VEGF/VEGFR axis and its signaling in melanoma: Current knowledge toward therapeutic targeting agents and future perspectives.

Melanoma is responsible for most skin cancer-associated deaths globally. The progression of melanoma is influenced by a number of pathogenic processes. Understanding the VEGF/VEGFR axis, which includes VEGF-A, PlGF, VEGF-B, VEGF-C, and VEGF-D and their receptors, VEGFR-1, VEGFR-2, and VEGFR-3, is of great importance in melanoma due to its crucial role in angiogenesis. This axis generates multifactorial and complex cellular signaling, engaging the MAPK/ERK, PI3K/AKT, PKC, PLC-γ, and FAK signaling pathways. Melanoma cell growth and proliferation, migration and metastasis, survival, and acquired resistance to therapy are influenced by this axis. The VEGF/VEGFR axis was extensively examined for their potential as diagnostic/prognostic biomarkers in melanoma patients and results showed that VEGF overexpression can be associated with unfavorable prognosis, higher level of tumor invasion and poor response to therapy. MicroRNAs linking to the VEGF/VEGFR axis were identified and, in this review, divided into two categories according to their functions, some of them promote melanoma angiogenesis (promotive group) and some restrict melanoma angiogenesis (protective group). In addition, the approach of treating melanoma by targeting the VEGF/VEGFR axis has garnered significant interest among researchers. These agents can be divided into two main groups: anti-VEGF and VEGFR inhibitors. These therapeutic options may be a prominent step along with the modern targeting and immune therapies for better coverage of pathological processes leading to melanoma progression and therapy resistance.

Chlorogenic Acid Derivatives: Structural Modifications, Drug Design, and Biological Activities: A Review.

BACKGROUND: Phenolic acids have recently gained considerable attention because of their numerous practical, biological, and pharmacological benefits. Various polyphenolic compounds are widely distributed in plant sources. Flavonoids and phenolic acids are the two main polyphenolic compounds that many plants contain abundant polyphenols. Chlorogenic acid, one of the most abundant phenolic acids, has various biological activities, but it is chemically unstable and degrades into other compounds or different enzymatic processes. METHODS: In this review, we have studied many publications about CA and its derivatives. CA derivatives were classified into three categories in terms of structure and determined each part's effects on the body. The biological evaluations, structure-activity relationship, and mechanism of action of CA derivatives were investigated. The search databases for this review were ScienceDirect, Scopus, PubMed and google scholar. RESULTS: Many studies have reported that CA derivatives have demonstrated several biological effects, including anti-oxidant, anti-inflammatory, anti-microbes, anti-mutation, anti-carcinogenic, anti-viral, anti-hypercholesterolemia, anti-hypertensive, anti-bacterial, and hypoglycemic actions. The synthesis of new stable CA derivatives can enhance its metabolic stability and biological activity. CONCLUSION: The present study represented different synthetic methods and biological activities of CA derivatives. These compounds showed high antioxidant activity across a wide range of biological effects. Our goal was to help other researchers design and develop stable analogs of CA for the improvement of its metabolic stability and the promotion of its biological activity.

Drug design strategies that aim to improve the low solubility and poor bioavailability conundrum in quercetin derivatives.

INTRODUCTION: Scientists are especially interested in polyphenols, particularly flavonoids. Quercetin, a flavonoid, has demonstrated various therapeutic properties, such as antioxidant, anti-diabetic, anti-hypertensive, and anti-carcinogenic activities. Different plant sources contain varying quantities and types of quercetin. However, quercetin's bioavailability is frequently low due to its low water solubility, molecular stability, and absorption characteristics. AREAS COVERED: The primary goals of this review are related to the approaches for overcoming quercetin's limitations. Hence, the main tactics for structural modifications (addition of charged and polar groups, removing C2, C3 double bond or reducing aromaticity, disrupting intramolecular H-bond, and reducing crystal lattice stability) and drug delivery systems (cyclodextrin complexes, emulsions, nanoparticles, liposomes, etc.) were discussed to improve water solubility and bioavailability of quercetin. EXPERT OPINION: From a tactical perspective, enhancing the solubility of compounds can be simplified through decreasing hydrophobic properties or crystalline stability. In addition, an essential field of study focuses on creating appropriate molecular carriers for substances with low water solubility. However, pharmacokinetics, potency, and toxicology are all impacted by the structural factors and physical characteristics that regulate solubility. Poor water solubility is still a major problem in drug discovery, and new methods are always in demand to overcome it.

Sida rhombifolia Exerts Anti-Proliferative and Pro-Apoptotic Effects in Human Liver Cancer HepG2 Cells in Vitro.

PURPOSE: Modern research revealed that plants belonging to the Sida rhombifolia family (Malvaceae) contain biologically active compounds that make them prone to discovering and developing anticancer drugs. This study aimed to evaluate the apoptosis effects of S. rhombifolia extracts in HepG2 Cell Line was performed. METHODS: The extractions were prepared, and an MTT assay was applied to evaluate its role in decreasing the viability of HepG2 and HFF cells. Phenolic compounds were analyzed using High-performance liquid chromatography (HPLC). FlowCytometry and RT-qPCR evaluated apoptosis was performed to measure the mRNA expression of pro-and anti-apoptotic mediators. RESULTS: The results can be summarized as EtOAc extract was more cytotoxic against the HepG2 cells (IC50= 364.3 µg/mL) compared to MeOH and HEX extracts (720.2 µg/mL) (560.4 µg/mL) with less cytotoxicity in HFF cells (353.2 µg/mL). The HPLC analysis results revealed most phenolic compounds, such as Epicatechin(1.3 mg/g). The EtOAc extract (300 µg/mL) induced 34% apoptosis in HepG2 cells. RT-qPCR data showed upregulation of the proapoptotic gene (Bax) and increased Bax/BCL-2 ratio by S. rhombifolia EtOAc extract (300 µg/mL). CONCLUSION: In conclusion, the EtOAc extract of S. rhombifolia is capable of inducing apoptosis in HepG2 cells through modulation of the mitochondrial pathway, which explains their antitumor activity.

Topical administration of Juglans regia L. leaf extract accelerates diabetic wound healing.

BACKGROUND: Diabetic wounds are one of the most important issues in diabetic patients. It seems that Juglans regia L. leaf with antioxidant and anti-inflammatory potentials can be profitable for healing of diabetic wounds. The aim of present study was to investigate the topical administration of Juglans regia L. leaf extract in diabetic wound healing. METHODS: Seventy-five diabetic male rats were randomly divided into 5 groups (n = 15), including: untreated (Control) group, Eucerin group, 2% Juglans regia L. ointment (JRL 2%) group, 5% Juglans regia L. ointment (JRL 5%) group, and Phenytoin group as a reference drug. Sampling was performed at days 7, 14, and 21 after surgery. Evaluation tests included stereology, immunohistochemistry, molecular, and biomechanical. RESULTS: Our results showed that the wound closure rate, volumes of newly formed of epidermis and dermis, density of fibroblasts and blood vessels, collagen deposition, density of proliferation cells, expression levels of TGF-ß and VEGF genes, and biomechanical characteristics were significantly higher in extract groups compared to control and eucerin groups, however, these changes were considerable in the JRL 5% group (P < 0.05). This is while that the density of neutrophils and expression levels of TNF-α and IL-1ß genes in the extract groups, especially in the JRL 5% group, were significantly reduced compared to control and eucerin groups (P < 0.05). CONCLUSION: Topical administration of Juglans regia L. leaf extract, especially in 5% concentration, considerably accelerates diabetic wound healing.

The effects of Feijoa sellowiana fruit extract on wound healing in rats: a stereological and molecular study.

OBJECTIVE: The aim of this study was to evaluate the anti-inflammatory and wound-healing potential of Feijoa sellowiana fruit extract using stereological and molecular methods in experimental rat models. MATERIALS: Male Wistar rats were divided into four equal groups: non-treated, vehicle, Feijoa sellowiana fruit extract ointment (5% weight/weight) and the reference drug (madecassol). All animals were treated topically once per day. At the end of the study, wound samples were harvested for histological, stereological, immunohistochemical and molecular assessments to determine the in vivo healing potential and anti-inflammatory activity. A high-performance liquid chromatography (HPLC) analysis was performed for the characterisation of the phenolic acids in the extract. RESULTS: The study included 64 rats in total. Our results showed that the wound closure, volume of new epidermis and dermis, density of fibroblasts and blood vessels, and the deposition of collagen were significantly higher in both extract and madecassol groups compared to the non-treated and vehicle groups, with superior healing in the extract group. The transcript for the transforming growth factor (TGF)-ß gene was significantly upregulated in both extract and madecassol groups compared to non-treated and vehicle groups and was highest for the extract group. The density of inflammatory cells and expression levels of the cyclooxygenase (COX)-2 protein and tumour necrosis factor (TNF)-α gene in the extract and madecassol groups, especially in the extract group, were significantly reduced compared to non-treated and vehicle groups. CONCLUSION: Our results confirm that the Feijoa sellowiana fruit extract is a valuable source of antioxidant and anti-inflammatory activities and can allow for damaged tissue in wounds to recover markedly.

Naked Eye Chemosensor and In Vivo Chelating Activity of Iron (III) By Bromopyridine Quinoxaline (BPQ).

A wide variety of medical, biomedical, and industrial applications has been reported for quinoxalines derivatives. In this work, a novel quinoxaline derivative was designed and synthesized. Naked-eye and quantitative detection of Fe3+ among several cations were evaluated using UV-Vis spectroscopy. New chemosensor, 2,3-bis(6-bromopyridine-2-yl)-6-chloroquinoxaline named BPQ, showed a selective interaction for iron ion over other tested cations by changing color. Iron overloaded mice were prepared as a thalassemia model and then the effects of iron-chelating activities of BPQ were experienced. The job's plot methods determined the stoichiometric ratio of ligand to Fe3+ (1:1). The iron content in serum was evaluated by atomic absorption spectroscopy (AAS). Results showed significant differences (two-fold decrease in total iron and Fe3+) between the iron overloaded and BPQ (dose of 20 mgkg-1). The BPQ was identified as a ligand, which can be applied as a new chelator for decreasing the excess iron of blood.

Vascular Endothelial Growth Factor Receptors [VEGFR] as Target in Breast Cancer Treatment: Current Status in Preclinical and Clinical Studies and Future Directions.

Breast cancer [BC] is one of the most common cancers among women, one of the leading causes of a considerable number of cancer-related death globally. Among all procedures leading to the formation of breast tumors, angiogenesis has an important role in cancer progression and outcomes. Therefore, various anti-angiogenic strategies have been developed so far to enhance treatment's efficacy in different types of BC. Vascular endothelial growth factors [VEGFs] and their receptors are regarded as the most well-known regulators of neovascularization. VEGF binding to vascular endothelial growth factor receptors [VEGFRs] provides cell proliferation and vascular tissue formation by the subsequent tyrosine kinase pathway. VEGF/VEGFR axis displays an attractive target for anti-angiogenesis and anti-cancer drug design. This review aims to describe the existing literature regarding VEGFR inhibitors, focusing on BC treatment reported in the last two decades.

Evaluation of Alterations in DNA Methylation of CYP3A4 Gene Upstream Regulatory Elements in Gastric Cancer and in Response to Diazinon Treatment.

BACKGROUND: Little is known about cytochrome P450 3A4 (CYP3A4) DNA methylation and transcription alterations in gastric cancer. OBJECTIVE: In this paper, we initially aimed to address the effect of diazinon pesticide on DNA methylation and transcription changes of the CYP3A4 gene in a human gastric cell line. In the next step, we studied the methylation differences of CpG sites within the upstream regulatory regions of the CYP3A4 gene among human gastric cancerous and healthy tissues. METHODS: For the in vitro assay, the methylation changes of the C/EBP response element and transcript level of the CYP3A4 gene were studied following treatment of the AGS cell line with various concentrations of diazinon pesticide. In the next phase, the methylation percentages of 24 CpG sites within or around the upstream regulatory elements, including near promoter, C/EBP binding site, XREM, and CLEM4, in 11 specimens of human gastric cancer tissue were compared to their adjacent healthy tissues. RESULTS: Treatment with 10 µM Diazinon significantly increased the CYP3A4 gene transcription by approximately 27-fold, which was correlated with the hypermethylation of 3 CpGs in C/EBP binding sites, including -5998, -5731 and -5725 (p<0.001 for all comparisons). Results of bisulfite sequencing revealed that the CpG sites which are located in -1521 (p=0.003), -1569 (p=0.027), -10813 (p=0.003), -10851 (p=0.001) and -10895 (p=0.0) bp from transcription start site, were significantly hypermethylated in cancerous tissues comparing to their healthy cohort. CONCLUSION: Hypermethylation of CLEM4 and a region near the core promoter may have a significant association with gastric cancer incidence.

CYP1A1 contiguous hypermethylation within a putative CpG block is associated with breast cancer progression: Feasibility to define boundary motives.

Having broad specificity for xenobiotics metabolism throughout the body, cytochrome P450 (CYP) isoform 1A1 is of key relevance for carcinogenesis. However, the oncogenic potential of its altered transcription and the underlying mechanism has not been well-established in breast cancer. Direct bisulfite sequencing PCR (BSP) of the CYP1A1 promoter, enriched by 113 CpGs within and flanking the xenobiotic response elements (XREs) 2 to 10, in paired cancerous and normal tissues from 40 breast cancer patients revealed three distinctly methylated patterns; unmethylated (XREs 2 to 6) and completely methylated (XREs 7 and 8) CpGs, in common for the normal and cancerous tissues, and a putative 171bp CpG block (XREs 9 and 10) contiguously hypermethylated in the tumor tissues. Increased transcription of CYP1A1, observed for the cancerous tissues, was correlated with the hypermethylation of given CpG block, besides simultaneously being associated with upregulation of the anti-apoptotic BCL-2. Clinical value of the methylation changes, investigated based on the comparisons between the tissue cohorts of different clinicopathological features, exhibited gradual hypermethylation of the corresponding CpG block following disease progression as well as lymphatic involvement. Hypermethylation of given CpG block may has potential to be used as a biomarker for diagnosis and progression of breast cancer.

O-Glycoside quercetin derivatives: Biological activities, mechanisms of action, and structure-activity relationship for drug design, a review.

Quercetin as a valuable natural flavonoid has shown extensive biological activities, including anticancer, antioxidant, antibacterial, antiinflammatory, anti-Alzheimer, antifungal, antiviral, antithalassemia, iron chelation, antiobesity, antidiabetic, antihypertension, and antiphospholipase A2 (PLA2) activities, by the modulation of various targets and signaling pathways that have attracted much attention. However, the low solubility and poor bioavailability of quercetin have limited its applications; therefore, the researchers have tried to design and synthesize many new derivatives of quercetin through different strategies to modify quercetin restrictions and improve its biological activities. This review categorized the O-glycoside derivatives of Quercetin into two main classes, 3-O-glycoside and other O-glycoside derivatives. Also, it studied biological activities, structure-activity relationship (SAR), and the action mechanism of O-glycoside quercetin derivatives. Overall, we summarized past and present research for discovering new potent lead compounds. HIGHLIGHTS: Quercetin is a natural flavonoid with a valuable scaffold. O-Glycoside quercetin derivatives represents broad-spectrum biological activities. The structure-activity relationship investigation is discussed after modifying the scaffold of quercetin. This review can help researchers to rationally design/develop various drugs.

Quercetin derivatives: Drug design, development, and biological activities, a review.

More studies are needed to develop new drugs for problems associated with drug resistance and unfavorable side effects. The natural flavonoid of quercetin revealed a wide range of biological activities by the modulation of various targets and signaling pathways. However, quercetin's low solubility and poor bioavailability have restricted its applicability; as a result, researchers have attempted to design and synthesize numerous novel quercetin derivatives using various methodologies in order to modify quercetin's constraints; the physico-chemical properties of quercetin's molecular scaffold make it appealing for drug development; low molecular mass and chemical groups are two of these characteristics. Therefore, the biological activities of quercetin derivatives, as well as the relationship between activity and chemical structure and their mechanism of action, were investigated. These quercetin-based molecules could be valuable in the creation and discovery of medications for a number of diseases.

Anti-inflammatory and anti-nociceptive activities of polyphenols from Feijoa fruit and leaves.

Many pharmacological activities have been reported from plants polyphenols. The aim of this study was to investigate anti inflammatory and antinociceptive activities of polyphenols from Feijoa sellowiana fruit and leaves. For the anti-inflammatory activity evaluation, inhibition of carrageenan induced edema was used. While for the evaluation of antinociceptive activity of the extract, writhing and hot plate tests in mice were used. Impairment in mouse coordination was evaluated by rota-rode test. Carrageenan induced edema was significantly inhibited by the extract at 50-400 mg kg-1 doses, when comparison was made with control group. The extract of leaf at the dose of 50 mg kg-1 i.p. the activity was equipotent with diclofenac (p>0.05). Extract reduced the writhing count in 50-400 mg kg-1 of doses. Fruit extract showed higher activity than diclofenac (p<0.001) at 400 mg kg-1 doses. In all tested doses, the extract significantly augmented the pain threshold in hot plate thermal test. No locomotor impairment in mice was induced by the extract at any tested doses. Extract was safe and didnot demonstrate any noxiousness up to 1 g kg-1 .This study indicates the potential therapeutic use of Feijoa as a potent anti-inflammatory and antinociceptive agent.

Protective effects of rutin and chlorogenic acid against antihypoxic conditions in mice.

Almost all plants contain polyphenols. Literature shows that polyphenols exhibit many biological activities. Little has known about their protective effects against hypoxia-induced lethality. The protective effects of rutin (1) and chlorogenic acid (2) against hypoxia conditions in mice were determined by three different experimental models. Antihypoxic activity was especially pronounced in asphytic hypoxia. Both compounds (1&2) showed statistically significant (p>0.05) activities respect to the control. Compound (1) significantly prolonged the latency for death with respect to control (39.20±8.70 vs. 13.20±2.58min, p<0.001). Compound (1) was the most effective compound in circulatory hypoxia. It significantly prolonged the latency for death with respect to control (14.44±2.82 vs. 9.82±0.79 min, p<0.01). On the other hand, Chlorogenic acid (2) at a dose of 100 mg kg-1 kept mice alive for 12.76±1.30min (p>0.05). None of two phenolic acids had any activity in haemic hypoxia when compared to control.

The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma.

Adaptation to the loss of O2 is regulated via the activity of hypoxia-inducible factors such as Hypoxia-Inducible Factor-1 (HIF-1). HIF-1 acts as a main transcriptional mediator in the tissue hypoxia response that regulates over 1000 genes related to low oxygen tension. The role of HIF-1α in oncogenic processes includes angiogenesis, tumor metabolism, cell proliferation, and metastasis, which has been examined in various malignancies, such as melanoma. Melanoma is accompanied by a high death rate and a cancer type whose incidence has risen over the last decades. The linkage between O2 loss and melanogenesis had extensively studied over decades. Recent studies revealed that HIF-1α contributes to melanoma progression via different signaling pathways such as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, JAK/STAT, Wnt/ß-catenin, Notch, and NF-κB. Also, various microRNAs (miRs) are known to mediate the HIF-1α role in melanoma. Therefore, HIF-1α offers a diagnostic/prognostic biomarker and a candidate for targeted therapy in melanoma.

Pyrazolotriazines: Biological activities, synthetic strategies and recent developments.

Heterocyclic compounds create an important class of molecules that demonstrates various chemical spaces for the definition of effective medicines. Many N-heterocycles display numerous biological activities. Among condensed heterocycles, pyrazolotriazine derivatives have received the attention of researchers owing to the extensive spectrum of biological activities. The reactivity of identified compounds was similar to the free azoles and triazines. The pyrazolotriazine scaffold exhibited antiasthma, antiinflammatory, anticancer, antithrombogenic activity and showed activity for major depression and pathological anxiety. Pyrazolotriazine derivatives also exhibited antibacterial, anticancer, antimetabolites, antidiabetic, antiamoebic, anticonvulsant, antiproliferative activity, human carbonic anhydrase inhibition, cyclin-dependent kinase 2 inhibition, tyrosinase and urease inhibition, MAO-B inhibition, TTK inhibition, thymidine phosphorylase inhibition, tubulin polymerization inhibition, protoporphyrinogen oxidase inhibition, GABAA agonistic activity, hCRF1 receptor antagonistic activity, and CGRP receptor antagonistic activity. This paper structurally categorized various pyrazolotriazines to isomeric classes into six groups that containing pyrazolo [1,5-d] [1,2,4] triazine, pyrazolo [5,1-c] [1,2,4] triazine, pyrazolo [3,4-e] [1,2,4] triazine, pyrazolo [4,3-e] [1,2,4] triazines, pyrazolo [1,5-a] [1,3,5] triazine, and pyrazolo [3,4-d] [1,2,3] triazine and expressed biological activity, the synthetic procedures for each class of pyrazolotriazines, structure-activity relationship and their mechanism of action. Generally, this review summarily indicated the past and present studies about the discovery of new lead compounds with good biological activity.

Antiviral Activities of Pyridine Fused and Pyridine Containing Heterocycles, A Review (from 2000 to 2020).

Heterocyclic compounds play a critical role in medicinal chemistry, and many available drugs contain heterocyclic rings. A six-membered heterocyclic compound, pyridine, showed various applications, including being an important solvent, reagent, and precursor in agrochemicals and pharmaceuticals. Due to the increase in drug resistance, there is an apparent medical need to develop new antiviral agents. Various derivatives of pyridine scaffold display broad biological activities such as anti-microbial, antiviral, antioxidant, anti-diabetic, anti-cancer, anti-malarial, analgesic, and antiinflammatory activities. Furthermore, they display psychopharmacological, antagonistic, anti-amoebic agents, and anti-thrombic activities. Due to the high importance of pyridine derivatives, in the present review, we tried to collect and classify many pyridine derivatives based on their structures from 2000 to 2020. Pyridine derivatives were classified into two general categories, including pyridine containing heterocycles and pyridine fused rings. The structure-activity relationship (SAR) and the action mechanism of derivatives were also investigated. According to the recent studies, these derivatives exhibited good antiviral activity against different types of viruses such as the human immunodeficiency viruses (HIV), the hepatitis C virus (HCV), the hepatitis B virus (HBV), respiratory syncytial virus (RSV), and cytomegalovirus (CMV). These derivatives inhibited viral application with different action mechanism such as RT inhibition, polymerase inhibition, inhibition of RNase H activity, inhibition of maturation, inhibition of the viral thymidine kinase, AAK1 (Adaptor-Associated Kinase 1) inhibition, GAK (Cyclin G-associated kinase) inhibition, inhibition of post-integrational event, inhibition of HDAC6, CCR5 antagonistic activity, DNA and RNA replication inhibition, gene expression inhibition, cellular NF-jB signaling pathway and neuraminidase (NA) inhibition, protein synthesis inhibition, and generally inhibition of viral replication cycle. This paper summarized the past and present results about the discovery of novel lead compounds with good antiviral activity. Studies exhibited that almost all of the evaluations were performed by way of in vitro testing. It is necessary to investigate in vivo and clinical testing for better evaluations in the future. We believe that pyridine derivatives can be used as promising antiviral agents and more broad investigations in this field need to be performed.

Protective effect of Feijoa sellowianan fruit on testicular toxicity-induced by cadmium chloride.

The purpose of the present study was to investigate the protective potential of Feijoa fruit extract on cadmium chloride (CdCl2 )-induced testicular injury and pituitary-gonadal axis. Adult male Wistar rats were randomly divided into four groups: (a) control (normal saline, orally), (b) cadmium chloride (0.1 mg/kg, single dose, intraperitoneally), (c) Feijoa fruit extract (400 mg/kg, orally for 30 consecutive days) and (d) CdCl2  + Feijoa fruit extract. One day after receiving the last medicine, the LH, FSH, prolactin and testosterone concentration were assayed. Also, sperm parameters and tissue structure of the testis were evaluated. Administration of Feijoa fruit extract after CdCl2 injection in rats ameliorated sperm parameters such as sperm count, morphology, motility and sperm viability, increased levels of LH, FSH, prolactin and testosterone and improved testicular histology. According to the results of this study, it was shown that Feijoa can reduce the destructive side effects of CdCl2 on testicular tissue and sex hormones of the pituitary-gonadal pathway.

Dexamethasone vs COVID-19: An experimental study in line with the preliminary findings of a large trial.

BACKGROUND: The preliminary report of the RECOVERY large randomised controlled trial indicated a promising survival effect for dexamethasone therapy of coronavirus disease 2019 (COVID-19). This study aimed to investigate the anti-hypoxic activities of dexamethasone to understand a possible mechanism of its action in hypoxia-induced lethality through experimental models of hypoxia. METHODS: In this investigation, 84 Male BALB/c mice were randomly divided into groups of seven (12 groups). Treatment groups received 10 days of dexamethasone intraperitoneal injection at both human dose (~0.1 mg/kg) and the animal does (~1 mg/kg). Control negative and positive groups were treated with 10 ml/kg of normal saline and 30 mg/kg of propranolol, respectively. Three experimental models of hypoxia, asphyctic, circulatory, and hemic were applied in this study. RESULTS: The findings showed that dexamethasone significantly prolonged the latency for death in the asphyctic model concerning the control group in both humans (P < .0001) and animal dose (P < .0001). The results were also highly significant for both doses in the hemic model (P < .001). In the circulatory model, although a small increase was observed in death prolongation, results were not statistically significant for both doses in this model (P > .05). CONCLUSIONS: This experimental in vivo investigation demonstrated an excellent protective effect for 10 days of dexamethasone treatment against hypoxia, especially in asphyctic and hemic models. In addition to promising dexamethasone outcomes, using propranolol as the positive control illustrated a very substantial anti-hypoxic effect even much better than dexamethasone in all models. It seems that propranolol would be a safe, potential, and prudent choice to invest in treating COVID-19 patients.

Magnesium Sulfate Attenuates Lethality and Oxidative Damage Induced by Different Models of Hypoxia in Mice.

Mg2+ is an important cation in our body. It is an essential cofactor for many enzymes. Despite many works, nothing is known about the protective effects of MgSO4 against hypoxia-induced lethality and oxidative damage in brain mitochondria. In this study, antihypoxic and antioxidative activities of MgSO4 were evaluated by three experimental models of induced hypoxia (asphyctic, haemic, and circulatory) in mice. Mitochondria protective effects of MgSO4 were evaluated in mouse brain after induction of different models of hypoxia. Antihypoxic activity was especially pronounced in asphyctic hypoxia, where MgSO4 at dose 600 mg/kg showed the same activity as phenytoin, which used as a positive control (P < 0.001). In the haemic model, MgSO4 at all used doses significantly prolonged latency of death. In circulatory hypoxia, MgSO4 (600 mg/kg) doubles the survival time. MgSO4 significantly decreased lipid peroxidation and protein carbonyl and improved mitochondrial function and glutathione content in brain mitochondria compared to the control groups. The results obtained in this study showed that MgSO4 administration has protective effects against lethality induced by different models of hypoxia and improves brain mitochondria oxidative damage.