Neuroprotective effect of polysaccharide separated from Perilla frutescens Britton var. acuta Kudo against H2O2-induced oxidative stress in HT22 hippocampus cells.

This study was carried out to evaluate the neuroprotective activity of polysaccharide extracts isolated from Perilla frutescens (PEPF) in H2O2-treated HT22 hippocampus cells. The PEPF treatment was found to increase the anti-oxidant activities of HT22 hippocampus cells. PEPF treatment resulted in a significant protection of HT22 hippocampus cells against H2O2-induced neurotoxicity, this protection ultimately occurred through an inhibition of ROS-mediated intracellular Ca2+ levels leading to MAPKs and NF-κB, as well as the accumulation of PI3K/AKT and Nrf2-mediated HO-1/NQO1 pathways. Furthermore, PEPF not only decreased the expression of Bax, cytochrome c, and cleaved caspases-3, -8, and -9, but also increased the expression of PARP and Bcl-2 in the H2O2-treated HT22 hippocampus cells, which overall contributed to the neuroprotective action. PEPF retains its mitochondrial membrane potential and reduces the elevated levels of sub-G1 phase and apoptotic morphological features induced by H2O2. It also reduces the malondialdehyde levels and enhances the intracellular SOD activity.

Sphingosine-1-phosphate receptors 2 and 3 reprogram resting human macrophages into M1 phenotype following mycobacteria infection.

Mycobacteria tuberculosis (M.tb) the causative agent for tuberculosis has been accredited for a high rate of morbidity and mortality worldwide. The rise in MDR and XDR cases has further created new obstacles in achieving the "End TB Strategy", which is aimed for 2035. In this article, we have demonstrated the potential of sphingosine-1-phosphate (S1P) analogs in providing an anti-mycobacterial effector response by altering macrophage polarity into M1. Among S1PR1 and S1PR3 analogs, S1PR2 analogs proficiently favor selective polarization of infected human macrophages into M1 phenotypes, marked by increased expression of M1 markers and decreased M2 markers. Furthermore, S1PR1-3 analogs treated macrophages were also able to decrease the secretion of anti-inflammatory cytokine IL-10 and can induce NO secretion in infected macrophages. Lastly, only S1PR2-3 analogs were able to restrict the growth of mycobacteria in human macrophages. Taken together our study reflects the potential of S1PR2-3 analogs in providing host defenses following mycobacterial infection by favoring M1 macrophage polarization.

BMP antagonists in tissue development and disease.

Bone morphogenic proteins (BMPs) are important growth regulators in embryogenesis and postnatal homeostasis. Their tight regulation is crucial for successful embryonic development as well as tissue homeostasis in the adult organism. BMP inhibition by natural extracellular biologic antagonists represents the most intensively studied mechanistic concept of BMP growth factor regulation. It was shown to be critical for numerous developmental programs, including germ layer specification and spatiotemporal gradients required for the establishment of the dorsal-ventral axis and organ formation. The importance of BMP antagonists for extracellular matrix homeostasis is illustrated by the numerous human connective tissue disorders caused by their mutational inactivation. Here, we will focus on the known functional interactions targeting BMP antagonists to the ECM and discuss how these interactions influence BMP antagonist activity. Moreover, we will provide an overview about the current concepts and investigated molecular mechanisms modulating BMP inhibitor function in the context of development and disease.

The potential of glycyrrhizin and licorice extract in combating COVID-19 and associated conditions.

Background: Several recent studies have stated that glycyrrhizin and licorice extract are present in most traditional Chinese medicine formulas used against SARS-CoV-2 in China. Significant data are showing that glycyrrhizin and licorice extract have multiple beneficial activities in combating most features of SARS-CoV-2. Purpose: The aim of current review was to highlight recent progresses in research that showed the evidence of the potential use of glycyrrhizin and licorice extract against COVID-19. Methodology: We have reviewed the information published from 1979 to October 2020. These studies demonstrated the effects , use and safety of glycyrrhizin and icorice extract against viral infections,bacterial infections, inflammatory disorders of lung ( in vitro and in vivo).  These studies were collated through online electronic databases research (Academic libraries as PubMed, Scopus, Web of Science and Egyptian Knowledge Bank). Results: Pooled effect size of articles provides information about the rationale for using glycyrrhizin and licorice extract to treat COVID-19. Fifty studies demonstrate antiviral activity of glycyrrhizin and licorice extract. The most frequent mechanism of the antiviral activity is due to disrupting viral uptake into the host cells and disrupting the interaction between receptor- binding domain (RBD) of SARS-COV2 and ACE2 in recent articles. Fifty studies indicate that glycyrrhizin and licorice extract have significant antioxidant, anti-inflammatory and immunomodulatory effects. Twenty five studies provide evidence for the protective effect of glycyrrhizin and licorice extract against inflammation-induced acute lung injury and cardiovascular disorders. Conclusion: The current study showed several evidence regarding the beneficial effects of glycyrrhizin and licorice extract in combating COVID-19. More randomized clinical trials are needed to obtain a precise conclusion.

Naringin prevents cyclophosphamide-induced erythrocytotoxicity in rats by abrogating oxidative stress.

Earlier reports have shown that Cyclophosphamide (CYCP), an anti-malignant drug, elicited cytotoxicity; and that naringin has several beneficial potentials against oxidative stress and dyslipidaemias. We investigated the influence of naringin on free radical scavenging, cellular integrity, cellular ATP, antioxidants, oxidative stress, and lipid profiles in the CYCP-induced erythrocytotoxicity rat model. Rats were pretreated orally by gavage for fourteen consecutive days with three doses (50, 100, and 200 mg/kg) naringin before single CYCP (200 mg/kg, i.p.) administration. Afterwards, the rats were sacrificed. Naringin concentrations required for 50 % scavenging hydrogen peroxide and nitric oxide radical were 0.27 mg/mL and 0.28 mg/mL, respectively. Naringin pretreatment significantly (p < 0.05) protected erythrocytes plasma membrane architecture and integrity by abolishing CYCP-induced decrease in the activity of erythrocyte LDH (a marker of ATP). Pretreatment with naringin remarkably (p < 0.05) reversed CYCP-induced decreases in the erythrocytes glutathione levels, activities of glutathione-S-transferase, catalase, glutathione peroxidase, and glutathione reductase; attenuated CYCP-mediated increases in erythrocytes levels of malondialdehyde, nitric oxide, and major lipids (cholesterol, triacylglycerol, phospholipids, and non-esterified fatty acids). Taken together, different acute pretreatment doses of naringin might avert CYCP-mediated erythrocytes dysfunctions via its antioxidant, free-radical scavenging, and anti-dyslipidaemia properties.

Activation of Nrf2/HO-1 signaling: An important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress.

Introduction: Recently, Nrf2/HO-1 has received extensive attention as the main regulatory pathway of intracellular defense against oxidative stress and is considered an ideal target for alleviating endothelial cell (EC) injury. Objectives: This paper aimed to summarized the natural monomers/extracts that potentially exert protective effects against oxidative stress in ECs. Methods: A literature search was carried out regarding our topic with the keywords of "atherosclerosis" or "Nrf2/HO-1" or "vascular endothelial cells" or "oxidative stress" or "Herbal medicine" or "natural products" or "natural extracts" or "natural compounds" or "traditional Chinese medicines" based on classic books of herbal medicine and scientific databases including Pubmed, SciFinder, Scopus, the Web of Science, GoogleScholar, BaiduScholar, and others. Then, we analyzed the possible molecular mechanisms for different types of natural compounds in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. In addition, perspectives for possible future studies are discussed. Results: These agents with protective effects against oxidative stress in ECs mainly include phenylpropanoids, flavonoids, terpenoids, and alkaloids. Most of these agents alleviate cell apoptosis in ECs due to oxidative stress, and the mechanisms are related to Nrf2/HO-1 signaling activation. However, despite continued progress in research on various aspects of natural agents exerting protective effects against EC injury by activating Nrf2/HO-1 signaling, the development of new drugs for the treatment of atherosclerosis (AS) and other CVDs based on these agents will require more detailed preclinical and clinical studies. Conclusion: Our present paper provides updated information of natural agents with protective activities on ECs against oxidative stress by activating Nrf2/HO-1. We hope this review will provide some directions for the further development of novel candidate drugs from natural agents for the treatment of AS and other CVDs.

Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression.

Secalonic acid D (SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant (MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1, H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest via the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis via c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mRNA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mRNA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2 (ABCG2)-mediated MDR cells.

Kobophenol A Isolated from Roots of Caragana sinica (Buc'hoz) Rehder Exhibits Anti-inflammatory Activity by Regulating NF-κB Nuclear Translocation in J774A.1 Cells.

Kobophenol A (KPA) is a biologically active natural compound isolated from the roots of Caragana sinica (Buc'hoz) Rehder (C. sinica). However, the anti-inflammatory effects of KPA have not been reported. This study aims to find out whether KPA isolated from roots of C. sinica can act as a potential substance on inflammation and analyze the molecular mechanism using the lipopolysaccharide (LPS)-stimulated J774 A.1 macrophage cell line. We showed that KPA treatment significantly suppressed the production of nitric oxide (NO) by inhibiting inducible nitric oxide synthase (iNOS) expression in a dose-dependent manner without cytotoxicity. In the KPA also inhibited pro-inflammatory cytokine gene expression and production, such as interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in LPS-stimulated J774 A.1 cells. As continuing study on the mechanisms involved, we confirmed that these effects of KPA were related to the inhibition of nuclear factor-κB (NF-κB) pathway including the suppression of IκB kinase α/ß (IKKα/ß) phosphorylation and translocation of NF-κB into the nucleus. Taken together, the present study is the first to demonstrate that KPA isolated from C. sinica suppresses the expression of inflammatory mediators and cytokines by inhibiting NF-κB nuclear translocation in LPS-stimulated J774 A.1 macrophages. KPA may be a potential candidate for the treatment of inflammatory diseases in the future.

Hyperammonemia in Hepatic Encephalopathy.

The precise mechanism underlying the neurotoxicity of Hepatic Encephalopathy (HE) is remains unclear. The dominant view has been that gut-derived nitrogenous toxins are not extracted by the diseased liver and thereby enter the brain. Among the various toxins proposed, the case for ammonia is most compelling. Events that lead to increased levels of blood or brain ammonia have been shown to worsen HE, whereas reducing blood ammonia levels alleviates HE. Clinical, pathological, and biochemical changes observed in HE can be reproduced by increasing blood or brain ammonia levels in experimental animals, while exposure of cultured astrocytes to ammonium salts reproduces the morphological and biochemical findings observed in HE. However, factors other than ammonia have recently been proposed to be involved in the development of HE, including cytokines and other blood and brain immune factors. Moreover, recent studies have questioned the critical role of ammonia in the pathogenesis of HE since blood ammonia levels do not always correlate with the level/severity of encephalopathy. This review summarizes the vital role of ammonia in the pathogenesis of HE in humans, as well as in experimental models of acute and chronic liver failure. It further emphasizes recent advances in the molecular mechanisms involved in the progression of neurological complications that occur in acute and chronic liver failure.

Fas Receptor Activation by Endogenous Opioids Is A New Mechanism for Cardiomyopathy in Cirrhotic Rats.

BACKGROUND: Cirrhosis, a common consequence of chronic liver inflammation is associated with various cardiovascular dysfunctions which are called cirrhotic cardiomyopathy (CC). Among the various possible causes of CC, apoptosis is considered to have a pivotal role. OBJECTIVES: To explore the contribution of endogenous opioids in the apoptosis process in a rat model of CC. MATERIAL AND METHODS: Four genes were selected to cover both intrinsic and extrinsic pathways of apoptosis. Cardiac samples from 4 groups of rats were evaluated. Two groups were cirrhotic through bile duct ligation (BDL) receiving either naltrexone (BDL-naltrexone) or saline (BDL-saline), two others were normal rats as sham groups receiving either naltrexone (sham-naltrexone) or saline (sham-saline). Expression level of BCL2, Caspase3, Fas and FasL was explored in all groups using reverse transcriptase real-time PCR. RESULTS: BDL-saline group showed significant over-expression of BCL2, caspase3 and Fas. BCL2 expression was 1.44 (P < 0.001) and caspasse3 was 1.35 (P < 0.001) times higher than sham-saline group, Fas was also overexpressed 1.3 (P < 0.001) times higher than BDL-naltrexone group and 1.91 (P < 0.001) compared to sham-naltrexone group. Caspase3 expression was 1.35 (P < 0.001) folds higher than sham-naltrexone group. The expression pattern of FasL revealed no statistically significant change among study groups. CONCLUSION: Fas molecule enrollment during CC is a novel finding. Fas molecule is activated during cirrhosis through elevated levels of endogenous opioids. This pathway is one of the leading causes of CC. Our findings also demonstrated the protective role of naltrexone as opioids antagonist on cardiomyocytes in a rat model of CC.

Comparative study of the efficacy of pulsed electromagnetic field and low level laser therapy on mitogen-activated protein kinases.

Mitogen-Activated Protein Kinases (MAPKs) consist of three major signaling members: extracellular signal-regulated kinase (ERK), p38 and C-JUN N-terminal kinase (JNK). We investigated physiological effects of Pulsed Electromagnetic Field Therapy (PEMFT) and Low Level Laser Therapy (LLLT) on human body, adopting the expression level of mitogen-activated protein kinases as an indicator via assessment of the activation levels of three major families of MAPKS, ERK, p38 and JNK in the peripheral lymphocytes of patients before and after the therapies. Assessment for the expression levels of MAPKs families' were done, in the peripheral lymphocytes of patients recently have appendectomy, using flow cytometric analysis of multiple signaling pathways, pre and post LLLT and PEMFT application (twice daily for 6 successive days) on the appendectomy wound. There were non-significant differences in the expression levels of MAPKs families' pre- therapies application. But there were significant increase in the ERK expression levels post application of LLLT compared to its pre application (p<0.01). Also, there was significant increase in the ERK, p38 and C-Jun N terminal expression level values post application of PEMFT compared to its pre application expression levels (p<0.01 for each). The present study demonstrates that PEMFT has a powerful healing effect more than LLLT as it increase the activation of ERK, P38 and C-Jun-N Terminal while LLLT only increase the activation of ERK. LLLT has more potent pain decreasing effect than PEMFT as it does not activate P38 pathway like PEMFT.