α, and IL-1β levels and significantly decreased antioxidant factors such as GSH, CAT, GPx, and SOD. The API pretreatment group showed a significant rise in hepatic antioxidant markers, besides significant reductions in the serum levels of AST, ALT, and ALP and hepatic content of MDA, TNF-α, NO, and IL-1β. In addition, the hepatoprotective effect of API was confirmed by histological evaluation of the liver. API can prevent MTX-induced hepatotoxicity through mitigation of oxidative stress and inflammation.

Cardioprotective role of GTS-21 by attenuating the TLR4/NF-κB pathway in streptozotocin-induced diabetic cardiomyopathy in rats

Abstract: The cholinergic anti-inflammatory pathway (CAP) was investigated in a variety of inflammatory conditions and constitutes a valuable line in their treatment. In the current study, we investigated the anti-inflammatory effect of GTS-21 (GTS) as a partial selective α7 nicotinic acetylcholine receptor (α7-nAchR) agonist in diabetic cardiomyopathy model in rats. This mechanism was elaborated to study whether it could alleviate the electrocardiographic, histopathological, and molecular levels of Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway proteins. Diabetes was induced by the injection of streptozotocin (STZ) (50 mg/kg). Diabetic rats were treated with GTS (1 or 2 mg/kg/day), methyllycaconitine (MLA), a selective α7-nAchR antagonist (2 mg/kg/day) plus GTS (2 mg/kg/day), or the vehicle. All treatments were given by the intraperitoneal route. Ventricular rate and different electrocardiograph (ECG) anomalies were detected. Plasma levels of cardiac troponin T (cTnT) and creatine kinase MB (CK-MB) were measured by ELISA. Additionally, we elucidated the levels of several proteins involved in the TLR4/NF-κB pathway. Cardiac levels of TLR4 and phosphorylated protein kinase B (p-Akt) were detected by ELISA. The cardiac expression of myeloid differentiation primary response 88 (Myd88), tumor necrosis factor receptor-associated factor 6 (TRAF6), NF-κB, interleukin 1β (IL-1β), and active caspase-1 were evaluated by immunohistochemical staining. Finally, the cardiac levels of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were determined by ELISA. Diabetic rats showed (i) ECG signs of cardiomyopathy such as significant ST segment elevations, prolonged QRS, QT intervals, and ventricular tachycardia; (ii) increased plasma levels of cTnT and CK-MB; (iii) increased expression of cardiac TLR4; (iv) elevated immunohistochemical expression of cardiac, Myd88, TRAF6, and NF-κB; (v) diminution in the cardiac expression of p-Akt; and (vi) adaptive increases in cardiac expression of TNF-α and IL-6. These effects were ameliorated in diabetic rats treated with both doses of GTS. Pretreatment with MLA did not completely reverse the ameliorative effect of GTS on cTnT, TRAF6, TNF-α, and IL-6, thereby reinforcing the presence of possible α7-nAchR-independent mechanisms. The activation of α7-nAchR with GTS offers a promising prophylactic strategy for diabetic cardiomyopathy by attenuating the TLR4/NF-κB pathway.

Melatonin alleviates sepsis-induced heart injury through activating the Nrf2 pathway and inhibiting the NLRP3 inflammasome

Abstract: Melatonin improved the outcome of septic cardiomyopathy by inhibiting NLRP3 priming induced by reactive oxygen species. To get insights into these events, we studied the melatonin/Nrf2 antioxidant pathways during sepsis in the heart of NLRP3-deficient mice. Sepsis was induced by cecal ligation and puncture and melatonin was given at a dose of 30 mg/kg. Nuclear turnover of Nrf2 and p-Ser40 Nrf2 and expression of ho-1 were enhanced in nlrp3+/+ and nlrp3−/− mice during sepsis. Sepsis caused higher mitochondria impairment, apoptotic and autophagic events in nlrp3+/+ mice than in nlrp3−/− animals. These findings were accompanied by greater levels of Parkin and PINK-1, and lower Mfn2/Drp-1 ratio in nlrp3+/+ than in nlrp3−/− mice during sepsis, supporting less mitophagy in the latter. Ultrastructural analysis of myocardial tissue further confirmed these observations. The activation of NLRP3 inflammasome accounted for most of the deleterious effects of sepsis, whereas the Nrf2-dependent antioxidative response activation in response to sepsis was unable to neutralize these events. In turn, melatonin further enhanced the Nrf2 response in both mice strains and reduced the NLRP3 inflammasome activation in nlrp3+/+ mice, restoring myocardial homeostasis. The data support that the anti-inflammatory efficacy of melatonin against sepsis depends, at least in part, on Nrf2 activation.

How Naunyn-Schmiedeberg's Archives of Pharmacology deals with fraudulent papers from paper mills.

Abstract: Fraudulent papers from paper mills are a serious threat to the entire scientific community. Naunyn-Schmiedeberg’s Archives of Pharmacology has become the target of a massive attack of fraudulent papers originating from paper mills. This editorial highlights 20 important features we observed with paper mills and explains how the journal is responding to this serious threat to restore the integrity of science. Hopefully, this editorial is also helpful for editors of other scientific journals.

Safranal protects against ischemia-induced PC12 cell injury through inhibiting oxidative stress and apoptosis

Abstract: Safranal, isolated from saffron (Crocus sativus L.), is known to possesses neuroprotective effects. In this study, the neuroprotective potential of safranal against PC12 cell injury triggered by ischemia/reperfusion was investigated. PC12 cells were pretreated with safranal at concentration ranges of 10–160 μM for 2 h and then deprived from oxygen-glucose-serum for 6 h, followed by reoxygenation for 24 h (OGD condition). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 2,7-dichlorofluorescin diacetate (DCF-DA), and comet assays were used to measure the extent of cellular viability, reactive oxygen substances (ROS), and DNA damage, respectively. Also, propidium iodide (PI) flow cytometry assay and western blotting of bax, bcl-2, and cleaved caspase-3 were performed for assessment of apoptosis. OGD exposure reduced the cell viability and increased intracellular ROS production, oxidative DNA damage, and apoptosis, in comparison with untreated control cells. Pretreatment with safranal (40 and 160 μM) significantly attenuated OGD-induced PC12 cell death, oxidative damage, and apoptosis. Furthermore, safranal markedly reduced the overexpression of bax/bcl-2 ratio and active caspase-3 following OGD (p < 0.05). The present findings indicated that safranal protects against OGD-induced neurotoxicity via modulating of oxidative and apoptotic responses. Graphical abstract

Beneficial effects of vitamin D on anxiety and depression-like behaviors induced by unpredictable chronic mild stress by suppression of brain oxidative stress and neuroinflammation in rats.

Abstract: The objective of this study was to investigate the protective effects of vitamin D (Vit D) on anxiety and depression-like behaviors induced by unpredictable chronic mild stress and brain tissue oxidative damage criteria and neuroinflammation in rats. The rats were treated as follows: (1) control, (2) UCMS, (3–5) Vit D 100, 1000, and 10,000 iu + UCMS. Rats were subjected to UCMS for a total of 4 weeks. During week 4, they received seven training trials. The brains were then collected to examine inflammation and oxidative stress criteria. Pretreatment with Vit D enhanced performances of the rats in the elevated plus maze (EPM) and open field (OF) and forced swimming test (FST). UCMS also increased MDA and interleukin-6 (IL-6) levels while decreased CAT, SOD, and thiol. Vit D reversed the effects of UCMS. The results of the current research revealed that Vit D improved UCMS-induced anxiety and depression via decreasing brain oxidative stress and inhibiting neuroinflammation.

The targets of β-sitosterol as a novel therapeutic against cardio-renal complications in acute renal ischemia/reperfusion damage

Abstract: This research is the first to use β-sitosterol on myocardial and renal tissues in renal ischemia/reperfusion (IR) damage. Female Wistar rats were randomly divided into three groups: control (sham), renal IR (50 min ischemia – 3 h reperfusion), and renal IR + 150 mg/kg/p.o. β-sitosterol (the rats were treated with β-sitosterol orally once 1 h before the IR procedure). β-Sitosterol pretreatment caused an increase in superoxide dismutase and glutathione activities and a decrease in malondialdehyde levels in the kidney and heart. Moreover, it alleviated histopathological changes and downregulated the levels of tumor necrosis factor-alpha and interleukin-6 and upregulated the levels of endothelial nitric oxide synthase. As conclusion, the potential of β-sitosterol for renal and cardiac necrosis and apoptosis appears to act by limiting inflammatory response and oxidative stress. Thus, the potential of this compound is noteworthy and may serve as a potential therapeutic in the treatment of acute organ damages due to renal IR.

Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer's disease.

Abstract: With the increasing aging population and progressive nature of the disease, Alzheimer’s disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of β-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor, is a more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing the first-pass metabolism exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver them efficiently to the brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to the brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in acute scopolamine-induced amnesia and chronic colchicine induced cognitive dysfunction animal models, and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modeling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax = 5 min), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F = 118.65 ± 23.54; AUC = 35,921.75 ± 9559.46), increased half-life (30.92 ± 8.38 min), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax = 15 min; Cmax = 56.29 ± 27.05; F = 4.39 ± 1.82; AUC = 1663.79 ± 813.54; t1/2 = 13.48 ± 5.79; Kel (1/min) = 0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine as well as colchicine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modeling demonstrated a strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation.

Formulation and evaluation of rutin-loaded solid lipid nanoparticles for the treatment of brain tumor

Abstract: The primary requirement for curing cancer is the delivery of essential drug load at the cancer microenvironment with therapeutic efficacy. Considering this, the present study aims to formulate “Rutin”-encapsulated solid lipid nanoparticles (SLNs) for effective brain delivery across the blood-brain barrier (BBB). Rutin-loaded SLNs were fabricated by oil-in-water microemulsion technique and were characterized for their physicochemical properties. The in vivo biodistribution study of rutin-loaded SLNs was studied using Rattus norvegicus rats. Subsequently, in silico molecular docking and dynamic calculations were performed to examine the binding affinity as well as stability of rutin at the active site of target protein “epidermal growth factor receptor (EGFR).” Formulated rutin-loaded SLNs were predominantly spherical in shape with an average particle diameter of 100 nm. Additionally, the biocompatibility and stability have been proved in vitro. The presence and biodistribution of rutin in vivo after 54 h of injection were observed as 15.23 ± 0.32% in the brain, 8.68 ± 0.63% in the heart, 4.78 ± 0.28% in the kidney, 5.04 ± 0.37% in the liver, 0.92 ± 0.04% in the lung, and 11.52 ± 0.65% in the spleen, respectively. Molecular docking results revealed the higher binding energy of − 150.973 kJ/mol of rutin with EGFR. Molecular dynamic simulation studies demonstrated that rutin with EGFR receptor complex was highly stable at 30 ns. The observed results exemplified that the formulated rutin-loaded SLNs were stable in circulation for a period up to 5 days. Thus, rutin-encapsulated SLN formulations can be used as a promising vector to target tumors across BBB.

GLUT1 participates in tamoxifen resistance in breast cancer cells through autophagy regulation

Abstract: Tamoxifen is an estrogen modulator widely used in the treatment of patients with ESR/ER-positive breast cancer; however, resistance limits its clinical application. Autophagy alterations have recently been suggested as a new mechanism for tamoxifen resistance. Glucose transporter 1 (GLUT1) has been reported to be associated with the development and metastasis of breast cancer, but the relationship among GLUT1, autophagy, and endocrine resistance remains unclear. Our present study found that GLUT1 expression and autophagy flux were upregulated in the tamoxifen-resistant breast cancer cell line MCF-7/TAMR-1 and that knockdown of GLUT1 promoted sensitization to tamoxifen. Moreover, knockdown of GLUT1 significantly decreased the enhancement of autophagy flux in tamoxifen-resistant cell lines. Furthermore, inhibiting autophagy in tamoxifen-resistant cells resulted in sensitization to tamoxifen. We conclude that GLUT1 contributes to tamoxifen resistance in breast cancer and that tamoxifen-resistant cells become resensitized to tamoxifen after GLUT1 silencing. These findings suggest GLUT1 as a new factor clinically associated with resistance to tamoxifen.

Inflammation suppression in doxorubicin-induced cardiotoxicity: natural compounds as therapeutic options.

Abstract: Doxorubicin (DOX) is a potent chemotherapeutic agent; however, the accompanying cardiotoxicity is a significant complication of the usefulness of treatment with DOX. Multiple mechanisms have been suggested for this often fatal side effect, one of which is inflammation. Several pathways with different targets have been reported to result in DOX-induced heart inflammation. Some natural occurring compounds (NCs) have been reported to interact with the DOX-induced cardiotoxicity through targeting one or more of several pathways, including the Nrf2/NF-kB, TLR-4/NF-kB, MAPK/NF-kB, and NLRP3 inflammasome pathways. This article reviews several of these pathways and the potential protective effect of some NCs against the cardiac inflammation induced by DOX.

Effects of metal nanoparticle-mediated treatment on seed quality parameters of different crops.

Abstract: The increasing population of the world requires novel techniques to feed everyone, which can replace or work along with traditional methods to increase production of agricultural crops. In recent times, nanotechnology is considered as a promising and emerging approach to be incorporated in agriculture to improve productivity of different crops by the administration of nanoparticles through seed treatment, foliar spray on plants, nano-fertilizers for balanced crop nutrition, nano-herbicides for effective weed control, nanoinsecticides for plant protection, early detection of plant diseases and nutrient deficiencies using diagnostics kits, and nano-pheromones for effective monitoring of pests. Further, distinct nanoparticles with unique physicochemical and biological properties are used in agriculture to increase the percentage of seed germination, which is the initial step to increase the crop yield. In the context of agricultural crops, nanoparticles have both positive effects on seed quality parameters, such as germination percentage, seedling length, seedling dry weight and vigor indices, as well as negative impacts of causing toxicity toward the environment. Thus, the aim of this review article is to provide a comprehensive overview on the effects of super-dispersive metal powders, such as zinc, silver, and titanium nanoparticles on the seed quality parameters of different crops. In addition, the drawback of conventional seed growth enhancers, impact of metal nanoparticles toward seeds, and mechanism of nanoparticles to increase seed germination were also discussed.

Interleukin-38 overexpression prevents bleomycin-induced mouse pulmonary fibrosis.

Abstract: Pulmonary fibrosis is a kind of pulmonary disorder with chronic inflammation and excessive collagen deposition, and its etiology is not clear Interleukin (IL)-38 is a new member of IL-1 family cytokines, but its role in pulmonary fibrosis has not been elucidated In this study, a lentivirus expressing IL-38 was injected into the nasal cavity of mice with bleomycin-induced pulmonary fibrosis We found that IL-38 overexpression reduced the body weight loss and improved the survival of mice induced by bleomycin Furthermore, IL-38 expression attenuated the pulmonary inflammation and fibrosis damage induced by bleomycin, decreased the production of pro-inflammatory and pro-fibrotic cytokines such as IL-1β, IL-6, IL-17A, monocyte chemoattractant protein-1, and tumor necrosis factor-α, but increased the release of anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) in the lungs of bleomycin-challenged mice Our data suggest that IL-38 may inhibit bleomycin-induced pulmonary inflammation and fibrosis through its anti-inflammatory effect and regulation of IL-1β/IL-1Ra balance, and IL-38 may be a new strategy for the treatment of pulmonary fibrosis

Deferasirox, a trivalent iron chelator, ameliorates neuronal damage in hemorrhagic stroke models.

Abstract: Intracranial hemorrhage (ICH) is a devastating disease with high mortality and morbidity. After ICH, iron released from the hematoma plays a crucial role in secondary brain injury. Deferasirox (DFR) is a trivalent iron chelator, which was approved to treat iron overload syndrome after transfusion. The aim of the present study was to investigate the protective effects of DFR in both in vitro and in vivo ICH models. Using a hemin-induced SH-SY5Y cell damage model, we performed an intracellular bivalent iron (Fe2+) accumulation assay, cell death assay, oxidative stress assessments, and Western blotting analysis. Moreover, the effects of DFR intraventricular administration on hematoma, neurological deficits, and histological alteration were evaluated in an in vivo ICH mouse model by collagenase. DFR significantly suppressed the intracellular Fe2+ accumulation and cell death caused by hemin exposure. These effects were related to the suppression of both reactive oxygen species and lipid peroxidation over-production. In Western blotting analysis, hemin increased the expression of ferritin (an iron storage protein), LC3 and p62 (autophagy-related markers), phosphorylated p38 (a stress response protein), and cleaved-caspase3 and cleaved-poly (adenosine diphosphate ribose) polymerase (PARP) (apoptosis-related makers). However, DFR suppressed the increase of these proteins. In addition, DFR attenuated the neurological deficits until 7 days after ICH without affecting hematoma and injury area. Furthermore, DFR also suppressed microglia/macrophage activation in peri-hematoma area at 3 days after ICH. These findings indicate that DFR might be a useful therapeutic agent for the therapy of ICH.

Acquired ABC-transporter overexpression in cancer cells: transcriptional induction or Darwinian selection?

Abstract: Acquired multidrug resistance (MDR) in tumor diseases has repeatedly been associated with overexpression of ATP-binding cassette transporters (ABC-transporters) such as P-glycoprotein. Both in vitro and in vivo data suggest that these efflux transporters can cause MDR, albeit its actual relevance for clinical chemotherapy unresponsiveness remains uncertain. The overexpression can experimentally be achieved by exposure of tumor cells to cytotoxic drugs. For simplification, the drug-mediated transporter overexpression can be attributed to two opposite mechanisms: First, increased transcription of ABC-transporter genes mediated by nuclear receptors sensing the respective compound. Second, Darwinian selection of sub-clones intrinsically overexpressing drug transporters being capable of extruding the respective drug. To date, there is no definite data indicating which mechanism truly applies or whether there are circumstances promoting either mode of action. This review summarizes experimental evidence for both theories, suggests an algorithm discriminating between these two modes, and finally points out future experimental approaches of research to answer this basic question in cancer pharmacology.

Recent progresses in the pharmacological activities of caffeic acid phenethyl ester

Abstract: The past decades have seen a growing interest in natural products. Caffeic acid phenethyl ester (CAPE), a flavonoid isolated from honeybee propolis, has shown multiple pharmacological potentials, including anti-cancer, anti-inflammatory, antioxidant, antibacterial, antifungal, and protective effects on nervous systems and multiple organs, since it was found as a potent nuclear factor κB (NF-κB) inhibitor. This review summarizes the advances in these beneficial effects of CAPE, as well as the underlying mechanisms, and proposes that CAPE offers an opportunity for developing therapeutics in multiple diseases. However, clinical trials on CAPE are necessary and encouraged to obtain certain clinically relevant conclusions.

Postoperative peritoneal adhesion: an update on physiopathology and novel traditional herbal and modern medical therapeutics.

Abstract: Postoperative peritoneal adhesion (PPA) is a serious clinical condition that affects the high percentage of patients after abdominal surgery. In this review, we have tried to focus on pathophysiology and different underlying signal pathways of adhesion formation based on recent progress in the molecular and cellular mechanisms. Also, the strategies, developed based on traditional herbal and modern medicines, to prevent and treat the PPA via regulation of the molecular mechanisms were investigated. The search engines such as Google Scholar, PubMed, Scopus, and Science Direct have been used to evaluate the current literature related to the pathogenesis of adhesion formation and novel products. Recently, different mechanisms have been defined for adhesion formation, mainly categorized in fibrin formation and adhesion fibroblast function, inflammation, and angiogenesis. Therefore, the suppression of these mechanisms via traditional and modern medicine has been suggested in several studies. While different strategies with encouraging findings have been developed, most of the studies showed contradictory results and were performed on animals. The herbal products have been introduced as safe and effective agent which can be considered in future preclinical and clinical studies. Although a wide range of therapeutics based on traditional and modern medicines have been suggested, there is no agreement in the efficacy of these methods to prevent or treat adhesion formation after surgeries. Further basic and clinical researches are still needed to propose the efficiency of recommended strategies for prevention and treatment of PPA.

Cardioprotective effect of pioglitazone and curcumin against diabetic cardiomyopathy in type 1 diabetes mellitus: impact on CaMKII/NF-κB/TGF-β1 and PPAR-γ signaling pathway

Abstract: Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients, which is currently without available specific treatment. This study aimed to investigate the potential protective effects of pioglitazone (Pio) and curcumin (Cur) against DCM in type 1 diabetes mellitus (T1DM), with pointing to their role on Ca+2/calmodulin-dependent protein kinase II (CaMKII) and peroxisome proliferator–activated receptor gamma (PPAR-γ) expression. Diabetes was induced in adult male Sprague Dawley rats by administration of single intraperitoneal injection of streptozotocin (STZ) (52.5 mg/kg). Diabetic rats were administered either Pio (20 mg/kg/day) or Cur (100 mg/kg/day) orally for 6 weeks. Treatment with Pio and/or Cur markedly reduced serum cardiac injury markers and lipid profile markers in diabetic animals. Additionally, Pio and/or Cur treatment mitigated oxidative stress and fibrosis in diabetic rats as evident from the significant suppression in myocardial lipid peroxidation and tumor growth factor beta 1 (TGF-β1) level, with concomitant significant elevation in total antioxidant capacity (TAC) and improvement in histopathological architecture of heart tissue. Pio/Cur treatment protocol accomplished its cardioprotective effect by depressing cardiac CaMKII/NF-κB signaling accompanied by enhancement in PPAR-γ expression. Conclusively, these findings demonstrated the therapeutic potential of Pio/Cur regimen in alleviating DCM in T1DM through modulation of CaMKII and PPAR-γ expression.

Apoptosis-inducing factor plays a role in the pathogenesis of hepatic and renal injury during cholestasis

Abstract: Cholestasis is a clinical complication with different etiologies. The liver is the primary organ influenced in cholestasis. Renal injury is also a severe clinical complication in cholestatic/cirrhotic patients. Several studies mentioned the importance of oxidative stress and mitochondrial impairment as two mechanistically interrelated events in cholestasis-induced organ injury. Apoptosis-inducing factor (AIF) is a flavoprotein located in the inner mitochondrial membrane. This molecule is involved in a distinct pathway of cell death. The current study aimed to evaluate the role of AIF in the pathophysiology of cholestasis-associated hepatic and renal injury. Bile duct ligation (BDL) was used as an animal model of cholestasis. Serum, urine, and tissue samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Tissues' AIF mRNA levels, as well as serum, urine, and tissue activity of AIF, were measured. Moreover, markers of DNA fragmentation and apoptosis were assessed in the liver and kidney of cholestatic animals. A significant increase in liver and kidney AIF mRNA levels, in addition to increased AIF activity in the liver, kidney, serum, and urine, was detected in BDL rats. DNA fragmentation and apoptosis were raised in the liver and kidney of cholestatic animals, especially at the early stage of the disease. The apoptotic mode of cell death in the liver and kidney was connected to a higher AIF level. These data mention the importance of AIF in the pathogenesis of cholestasis-induced organ injury, especially at the early stage of this disease. Mitochondrial release of apoptosis-inducing factor (AIF) seems to play a pathogenic role in cholestasis-associated hepatic and renal injury. AIF release is directly connected to oxidative stress and mitochondrial impairment in cholestatic animals.

Calcium dobesilate prevents cisplatin-induced nephrotoxicity by modulating oxidative and histopathological changes in mice.

Abstract: Cisplatin is one of the synthetic cancer medicines with nephrotoxicity being one of its major side effects. Past research shows that calcium dobesilate (CaD), as a vascular protective agent in diabetic retinopathy, has antioxidant properties. Thus, this study aims to evaluate the protective effects of CaD in cisplatin-induced nephrotoxicity in mice. A many as 28 mice, in the present experimental research, were randomly distributed into four groups, including control, cisplatin (the intraperitoneal administration of 20 mg/kg cisplatin only on the first day of the experiment), cisplatin + CaD 50 (cisplatin with the oral administration of 50 mg/kg CaD), and cisplatin + CaD 100 (cisplatin with the oral administration of 100 mg/kg CaD). The treated groups received CaD by oral gavage for 4 constitutive days. On the fifth day, the mice were sacrificed, and some biochemical (serum levels of Cr and BUN, renal tissue levels of MDA, and renal activities of SOD and GPx) and pathological parameters were evaluated. Based on the results, there was a significant decrease in the renal SOD and GPx activities; in contrast, there was a significant increase in the BUN, Cr, and renal MDA levels following administering cisplatin. However, the CaD treatment (100 mg/kg) significantly attenuated these alterations. In addition, the kidney’s histological examination of kidneys confirmed the nephroprotective effects of CaD. The findings proved the protective impact of CaD on cisplatin-induced nephrotoxicity by an improvement in the oxidative stress factors.